Agathe Roubertie

In seven selected patients with dystonia musculorum deformans-1 generalised dystonia (DYT1), continuous bilateral stimulation of the globus pallidus internus was associated with substantial improvement of dystonia and functional disability.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials.In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins.74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity.AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials.European Union's Seventh Framework Programme; European Research Council.

Mutations in the TUBB3 gene, encoding β-tubulin isotype III, were recently shown to be associated with various neurological syndromes which all have in common the ocular motility disorder, congenital fibrosis of the extraocular muscle type 3 (CFEOM3). Surprisingly and in contrast to previously described TUBA1A and TUBB2B phenotypes, no evidence of dysfunctional neuronal migration and cortical organization was reported. In our study, we report the discovery of six novel missense mutations in the TUBB3 gene, including one fetal case and one homozygous variation, in nine patients that all share cortical disorganization, axonal abnormalities associated with pontocerebellar hypoplasia, but with no ocular motility defects, CFEOM3. These new findings demonstrate that the spectrum of TUBB3-related phenotype is broader than previously described and includes malformations of cortical development (MCD) associated with neuronal migration and differentiation defects, axonal guidance and tract organization impairment. Complementary functional studies revealed that the mutated βIII-tubulin causing the MCD phenotype results in a reduction of heterodimer formation, yet produce correctly formed microtubules (MTs) in mammalian cells. Further to this, we investigated the properties of the MT network in patients' fibroblasts and revealed that MCD mutations can alter the resistance of MTs to depolymerization. Interestingly, this finding contrasts with the increased MT stability observed in the case of CFEOM3-related mutations. These results led us to hypothesize that either MT dynamics or their interactions with various MT-interacting proteins could be differently affected by TUBB3 variations, thus resulting in distinct alteration of downstream processes and therefore explaining the phenotypic diversity of the TUBB3-related spectrum.

Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy. Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy. Early-onset epileptic encephalopathy (EOEE) is a highly heterogeneous group of severe epileptic disorders characterized by pharmacoresistant seizures and abnormal interictal electroencephalogram (EEG) that leads to neurological impairment, developmental delay, and high mortality rate.1Dulac O. Epileptic encephalopathy.Epilepsia. 2001; 42: 23-26Crossref PubMed Google Scholar, 2Berg A.T. Berkovic S.F. Brodie M.J. Buchhalter J. Cross J.H. van Emde Boas W. Engel J. French J. Glauser T.A. Mathern G.W. et al.Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009.Epilepsia. 2010; 51: 676-685Crossref PubMed Scopus (3259) Google Scholar, 3Covanis A. Epileptic encephalopathies (including severe epilepsy syndromes).Epilepsia. 2012; 53: 114-126Crossref PubMed Scopus (35) Google Scholar Given the extreme etiological heterogeneity of EOEE, clinical, electro-clinical, and genetic classification are of considerable importance for therapeutic management of affected individuals, prognosis, and genetic counseling.4Berg A.T. Nickels K. Wirrell E.C. Geerts A.T. Callenbach P.M.C. Arts W.F. Rios C. Camfield P.R. Camfield C.S. Mortality risks in new-onset childhood epilepsy.Pediatrics. 2013; 132: 124-131Crossref PubMed Scopus (94) Google Scholar Among EOEE, a number of electro-clinical neonatal-onset epileptic syndromes have been described, such as Ohtahara syndrome (MIM 308350), early myoclonic epilepsy (MIM 607208), and malignant migrating partial seizures (MIM 614959). Many forms of EOEE nonetheless remain difficult to delineate based on clinical and EEG findings only, and conventional metabolic and genetic screening remain tedious and low yield. This is particularly true for individuals with EOEE and onset of seizures in the first day of life with no evidence of neonatal suffering or environmental causes, because mutations in EOEE-associated genes have been only rarely found in such individuals. Although systematic screening of candidate genes has been shown to increase diagnostic yield, careful clinical and EEG description of epileptic syndromes is needed for improved management of affected individuals.5Helbig I. Lowenstein D.H. Genetics of the epilepsies: where are we and where are we going?.Curr. Opin. Neurol. 2013; 26: 179-185Crossref PubMed Scopus (67) Google Scholar, 6Carvill G.L. Heavin S.B. Yendle S.C. McMahon J.M. O’Roak B.J. Cook J. Khan A. Dorschner M.O. Weaver M. Calvert S. et al.Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.Nat. Genet. 2013; 45: 825-830Crossref PubMed Scopus (473) Google Scholar, 7Allen A.S. Berkovic S.F. Cossette P. Delanty N. Dlugos D. Eichler E.E. Epstein M.P. Glauser T. Goldstein D.B. Han Y. et al.Epi4K ConsortiumEpilepsy Phenome/Genome ProjectDe novo mutations in epileptic encephalopathies.Nature. 2013; 501: 217-221Crossref PubMed Scopus (1086) Google Scholar We ascertained two families comprising seven affected individuals with strikingly similar clinical presentations of EOEE. The pedigrees (families 1 and 2, shown in Figure 1) were highly suggestive of an autosomal-recessive mode of inheritance. For all subjects, brain imaging (including magnetic resonance imaging [MRI] and computerized tomography scanner [CT-scan]), infectious work-up in blood as well as urine and cerebrospinal fluid (CSF), and metabolic work-ups were not conclusive. In family 1, subject 1 (II-1 in Figure 1) was born after an unremarkable full-term pregnancy. American Pediatric Gross Assessment Record (APGAR) was 10/10 with eutocic delivery. Clinical and neurological examinations were reported as unremarkable at birth. At day 1, he experienced a multifocal status epilepticus characterized by long-lasting focal seizures alternately involving right and left temporo-occipital areas. There was no evidence for a materno-fetal infection. Seizures were subclinical (Table 1) albeit almost continuous during the first days of life. Initial EEG revealed oscillating delta-theta waves that increased in amplitude, lasting more than 2 min and restricted to the temporal and occipital brain areas. Interictal EEG was low in amplitude, without suppression bursts. Overall, the recurrence of focal seizures with almost no interictal period for several hours led to the clinical diagnosis of neonatal multifocal status epilepticus. After the age of 2 months, epileptic activity became rarer and responded well to antiepileptic drugs, with persistence of some seizures triggered by fever. Clinical evolution was characterized by a major psychomotor delay with no eye contact and global hypotonia without pyramidal syndrome. No facial dysmorphism was noticed, except for widely spaced teeth. Growth, including occipito-frontal circumference (OFC), was normal. Subject 2 (II-3 in Figure 1) was born after an uneventful pregnancy at 35 weeks of gestation, with birth parameters in normal range. Delivery was complicated by inhalation of meconial amniotic fluid requiring an initial hospitalization in intensive care unit for assisted ventilation. APGAR was 3/5/7. At 5 days of life, she presented with a status epilepticus, controlled by the association of three antiepileptic drugs. Status epilepticus was well tolerated despite a succession of prolonged, focal seizures with very short interictal periods. Epileptic signs included chewing movements and modification of breath occurring several seconds after the beginning of the EEG discharge. EEG showed rhythmic theta-delta focal discharges originating alternatively from both hemispheres, mostly in the left and right temporal regions (a representative EEG is shown in Figure 2). No truly migrating seizures could be observed. Brain MRI showed no lesions suggestive of a perinatal insult. At 2 years and 4 months of age, clinical examination showed axial hypotonia without peripheral hypertonia or pyramidal syndrome. Ocular contact was good with smiling response. Head was controlled but sitting was not acquired. Voluntary grasping was absent. Growth and OFC were normal. Although subject 2 showed a better psychomotor development than subject 1 indicating some degree of intrafamilial phenotypic variability, both affected individuals from family 1 display a severe EE with absent speech and no sitting position.Table 1Clinical Hallmark of the Epileptic Disease and Psychomotor Acquisitions of the Eight Reported SubjectsClinical HallmarksFamily 1Family 2Family 3Subject 1Subject 2Subject 3Subject 4Subject 5Subject 6Subject 7Subject 8Epilepsia typeEOEEEOEEEOEEEOEEEOEEEOEEEOEEEOEEAge at first seizures1 day5 days1 day1 day1 day1 week1 week1 dayAge at first status epilepticus1 day5 days1 monthnone1 dayNANA1 daySeizure typesubclinicalsubclinicalpolymorphicsubclinicalsubclinicalNAsubclinicalsubclinicalPsychomotor acquisitionsprofound delaysevere delayprofound delaysevere delaysevere delayprofound delayprofound delayprofound delayEye contactnoyespooryesyesyesyesyesHead controlnoyesyesyesyesyesyesyesSitting acquirednononoyesnononoyesSpeechnonenonenonenonenonenonenonenoneAbbreviations are as follows: EOEE, early onset epileptic encephalopathy; NA, not available. Open table in a new tab Figure 2Subject 2: Epileptic Activity with Long-Lasting Multifocal Bilateral Seizures during the First Week of LifeShow full caption(A) Schematic representation of the electrode placement according to the international standards in neonate (subject 2 at fifth day of life).(B) Longitudinal (lines 1–6) and transverse montage (lines 7–10) showing a typical seizure beginning in the right hemisphere, temporal region (dotted line), lasting around 100 s and immediately followed by a seizure originating in the left hemisphere, temporal lobe (full trace) beginning at around 100 s and lasting 130 s. Clinically, the discharge was not symptomatic initially, then the neonate displayed chewing movements (20th s), discrete clonic jerks of the left limbs (50th s), and discrete clonic jerks of the right limbs (130th s).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Abbreviations are as follows: EOEE, early onset epileptic encephalopathy; NA, not available. (A) Schematic representation of the electrode placement according to the international standards in neonate (subject 2 at fifth day of life). (B) Longitudinal (lines 1–6) and transverse montage (lines 7–10) showing a typical seizure beginning in the right hemisphere, temporal region (dotted line), lasting around 100 s and immediately followed by a seizure originating in the left hemisphere, temporal lobe (full trace) beginning at around 100 s and lasting 130 s. Clinically, the discharge was not symptomatic initially, then the neonate displayed chewing movements (20th s), discrete clonic jerks of the left limbs (50th s), and discrete clonic jerks of the right limbs (130th s). Family 2 is an Algerian family harboring two consanguinity loops. In the first nuclear family, three out of five children developed a severe EE. In all children, antenatal period and delivery were unremarkable. Subject 3 (V-1 in Figure 1) presented polymorphic seizures beginning in the first day of life and associating cyanosis, hemibody abnormal movements, upper limbs clonus, and abnormal ocular movements. The first status epilepticus was reported at 1 month of life and required a therapeutic association of three antiepileptic drugs to stabilize a monthly occurrence of seizures. Psychomotor milestones were not acquired, with poor eye contact and no sitting at 5 years of age. Fewer epileptic manifestations were reported over follow-up. No facial dysmorphism was noticed except for widely spaced teeth, also observed in family 1. EEGs were asymmetrically slower on right side. A mild perceptive deafness was reported. Subject 4 (V-2 in Figure 1) was born after an uneventful pregnancy. A perinatal suffering was suspected and required resuscitation. He presented seizures at 8 hr of life. A neonatal subdural hematoma was reported. Given the family history, antiepileptic drugs were introduced early. Psychomotor acquisitions were markedly delayed. At 5 years of age, he was able to say several words. He kept presenting weekly seizures. Neurological examination showed axial hypotonia and peripheral hypertonia with brisk tendon reflexes. No facial dysmorphism was noticed, except for hypodontia. Growth parameters including OFC were in normal range. Subject 5 (V-5 in Figure 1) was born at full term of an uneventful pregnancy. Birth measurements and APGAR were normal. He presented a status epilepticus resistant to standard therapeutics at 20 hr of life. A maple syrup disease (MIM 248600) was diagnosed on plasmatic amino acid chromatographs, which was confirmed by the identification of a homozygous truncating mutation (c.799C>T [p.Gln267∗]) in BCKDHB (RefSeq accession number NM_183050.2, MIM 248611). Segregation analysis in other family members showed that subjects 3 and 4 were heterozygous carriers. Dietary care biochemically controlled perfectly the maple syrup disease, with normal chromatography at follow-up. Evolution was marked by a severe psychomotor delay. Walk had not been acquired by the age of 3 years. Epilepsy was very active in the first months of age with almost continuous subclinical seizures. EEG showed almost continuous sequences of focal seizures involving temporal and occipital regions of both hemispheres alternatively, mostly the left one, with rhythmic, large-amplitude spikes lasting several minutes. There was no suppression burst. After 1 month of age, EEG rapidly improved, and a background activity was recorded and found normal. After 3 months, some asymptomatic, short generalized discharges of spikes were recorded. Subjects 6 and 7 (V-6 and V-9 in Figure 1) presented a severe EE with seizure onset in the first days of life. Subject 6 (V-6 in Figure 1) died at 11 years of age of unknown cause. Subject 7 (V-9 in Figure 1) presents epileptic seizures at 5 years of age. We propose that the combination of clinical findings observed in affected individuals from the two families (summarized in Table 1, with additional clinical information in Table S1 available online) define a distinctive epileptic phenotype. Evidence supporting a genetic etiology included (1) the context of familial forms of EE; (2) brain imaging and clinical evolution, which did not support neonatal insult as the cause of the clinical presentation; and (3) the fact that neonatal suffering may be both a consequence of, and a contributing factor to, the observed epileptic disease. Clinical hallmarks comprise nonmotor and pharmacoresistant seizures with onset in the first days of life evolving to pharmacoresistant EE in the first months, profound psychomotor delay, and neonatal EEG showing a recurrent pattern of multifocal long-lasting temporo-occipital seizures involving both hemispheres. We hypothesized that the observed clinical presentation in the two families was due to mutations in the same gene and performed exome sequencing in three affected individuals (II-1, II-3, and V-5 in Figure 1). Written, informed consent was obtained from all subjects, legal representatives, and relatives before enrollment in the study. The ethics committee at participating institutions approved the research protocol. Genomic DNA was extracted from blood via standard procedures. Whole-exome capture and sequencing were performed at Integragen from 3 μg of genomic DNA per individual using the SureSelect Human All Exon V5 kit (Agilent). The resulting libraries were sequenced on a HiSeq 2000 (Illumina) according to the manufacturer’s recommendations for paired-end 76 bp reads. More than 4.8 gigabases of mappable sequences per individual were generated, resulting in a depth of coverage of at least ten reads for more than 93% of RefSeq coding exons (Table S2). Reads were aligned to the human genome reference sequence (GRCh37/hg19 build of UCSC Genome Browser) with the Burrows-Wheeler Aligner (BWA, v.0.6.2), and potential duplicate paired-end reads were marked with Picard v.1.77. The Genome Analysis Toolkit (GATK) v.2.6-4 was used for base quality score recalibration, indel realignment, and variant discovery (both single-nucleotide variants and indels).8McKenna A. Hanna M. Banks E. Sivachenko A. Cibulskis K. Kernytsky A. Garimella K. Altshuler D. Gabriel S. Daly M. DePristo M.A. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.Genome Res. 2010; 20: 1297-1303Crossref PubMed Scopus (14776) Google Scholar Variants were annotated with SeattleSeq SNP Annotation. Rare variants were identified by focusing on protein-altering and splice-site changes present at a frequency less than 1% in dbSNP 138 and the NHLBI GO Exome Sequencing Project and absent from 50 local exomes of unaffected individuals. Candidate genes consistent with an autosomal-recessive mode of inheritance were systematically identified based on the presence of at least one rare homozygous or two heterozygous variants as described previously.9Ng S.B. Buckingham K.J. Lee C. Bigham A.W. Tabor H.K. Dent K.M. Huff C.D. Shannon P.T. Jabs E.W. Nickerson D.A. et al.Exome sequencing identifies the cause of a mendelian disorder.Nat. Genet. 2010; 42: 30-35Crossref PubMed Scopus (1484) Google Scholar This strategy led to identification of a single gene mutated in all three affected individuals (Table S3), namely SLC13A5 (MIM 608305; RefSeq NM_177550.3), which encodes the only known neuronal cytoplasmic sodium-dependent citrate carrier.10Pajor A.M. Sodium-coupled dicarboxylate and citrate transporters from the SLC13 family.Pflügers Arch. 2014; 466: 119-130Crossref PubMed Scopus (99) Google Scholar Both affected individuals from family 1 were compound heterozygous for two SLC13A5 missense changes (c.655G>A [p.Gly219Arg] and c.680C>T [p.Thr227Met]) (Figure S1), and subject 5 from family 2 had a homozygous SLC13A5 missense change (c.1463T>C [p.Leu488Pro]) (Figure S1; Table 2). Cosegregation analysis in all available relatives by standard polymerase-chain-reaction (PCR) protocols using custom intronic primers (Table S4) and capillary sequencing confirmed the association of the identified SLC13A5 mutations with EOEE in both families (Figure 1).Table 2Main Characteristics of SLC13A5 MutationsFamiliesGenomic Change (hg19)dbSNP IDAllele Frequency in ESPTranscript ChangeProtein ChangeSodium Binding SiteGERP ScoreGrantham Matrix ScorePolyphen2 (HumVar)Condel FI ScoreCADD Phred ScoreInheritanceFamily 1chr17:g.6606325G>Anone0/13006c.680C>Tp.Thr227MetNa15.470811.0004.19525.3compound heterozygouschr17:g.6606350C>Trs144332569aReported in dbSNP 134 with neither frequency nor validation data.0/13006c.655G>Ap.Gly219ArgNa15.4701250.9984.319.74Family 2chr17:g.6590960A>Gnone0/13006c.1463T>Cp.Leu488ProNa25.150980.9973.15521.5homozygouschr17:g.6590960A>Gnone0/13006c.1463T>Cp.Leu488ProNa25.150980.9973.15521.5Family 3chr17:g.6606325G>Anone0/13006c.680C>Tp.Thr227MetNa15.470811.0004.19525.3compound heterozygouschr17:g.6606350C>Trs144332569aReported in dbSNP 134 with neither frequency nor validation data.0/13006c.655G>Ap.Gly219ArgNa15.4701250.9984.319.74Family 4chr17:g.6606350C>Trs144332569aReported in dbSNP 134 with neither frequency nor validation data.0/13006c.655G>Ap.Gly219ArgNa15.4701250.9984.319.74heterozygousbNo other SLC13A5 variants were detected in this subject.Abbreviations are as follows: hg19, Human Genome version 19; dbSNP ID, database of single nucleotide polymorphism identification; ESP, NHLBI GO Exome Sequencing Project.a Reported in dbSNP 134 with neither frequency nor validation data.b No other SLC13A5 variants were detected in this subject. Open table in a new tab Abbreviations are as follows: hg19, Human Genome version 19; dbSNP ID, database of single nucleotide polymorphism identification; ESP, NHLBI GO Exome Sequencing Project. We then screened SLC13A5 for mutations in 68 unrelated individuals with EOEE, including 61 subjects with unclassified epilepsy and 7 subjects with suppression-burst EEG patterns. Overall, 29 subjects had onset of seizures in the first week of life combined with severe psychomotor delay, and 15 out of these 29 individuals had been screened for mutations in STXBP1 and KCNQ2, which had failed to identify disease-associated variants. Coding regions of SLC13A5 were amplified by standard PCR protocols (primer sequences are listed in Table S4). For each individual, PCR products were pooled and libraries were prepared with the Nextera XT DNA Sample Preparation kit (Illumina). Generated libraries were sequenced on a MiSeq instrument (Illumina) according to the manufacturer’s recommendations for paired-end 150 bp reads. Sequencing data processing and variant identification were performed as described above, except that PCR duplicates were not marked. The average sequencing depth of SLC13A5 coding exons (RefSeq) and splice junctions was 2,158-fold, with 100% of targeted bases covered by at least 10 reads in all subjects. This experiment led to identification of one additional subject with identical compound heterozygous mutations as those found in family 1 (c.655G>A [p.Gly219Arg] and c.680C>T [p.Thr227Met]; family 3 in Figure 1). Single-nucleotide variants flanking the identified mutations seem to argue against identity by descent and support distinct mutational events in families 1 and 3, at least for one of the two variants (Table S5). In striking similarity with the clinical presentation of affected individuals from families 1 and 2, this subject developed subclinical seizures at 2 hr of life and presented with a severe epileptic disease that evolved to a pharmacoresistant EE associated with major developmental delay (Tables 1 and S1). Highly frequent focal seizures lasting several days were initially noticed, followed by periods of relative stability (with rare occasional seizures) alternating with clusters of seizures occurring once or twice a year. No seizures were recorded by video/EEG. Interictal EEGs were well organized. An additional heterozygous SLC13A5 variant (c.655G>A [p.Gly219Arg]) was detected in another subject (family 4, Table 2). Clinical presentation of this affected individual—which comprised seizure onset at 1 month of age and mild psychomotor delay associated with autism spectrum disorder—showed no similarity with the phenotype of affected individuals with recessive SLC13A5 mutations. In the absence of a second detectable mutation of SLC13A5 in this individual and given the fact that heterozygous carriers of the p.Gly219Arg mutation in families 1 and 3 are unaffected, we conclude that this mutation alone is unlikely to cause the observed phenotype. No other coding variants were identified in the remaining 66 individuals tested. Nucleotide-level conservation and impact of amino acid substitutions were assessed by the Genomic Evolutionary Rate Profiling (GERP),11Cooper G.M. Goode D.L. Ng S.B. Sidow A. Bamshad M.J. Shendure J. Nickerson D.A. Single-nucleotide evolutionary constraint scores highlight disease-causing mutations.Nat. Methods. 2010; 7: 250-251Crossref PubMed Scopus (137) Google Scholar Grantham matrix,12Grantham R. Amino acid difference formula to help explain protein evolution.Science. 1974; 185: 862-864Crossref PubMed Scopus (1686) Google Scholar Polyphen-2 (using the HumVar-trained model),13Adzhubei I.A. Schmidt S. Peshkin L. Ramensky V.E. Gerasimova A. Bork P. Kondrashov A.S. Sunyaev S.R. A method and server for predicting damaging missense mutations.Nat. Methods. 2010; 7: 248-249Crossref PubMed Scopus (9290) Google Scholar and Combined Annotation-Dependent Depletion (CADD)14Kircher M. Witten D.M. Jain P. O’Roak B.J. Cooper G.M. Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants.Nat. Genet. 2014; 46: 310-315Crossref PubMed Scopus (3676) Google Scholar scores. All mutation sites were found to affect highly conserved nucleotides and amino acids and were predicted as likely deleterious (Table 2, Figure S2). None of the three mutations were reported in the NHLBI GO Exome Sequencing Project. However, one of the mutations was reported in dbSNP v.134, with neither frequency nor validation data (Table 2). SLC13A5 encodes a highly conserved homodimeric cytoplasmic sodium-dependent citrate carrier composed of 11 transmembrane domains. Functional and structural work on VcINDY—the bacterial orthologous of SLC13A5—showed that sodium binding is required for citrate transport and identified two sodium binding domains:15Mancusso R. Gregorio G.G. Liu Q. Wang D.-N. Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter.Nature. 2012; 491: 622-626Crossref PubMed Scopus (130) Google Scholar one at residue VcINDY-Gly199 (HsSLC13A5-Gly226) and the second one between residues VcINDY-Glu374 and VcINDY-Cys413 (HsSLC13A5-Glu475 and HsSLC13A5-Phe500, respectively). Intracellular citrate transport was shown to be dramatically reduced when these latter two residues are mutated.16Griffith D.A. Pajor A.M. Acidic residues involved in cation and substrate interactions in the Na+/dicarboxylate cotransporter, NaDC-1.Biochemistry. 1999; 38: 7524-7531Crossref PubMed Scopus (27) Google Scholar, 17Inoue K. Fei Y.-J. Zhuang L. Gopal E. Miyauchi S. Ganapathy V. Functional features and genomic organization of mouse NaCT, a sodium-coupled transporter for tricarboxylic acid cycle intermediates.Biochem. J. 2004; 378: 949-957Crossref PubMed Scopus (67) Google Scholar In addition, systematic mutagenesis of SLC13A5 carboxy-terminal region demonstrated the conformational role of the highly conserved residue HsSLC13A5-Leu488 (rbSLC13A5-Leu502) for dicarboxylic acid binding and transport.18Kahn E.S. Pajor A.M. Determinants of substrate and cation affinities in the Na+/dicarboxylate cotransporter.Biochemistry. 1999; 38: 6151-6156Crossref PubMed Scopus (24) Google Scholar, 19Pajor A.M. Conformationally sensitive residues in transmembrane domain 9 of the Na+/dicarboxylate co-transporter.J. Biol. Chem. 2001; 276: 29961-29968Crossref PubMed Scopus (25) Google Scholar Strikingly, all three mutations sites reported here affect either the first sodium-binding site (p.Gly219Arg and p.Thr227Met in families 1 and 3) or the second one (p.Leu488Pro in family 2). This hypothesis is further supported by in silico predictions of the impact of p.Gly219Arg and p.Thr227Met mutations on the first sodium binding site, which show a marked disruption of hydrogen bonds (Figure 3). We can therefore speculate that these mutations may affect the ability of SLC13A5 to transport citrate across the plasma membrane to the cytosol by disrupting its ability to bind sodium. Citrate plays a pivotal role for cellular metabolism and neurotransmitter biogenesis such as glutamate in the brain. Intracellular citrate metabolism is essential for tri-carboxylic acids synthesis and mitochondrial energetic balance, and the rate of fatty-acid synthesis depends on the concentration of citrate in the cytosol, which is mainly controlled by SLC13A5.20Gopal E. Miyauchi S. Martin P.M. Ananth S. Srinivas S.R. Smith S.B. Prasad P.D. Ganapathy V. Expression and functional features of NaCT, a sodium-coupled citrate transporter, in human and rat livers and cell lines.Am. J. Physiol. Gastrointest. Liver Physiol. 2007; 292: G402-G408Crossref PubMed Scopus (57) Google Scholar Disruption of citrate metabolism and transport were previously associated with epilepsy. For instance, mutations in the mitochondrial di- and tri-carboxylic acid transporters SLC25A1 (MIM 190315) and SLC25A22 (MIM 609302) cause hydroxyglutaric aciduria (MIM 615182) and early infantile epileptic encephalopathy-3 (MIM 609304), respectively.21Nota B. Struys E.A. Pop A. Jansen E.E. Fernandez Ojeda M.R. Kanhai W.A. Kranendijk M. van Dooren S.J.M. Bevova M.R. Sistermans E.A. et al.Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria.Am. J. Hum. Genet. 2013; 92: 627-631Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 22Molinari F. Raas-Rothschild A. Rio M. Fiermonte G. Encha-Razavi F. Palmieri L. Palmieri F. Ben-Neriah Z. Kadhom N. Vekemans M. et al.Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy.Am. J. Hum. Genet. 2005; 76: 334-339Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar Conversely, increased citrate synthetase activity in rat brain homogenates was observed after convulsing doses of 3-mercaptopropionic acid, thus indicating that high intracellular citrate concentrations may be an endogenous anticonvulsive mechanism.23Girardi E. Lores Arnaiz G.R. Citrate synthase activity increases in homogenates of the cerebral cortex from rats treated with the convulsant 3-mercaptopropionic acid.Neurochem. Int. 1985; 7: 683-688Crossref PubMed Scopus (12) Google Scholar Finally, although Slc13a5-knockout mice have no signs of developmental or neurological abnormalities, knockout mice of two of the five SLC13 family members develop seizures.15Mancusso R. Gregorio G.G. Liu Q. Wang D.-N. Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter.Nature. 2012; 491: 622-626Crossref PubMed Scopus (130) Google Scholar, 24Birkenfeld A.L. Lee H.-Y. Guebre-Egziabher F. Alves T.C. Jurczak M.J. Jornayvaz F.R. Zhang D. Hsiao J.J. Martin-Montalvo A. Fischer-Rosinsky A. et al.Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice.Cell Metab. 2011; 14: 184-195Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 25Bergeron M.J. Clémençon B. Hediger M.A. Markovich D. SLC13 family of Na+-coupled di- and tri-carboxylate/sulfate transporters.Mol. Aspects Med. 2013; 34: 299-312Crossref PubMed Scopus (77) Google Scholar Neonatal epilepsies are highly heterogeneous in terms of etiology and electro-clinical features. Approximately 20% of neonatal-onset EE of genetic origin are caused by mutations in three major genes, namely STXBP126Saitsu H. Kato M. Mizuguchi T. Hamada K. Osaka H. Tohyama J. Uruno K. Kumada S. Nishiyama K. Nishimura A. et al.De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.Nat. Genet. 2008; 40: 782-788Crossref PubMed Scopus (429) Google Scholar (MIM 602926), KCNQ227Weckhuysen S. Ivanovic V. Hendrickx R. Van Coster R. Hjalgrim H. Møller R.S. Grønborg S. Schoonjans A.-S. Ceulemans B. Heavin S.B. et al.KCNQ2 Study GroupExtending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients.Neurology. 2013; 81: 1697-1703Crossref PubMed Scopus (164) Google Scholar (MIM 602235), and KCNT128Barcia G. Fleming M.R. Deligniere A. Gazula V.-R. Brown M.R. Langouet M. Chen H. Kronengold J. Abhyankar A. Cilio R. et al.De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy.Nat. Genet. 2012; 44: 1255-1259Crossref PubMed Scopus (325) Google Scholar (MIM 608167). Mutations in these genes are mostly associated with malignant migrating partial seizure28Barcia G. Fleming M.R. Deligniere A. Gazula V.-R. Brown M.R. Langouet M. Chen H. Kronengold J. Abhyankar A. Cilio R. et al.De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy.Nat. Genet. 2012; 44: 1255-1259Crossref PubMed Scopus (325) Google Scholar or with suppression-burst pattern.29Milh M. Villeneuve N. Chouchane M. Kaminska A. Laroche C. Barthez M.A. Gitiaux C. Bartoli C. Borges-Correia A. Cacciagli P. et al.Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations.Epilepsia. 2011; 52: 1828-1834Crossref PubMed Scopus (105) Google Scholar, 30Milh M. Boutry-Kryza N. Sutera-Sardo J. Mignot C. Auvin S. Lacoste C. Villeneuve N. Roubertie A. Heron B. Carneiro M. et al.Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2.Orphanet J. Rare Dis. 2013; 8: 80Crossref PubMed Scopus (75) Google Scholar Here, we describe a form of epilepsy associated with SLC13A5 mutations and presenting with status epilepticus in the first days of life, EEG patterns showing bilateral, multifocal, long-lasting nonmigrating seizures and severe neurological evolution despite a decrease of seizure frequency concomitant with a rapid improvement of the EEG background activity. Screening a cohort of 29 subjects with seizure onset in the first week of life combined with severe psychomotor delay identified one additional individual with SLC13A5 mutations and a very similar clinical and EEG presentation as the two index families. Given the rarity of epileptic seizures with onset in the first day of life and the recognizable EEG pattern described here, SLC13A5 may be considered as an additional gene to be screened in individuals with seizures in the first day of life for molecular diagnosis purposes. To conclude, we propose the existence of an autosomal-recessive and clinically distinctive EE associated with SLC13A5 mutations, whose main clinical features comprise seizure onset in the first days of life, subclinical epileptic status, and recognizable EEG patterns with bilateral, multifocal status epilepticus. Altogether, these findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE, might have direct implications for the clinical management of this subset of individuals with seizure onset in the first week of life, and further highlight the role of citrate metabolism in epilepsy. Finally, these findings may ultimately open therapeutic perspectives aimed at increasing intracellular citrate concentration, such as ketogenic diet or triheptanoin treatment.31Kovac S. Abramov A.Y. Walker M.C. Energy depletion in seizures: anaplerosis as a strategy for future therapies.Neuropharmacology. 2013; 69: 96-104Crossref PubMed Scopus (58) Google Scholar, 32Borges K. Sonnewald U. Triheptanoin—a medium chain triglyceride with odd chain fatty acids: a new anaplerotic anticonvulsant treatment?.Epilepsy Res. 2012; 100: 239-244Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar We wish to thank the subjects and families involved in the study, C.T. Gordon for kind advice, Integragen for the exome sequencing experiments, and the University of Burgundy Centre de Calcul (CCuB) for technical support and management of the informatics platform. This work was supported by the Regional Council of Burgundy and Dijon University Hospital. We also thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). Download .pdf (.82 MB) Help with pdf files Document S1. Figures S1–S5 and Tables S1 and S2 The URLs for data presented herein are as follows:dbSNP, http://www.ncbi.nlm.nih.gov/projects/SNP/NHLBI Exome Sequencing Project (ESP) Exome Variant Server, http://evs.gs.washington.edu/EVS/Online Mendelian Inheritance in Man (OMIM), http://www.omim.org/Picard, http://picard.sourceforge.net/RefSeq, http://www.ncbi.nlm.nih.gov/RefSeqSeattleSeq Annotation 138, http://snp.gs.washington.edu/SeattleSeqAnnotation138/Swiss PDB Viewer, http://www.expasy.org/spdbv/UCSC Genome Browser, http://genome.ucsc.eduUniversity of Burgundy Centre de Calcul, https://haydn2005.u-bourgogne.fr/dsi-ccub/

Human MutationVolume 32, Issue 1 p. E1959-E1975 Mutation in Brief Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females† Christel Depienne, Corresponding Author Christel Depienne christel.depienne@upmc.fr AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France UPMC Univ Paris 06, F-75005, Paris, FranceCRICM (UMR 975), Hôpital Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75013 Paris, France; Fax: +33 144 243 658Search for more papers by this authorOriane Trouillard, Oriane Trouillard AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, FranceSearch for more papers by this authorDelphine Bouteiller, Delphine Bouteiller INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, FranceSearch for more papers by this authorIsabelle Gourfinkel-An, Isabelle Gourfinkel-An INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France Pôle d'Epileptologie, Hôpital de la Salpêtrière, F-75013, Paris, France Centre de référence épilepsies rares, Inserm U567, UMR 8104, Université René Descartes, Paris V, FranceSearch for more papers by this authorKarine Poirier, Karine Poirier Institut Cochin, Inserm U567, UMR 8104, Université René Descartes, Paris V, FranceSearch for more papers by this authorFrançois Rivier, François Rivier CHU Montpellier, Service de Neuropédiatrie, Hôpital Gui de Chauliac, Montpellier, F-34000 FranceSearch for more papers by this authorPatrick Berquin, Patrick Berquin Service de neuropédiatrie, CHU Hôpital Nord Amiens, Amiens, FranceSearch for more papers by this authorRima Nabbout, Rima Nabbout Centre de référence épilepsies rares, Inserm U567, UMR 8104, Université René Descartes, Paris V, France Département de Neuropédiatrie, AP-HP, Hôpital Necker-Enfants malades, Paris-Descartes, Paris, FranceSearch for more papers by this authorDenys Chaigne, Denys Chaigne Service de Neuropédiatrie - Clinique Sainte-Odile, Strasbourg, FranceSearch for more papers by this authorDominique Steschenko, Dominique Steschenko Unité de Neurologie Pédiatrique, Hôpital d'Enfants, CHU de NancySearch for more papers by this authorAgnès Gautier, Agnès Gautier Clinique Médicale Pédiatrique, Hôpital Mère-Enfant, CHU de Nantes, FranceSearch for more papers by this authorDorota Hoffman-Zacharska, Dorota Hoffman-Zacharska Institute of Mother and Child Department of Medical Genetics, Warsaw, PolandSearch for more papers by this authorAnnie Lannuzel, Annie Lannuzel INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France Department of neurology, University Hospital of Pointe-à-Pitre, Guadeloupe, F.W.ISearch for more papers by this authorMarilyn Lackmy-Port-Lis, Marilyn Lackmy-Port-Lis Unit of genetics, university hospital of Pointe a Pitre,Guadeloupe, F.W.ISearch for more papers by this authorHélène Maurey, Hélène Maurey Service de Neuropédiatrie, CHU de Bicêtre, Le Kremlin Bicêtre, FranceSearch for more papers by this authorAnne Dusser, Anne Dusser Service de Neuropédiatrie, CHU de Bicêtre, Le Kremlin Bicêtre, FranceSearch for more papers by this authorMarie Bru, Marie Bru Service de neuropédiatrie, Hôpital Mère-Enfant, CHU de Nantes, FranceSearch for more papers by this authorBrigitte Gilbert-Dussardier, Brigitte Gilbert-Dussardier Service de Génétique, Centre de Référence Anomalies du Développement de l'Ouest, CHU Poitiers, FranceSearch for more papers by this authorAgathe Roubertie, Agathe Roubertie Service de Neuropédiatrie, CHU Montpellier, Hôpital Gui de Chauliac, and INSERM U827, Montpellier, FranceSearch for more papers by this authorAnna Kaminska, Anna Kaminska Département de Neuropédiatrie, AP-HP, Hôpital Necker-Enfants malades, Paris-Descartes, Paris, FranceSearch for more papers by this authorSandra Whalen, Sandra Whalen AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, FranceSearch for more papers by this authorCyril Mignot, Cyril Mignot AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France Service de Neuropédiatrie, Hôpital Trousseau, Paris, FranceSearch for more papers by this authorStéphanie Baulac, Stéphanie Baulac INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, FranceSearch for more papers by this authorGaetan Lesca, Gaetan Lesca Service de génétique, University Hospitals of Lyon (HCL), Lyon, France Institute for children and adolescents with Epilepsy IDEE, University Hospitals of Lyon (HCL), Lyon, FranceSearch for more papers by this authorAlexis Arzimanoglou, Alexis Arzimanoglou Institute for children and adolescents with Epilepsy IDEE, University Hospitals of Lyon (HCL), Lyon, France Inserm U821, FranceSearch for more papers by this authorEric LeGuern, Eric LeGuern AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France UPMC Univ Paris 06, F-75005, Paris, FranceSearch for more papers by this author Christel Depienne, Corresponding Author Christel Depienne christel.depienne@upmc.fr AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France UPMC Univ Paris 06, F-75005, Paris, FranceCRICM (UMR 975), Hôpital Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75013 Paris, France; Fax: +33 144 243 658Search for more papers by this authorOriane Trouillard, Oriane Trouillard AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, FranceSearch for more papers by this authorDelphine Bouteiller, Delphine Bouteiller INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, FranceSearch for more papers by this authorIsabelle Gourfinkel-An, Isabelle Gourfinkel-An INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France Pôle d'Epileptologie, Hôpital de la Salpêtrière, F-75013, Paris, France Centre de référence épilepsies rares, Inserm U567, UMR 8104, Université René Descartes, Paris V, FranceSearch for more papers by this authorKarine Poirier, Karine Poirier Institut Cochin, Inserm U567, UMR 8104, Université René Descartes, Paris V, FranceSearch for more papers by this authorFrançois Rivier, François Rivier CHU Montpellier, Service de Neuropédiatrie, Hôpital Gui de Chauliac, Montpellier, F-34000 FranceSearch for more papers by this authorPatrick Berquin, Patrick Berquin Service de neuropédiatrie, CHU Hôpital Nord Amiens, Amiens, FranceSearch for more papers by this authorRima Nabbout, Rima Nabbout Centre de référence épilepsies rares, Inserm U567, UMR 8104, Université René Descartes, Paris V, France Département de Neuropédiatrie, AP-HP, Hôpital Necker-Enfants malades, Paris-Descartes, Paris, FranceSearch for more papers by this authorDenys Chaigne, Denys Chaigne Service de Neuropédiatrie - Clinique Sainte-Odile, Strasbourg, FranceSearch for more papers by this authorDominique Steschenko, Dominique Steschenko Unité de Neurologie Pédiatrique, Hôpital d'Enfants, CHU de NancySearch for more papers by this authorAgnès Gautier, Agnès Gautier Clinique Médicale Pédiatrique, Hôpital Mère-Enfant, CHU de Nantes, FranceSearch for more papers by this authorDorota Hoffman-Zacharska, Dorota Hoffman-Zacharska Institute of Mother and Child Department of Medical Genetics, Warsaw, PolandSearch for more papers by this authorAnnie Lannuzel, Annie Lannuzel INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France Department of neurology, University Hospital of Pointe-à-Pitre, Guadeloupe, F.W.ISearch for more papers by this authorMarilyn Lackmy-Port-Lis, Marilyn Lackmy-Port-Lis Unit of genetics, university hospital of Pointe a Pitre,Guadeloupe, F.W.ISearch for more papers by this authorHélène Maurey, Hélène Maurey Service de Neuropédiatrie, CHU de Bicêtre, Le Kremlin Bicêtre, FranceSearch for more papers by this authorAnne Dusser, Anne Dusser Service de Neuropédiatrie, CHU de Bicêtre, Le Kremlin Bicêtre, FranceSearch for more papers by this authorMarie Bru, Marie Bru Service de neuropédiatrie, Hôpital Mère-Enfant, CHU de Nantes, FranceSearch for more papers by this authorBrigitte Gilbert-Dussardier, Brigitte Gilbert-Dussardier Service de Génétique, Centre de Référence Anomalies du Développement de l'Ouest, CHU Poitiers, FranceSearch for more papers by this authorAgathe Roubertie, Agathe Roubertie Service de Neuropédiatrie, CHU Montpellier, Hôpital Gui de Chauliac, and INSERM U827, Montpellier, FranceSearch for more papers by this authorAnna Kaminska, Anna Kaminska Département de Neuropédiatrie, AP-HP, Hôpital Necker-Enfants malades, Paris-Descartes, Paris, FranceSearch for more papers by this authorSandra Whalen, Sandra Whalen AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, FranceSearch for more papers by this authorCyril Mignot, Cyril Mignot AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France Service de Neuropédiatrie, Hôpital Trousseau, Paris, FranceSearch for more papers by this authorStéphanie Baulac, Stéphanie Baulac INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, FranceSearch for more papers by this authorGaetan Lesca, Gaetan Lesca Service de génétique, University Hospitals of Lyon (HCL), Lyon, France Institute for children and adolescents with Epilepsy IDEE, University Hospitals of Lyon (HCL), Lyon, FranceSearch for more papers by this authorAlexis Arzimanoglou, Alexis Arzimanoglou Institute for children and adolescents with Epilepsy IDEE, University Hospitals of Lyon (HCL), Lyon, France Inserm U821, FranceSearch for more papers by this authorEric LeGuern, Eric LeGuern AP-HP, Département de génétique et cytogénétique, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France INSERM, CRicm (U975), Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France UPMC Univ Paris 06, F-75005, Paris, FranceSearch for more papers by this author First published: 04 November 2010 https://doi.org/10.1002/humu.21373Citations: 89 † Communicated by William S. Oetting AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation. © 2010 Wiley-Liss, Inc. Citing Literature Volume32, Issue1January 2011Pages E1959-E1975 RelatedInformation

ART for the Aicardi–Goutieres Syndrome The genetic encephalopathy Aicardi–Goutieres syndrome is thought to be due to misidentification of self-derived nucleic acids and the induction of a type I in...

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.

Status dystonicus (SD) is a rare, life-threatening disorder characterized by acute worsening of generalized dystonia.This study was conducted to characterize the pathogenesis, clinical course, and prognosis of SD. We reviewed the records of six centers and analyzed them together with all the cases previously reported in the literature.Eighty-nine episodes occurring in 68 patients were studied. The majority of patients were males (64.7%), were <15 years of age (58.8%), and had secondary dystonia as the underlying condition (37.8%). The episodes were mainly characterized by tonic muscle spasms (68.5%), with phasic forms more common in secondary forms and among females. Almost all cases needed a multistaged approach, with surgery being the most successful strategy. Neurological conditions preceding the episode worsened in 16.2% of cases (ending in death in 10.3%).The course and outcome of SD is highly variable; male gender and prevalent tonic phenotype predict a poor outcome.

<h3>Background</h3> Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. <h3>Objectives</h3> To better characterise the natural history of PMM2-CDG. <h3>Methods</h3> Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. <h3>Results</h3> The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and <i>hydrops fetalis</i> (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His <i>PMM2</i> variant harboured by half of the patients, 45 different variants were observed. <h3>Conclusions</h3> PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

Abstract We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1–3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1–3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.PRRT2 was analyzed in 860 probands with hemiplegic migraine, and PRRT2 variations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with variations whose clinical manifestations were detailed.PRRT2 variations were found in 12 of 163 probands who previously tested negative for CACNA1A, ATP1A2, and SCN1A variations and in 18 of 697 consecutive probands screened simultaneously on the 4 genes. In this second group, pathogenic variants were found in 105 individuals, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%), and SCN1A (15%). The PRRT2 variations included 7 distinct variants, 5 of which have already been described in persons with paroxysmal kinesigenic dyskinesia and 2 new variants. Eight probands had a deletion of the whole PRRT2 gene. Among the 49 patients with variations in PRRT2, 26 had pure hemiplegic migraine and 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4), or abnormal movement (3). Three patients had epilepsy without migraine: 2 had paroxysmal kinesigenic dyskinesia without migraine, and 1 was asymptomatic.PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes. Further studies are needed to understand how the same loss-of-function PRRT2 variations can lead to a wide range of neurologic phenotypes, including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder, and hemiplegic migraine.

γ-Aminobutyric acid (GABA)A -receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABAA -receptor-related disorders as a whole and seek possible genotype-phenotype correlations.We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABAA -receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature.We gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABAA -receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes.GABAA -receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics.

To determine the prevalence of serum antibodies to the ionotropic glutamate receptor 3 (GluR3) in patients with Rasmussen encephalitis (RE), a severe epileptic disorder, and to compare with serum from control subjects and patients with intractable epilepsy (IE).The authors looked for serum immunoglobulin (Ig) G antibodies to GluR3 in 30 patients with RE, including two patients who had plasma exchange and 12 who had been treated with IV Igs with varying results, and 49 patients with IE and 23 healthy individuals, using ELISA with GluR3B peptide, Western blot analysis of recombinant full-length GluR3, immunoprecipitation of [35S]- and [125I]-labeled GluR3 extracellular domains, immunohistochemistry on rat brain sections, and electrophysiology of GluR3 expressed in Xenopus oocytes.Low levels of antibodies to the GluR3B peptide were detected using ELISA in only 4 of the 79 patients with epilepsy (2 with RE and 2 with IE); binding to GluR3B in other sera was shown to be nonspecific. One other patient with IE had antibodies to recombinant GluR3 on Western blot analysis. However, none of the sera tested precipitated either the [35S]- or the [125I]-labeled GluR3 domains; none bound to rat brain sections in a manner similar to rabbit antibodies to GluR3; and none of the nine sera tested affected the electrophysiologic function of GluR3.GluR3 antibodies were only infrequently found in Rasmussen encephalitis or intractable epilepsy.

We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to five previously described patients with TUBA1A mutations.We detected de novo TUBA1A mutations in six patients and highlight the existence of a prominent form of TUBA1A related lissencephaly. In four patients, the mutations identified, c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R), have not been reported before and in two others, the mutation corresponds to a recurrent missense mutation, c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific to TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia/tetraplegia.Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A related lissencephalies from those related to LIS1, DCX and ARX genes.

Human MutationVolume 31, Issue 4 p. 380-390 Mutation UpdateFree Access An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype–phenotype study† Marjan E. Steenweg, Marjan E. Steenweg Department of Child Neurology and VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorCornelis Jakobs, Cornelis Jakobs Metabolic Unit of the Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorAbdellatif Errami, Abdellatif Errami MRC Holland, Amsterdam, The NetherlandsSearch for more papers by this authorSilvy J.M. van Dooren, Silvy J.M. van Dooren Metabolic Unit of the Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorMaria T. Adeva Bartolomé, Maria T. Adeva Bartolomé Hospital Virgen del Puerto, Plasencia, Céceres, SpainSearch for more papers by this authorPeter Aerssens, Peter Aerssens Department of Pediatrics, Virga Jesse Hospital, Hasselt, BelgiumSearch for more papers by this authorPersephone Augoustides-Savvapoulou, Persephone Augoustides-Savvapoulou Department of Pediatrics-Metabolic Lab., Aristotle University of Thessaloniki, Hippocration General Hospital, Thessaloniki, GreeceSearch for more papers by this authorIvo Baric, Ivo Baric Department of Pediatrics, University Hospital Center, Zagreb, CroatiaSearch for more papers by this authorMatthias Baumann, Matthias Baumann Department of Pediatrics, Division of Pediatric Neurology and Inherited Metabolic Disorders, Medical University of Innsbruck, AustriaSearch for more papers by this authorLuisa Bonafé, Luisa Bonafé Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanna, SwitzerlandSearch for more papers by this authorBrigitte Chabrol, Brigitte Chabrol Department of Metabolic Disease, Hospital Timone Enfants, Marseille, FranceSearch for more papers by this authorJoe T.R. Clarke, Joe T.R. Clarke Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, CanadaSearch for more papers by this authorPeter Clayton, Peter Clayton Department of Paediatric Metabolic Disease and Hepatology, Institute of Child Health, University College London, Great Ormond Street Hospital for Children, London, United KingdomSearch for more papers by this authorMahmut Coker, Mahmut Coker Department of Pediatrics, Ege University Medical Faculty, Bornova, Izmir, TurkeySearch for more papers by this authorSarah Cooper, Sarah Cooper Department of Neurology, Southern General Hospital, Glasgow, United KingdomSearch for more papers by this authorTzipora Falik-Zaccai, Tzipora Falik-Zaccai Institute of Human Genetics, Western Galilee Hospital, Naharia, Rappaport Faculty of Medicine, Haifa, IsraelSearch for more papers by this authorMark Gorman, Mark Gorman Department of Neurology, Children's Hospital Boston, Boston, MassachusettsSearch for more papers by this authorAndreas Hahn, Andreas Hahn Department of Pediatric Neurology, Giessen, GermanySearch for more papers by this authorAlev Hasanoglu, Alev Hasanoglu Department of Pediatric Metabolism and Nutrition, At Gazi University Faculty of Medicine, TurkeySearch for more papers by this authorMary D. King, Mary D. King Department of Pediatric Neurology, Children's University Hospital, Dublin, IrelandSearch for more papers by this authorHans B.C. de Klerk, Hans B.C. de Klerk Department of Pediatrics, Erasmus mc/Sophia Childrens Hospital Rotterdam, Rotterdam, The NetherlandsSearch for more papers by this authorStanley H. Korman, Stanley H. Korman Metabolic Disease Unit, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelSearch for more papers by this authorCéline Lee, Céline Lee Children's Hospital, University of Bonn, Bonn, GermanySearch for more papers by this authorAllan Meldgaard Lund, Allan Meldgaard Lund Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, DenmarkSearch for more papers by this authorVlatka Mejaški-Bošnjak, Vlatka Mejaški-Bošnjak Department of Child Neurology, Children's Hospital Zagreb, Zagreb, CroatiaSearch for more papers by this authorIgnacio Pascual-Castroviejo, Ignacio Pascual-Castroviejo Department of Pediatric Neurology, Hospital “La Paz,” Madrid, SpainSearch for more papers by this authorAparna Raadhyaksha, Aparna Raadhyaksha Medical Genetics, University of Miami, FloridaSearch for more papers by this authorTerje Rootwelt, Terje Rootwelt Division of Pediatrics, Rikshospitalet, Oslo University Hospital, NorwaySearch for more papers by this authorAgathe Roubertie, Agathe Roubertie CHU Montpellier, Department of Pediatric Neurology, Hospital Gui de Chauliac, Montpellier, FranceSearch for more papers by this authorMaria L. Ruiz-Falco, Maria L. Ruiz-Falco Department of Pediatric Neurology, Hospital Niño Jesús, Madrid, SpainSearch for more papers by this authorEmmanuel Scalais, Emmanuel Scalais Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg, LuxembourgSearch for more papers by this authorUlf Schimmel, Ulf Schimmel General Hospital Hagen, Hagen, GermanySearch for more papers by this authorManuel Seijo-Martinez, Manuel Seijo-Martinez Department of Neurology, Hospital do Salnes, Villagarcia, SpainSearch for more papers by this authorMohnish Suri, Mohnish Suri Nottingham City Hospital, Clinical Genetics, Nottingham, United KingdomSearch for more papers by this authorJolanta Sykut-Cegielska, Jolanta Sykut-Cegielska Department of Metabolic Diseases, Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, PolandSearch for more papers by this authorFriedrich K. Trefz, Friedrich K. Trefz Department of Pediatrics, Klinikum am Steinenberg, Reutlingen, GermanySearch for more papers by this authorGraziella Uziel, Graziella Uziel Child Neurology Department, National Institute for Neurology “Carlo Besta,” Milan, ItalySearch for more papers by this authorVassili Valayannopoulos, Vassili Valayannopoulos Department of Neuro-Metabolism, Hospital Necker Des Enfants Malades, Paris, FranceSearch for more papers by this authorChristine Vianey-Saban, Christine Vianey-Saban Centre de Biotechnology Cellulaire, Hopital Debrousse, Lyon, FranceSearch for more papers by this authorStefan Vlaho, Stefan Vlaho Department of Pediatric Neurology, Klinik für Kinder-und Jugendmedizin, Johann Wolfgang Goethe-University, Frankfurt, GermanySearch for more papers by this authorJulia Vodopiutz, Julia Vodopiutz Department for Inborn Errors of Metabolism and Pediatric Genetics, University Children's Hospital Vienna, Vienna, AustriaSearch for more papers by this authorMoacir Wajner, Moacir Wajner Department of Medical Genetics, Hospital de Clínicas de Porto Alegre, Porto Alegre RS, BrasilSearch for more papers by this authorJohn Walter, John Walter Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, United KingdomSearch for more papers by this authorClaudia Walter-Derbort, Claudia Walter-Derbort Department of Pediatrics, Marienhospital Gelsenkirchen, Gelsenkirchen, GermanySearch for more papers by this authorZuhal Yapici, Zuhal Yapici Department of Neurology, Istanbul University, Faculty of Medicine, Istanbul, TurkeySearch for more papers by this authorDimitrios I. Zafeiriou, Dimitrios I. Zafeiriou Department of Child Neurology and Developmental Pediatrics, Aristotle University of Thessaloniki, Thessaloniki, GreeceSearch for more papers by this authorMarieke D. Spreeuwenberg, Marieke D. Spreeuwenberg Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorJacopo Celli, Jacopo Celli Leiden Genome Technology Center, Human and Clinical Genetics, Leiden University Medical Center, The NetherlandsSearch for more papers by this authorJohan T. den Dunnen, Johan T. den Dunnen Leiden Genome Technology Center, Human and Clinical Genetics, Leiden University Medical Center, The NetherlandsSearch for more papers by this authorMarjo S. van der Knaap, Marjo S. van der Knaap Department of Child Neurology and VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorGajja S. Salomons, Corresponding Author Gajja S. Salomons [email protected] Metabolic Unit of the Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The NetherlandsDepartment of Clinical Chemistry, Metabolic Unit, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsSearch for more papers by this author Marjan E. Steenweg, Marjan E. Steenweg Department of Child Neurology and VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorCornelis Jakobs, Cornelis Jakobs Metabolic Unit of the Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorAbdellatif Errami, Abdellatif Errami MRC Holland, Amsterdam, The NetherlandsSearch for more papers by this authorSilvy J.M. van Dooren, Silvy J.M. van Dooren Metabolic Unit of the Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorMaria T. Adeva Bartolomé, Maria T. Adeva Bartolomé Hospital Virgen del Puerto, Plasencia, Céceres, SpainSearch for more papers by this authorPeter Aerssens, Peter Aerssens Department of Pediatrics, Virga Jesse Hospital, Hasselt, BelgiumSearch for more papers by this authorPersephone Augoustides-Savvapoulou, Persephone Augoustides-Savvapoulou Department of Pediatrics-Metabolic Lab., Aristotle University of Thessaloniki, Hippocration General Hospital, Thessaloniki, GreeceSearch for more papers by this authorIvo Baric, Ivo Baric Department of Pediatrics, University Hospital Center, Zagreb, CroatiaSearch for more papers by this authorMatthias Baumann, Matthias Baumann Department of Pediatrics, Division of Pediatric Neurology and Inherited Metabolic Disorders, Medical University of Innsbruck, AustriaSearch for more papers by this authorLuisa Bonafé, Luisa Bonafé Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanna, SwitzerlandSearch for more papers by this authorBrigitte Chabrol, Brigitte Chabrol Department of Metabolic Disease, Hospital Timone Enfants, Marseille, FranceSearch for more papers by this authorJoe T.R. Clarke, Joe T.R. Clarke Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, CanadaSearch for more papers by this authorPeter Clayton, Peter Clayton Department of Paediatric Metabolic Disease and Hepatology, Institute of Child Health, University College London, Great Ormond Street Hospital for Children, London, United KingdomSearch for more papers by this authorMahmut Coker, Mahmut Coker Department of Pediatrics, Ege University Medical Faculty, Bornova, Izmir, TurkeySearch for more papers by this authorSarah Cooper, Sarah Cooper Department of Neurology, Southern General Hospital, Glasgow, United KingdomSearch for more papers by this authorTzipora Falik-Zaccai, Tzipora Falik-Zaccai Institute of Human Genetics, Western Galilee Hospital, Naharia, Rappaport Faculty of Medicine, Haifa, IsraelSearch for more papers by this authorMark Gorman, Mark Gorman Department of Neurology, Children's Hospital Boston, Boston, MassachusettsSearch for more papers by this authorAndreas Hahn, Andreas Hahn Department of Pediatric Neurology, Giessen, GermanySearch for more papers by this authorAlev Hasanoglu, Alev Hasanoglu Department of Pediatric Metabolism and Nutrition, At Gazi University Faculty of Medicine, TurkeySearch for more papers by this authorMary D. King, Mary D. King Department of Pediatric Neurology, Children's University Hospital, Dublin, IrelandSearch for more papers by this authorHans B.C. de Klerk, Hans B.C. de Klerk Department of Pediatrics, Erasmus mc/Sophia Childrens Hospital Rotterdam, Rotterdam, The NetherlandsSearch for more papers by this authorStanley H. Korman, Stanley H. Korman Metabolic Disease Unit, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelSearch for more papers by this authorCéline Lee, Céline Lee Children's Hospital, University of Bonn, Bonn, GermanySearch for more papers by this authorAllan Meldgaard Lund, Allan Meldgaard Lund Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, DenmarkSearch for more papers by this authorVlatka Mejaški-Bošnjak, Vlatka Mejaški-Bošnjak Department of Child Neurology, Children's Hospital Zagreb, Zagreb, CroatiaSearch for more papers by this authorIgnacio Pascual-Castroviejo, Ignacio Pascual-Castroviejo Department of Pediatric Neurology, Hospital “La Paz,” Madrid, SpainSearch for more papers by this authorAparna Raadhyaksha, Aparna Raadhyaksha Medical Genetics, University of Miami, FloridaSearch for more papers by this authorTerje Rootwelt, Terje Rootwelt Division of Pediatrics, Rikshospitalet, Oslo University Hospital, NorwaySearch for more papers by this authorAgathe Roubertie, Agathe Roubertie CHU Montpellier, Department of Pediatric Neurology, Hospital Gui de Chauliac, Montpellier, FranceSearch for more papers by this authorMaria L. Ruiz-Falco, Maria L. Ruiz-Falco Department of Pediatric Neurology, Hospital Niño Jesús, Madrid, SpainSearch for more papers by this authorEmmanuel Scalais, Emmanuel Scalais Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg, LuxembourgSearch for more papers by this authorUlf Schimmel, Ulf Schimmel General Hospital Hagen, Hagen, GermanySearch for more papers by this authorManuel Seijo-Martinez, Manuel Seijo-Martinez Department of Neurology, Hospital do Salnes, Villagarcia, SpainSearch for more papers by this authorMohnish Suri, Mohnish Suri Nottingham City Hospital, Clinical Genetics, Nottingham, United KingdomSearch for more papers by this authorJolanta Sykut-Cegielska, Jolanta Sykut-Cegielska Department of Metabolic Diseases, Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, PolandSearch for more papers by this authorFriedrich K. Trefz, Friedrich K. Trefz Department of Pediatrics, Klinikum am Steinenberg, Reutlingen, GermanySearch for more papers by this authorGraziella Uziel, Graziella Uziel Child Neurology Department, National Institute for Neurology “Carlo Besta,” Milan, ItalySearch for more papers by this authorVassili Valayannopoulos, Vassili Valayannopoulos Department of Neuro-Metabolism, Hospital Necker Des Enfants Malades, Paris, FranceSearch for more papers by this authorChristine Vianey-Saban, Christine Vianey-Saban Centre de Biotechnology Cellulaire, Hopital Debrousse, Lyon, FranceSearch for more papers by this authorStefan Vlaho, Stefan Vlaho Department of Pediatric Neurology, Klinik für Kinder-und Jugendmedizin, Johann Wolfgang Goethe-University, Frankfurt, GermanySearch for more papers by this authorJulia Vodopiutz, Julia Vodopiutz Department for Inborn Errors of Metabolism and Pediatric Genetics, University Children's Hospital Vienna, Vienna, AustriaSearch for more papers by this authorMoacir Wajner, Moacir Wajner Department of Medical Genetics, Hospital de Clínicas de Porto Alegre, Porto Alegre RS, BrasilSearch for more papers by this authorJohn Walter, John Walter Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, United KingdomSearch for more papers by this authorClaudia Walter-Derbort, Claudia Walter-Derbort Department of Pediatrics, Marienhospital Gelsenkirchen, Gelsenkirchen, GermanySearch for more papers by this authorZuhal Yapici, Zuhal Yapici Department of Neurology, Istanbul University, Faculty of Medicine, Istanbul, TurkeySearch for more papers by this authorDimitrios I. Zafeiriou, Dimitrios I. Zafeiriou Department of Child Neurology and Developmental Pediatrics, Aristotle University of Thessaloniki, Thessaloniki, GreeceSearch for more papers by this authorMarieke D. Spreeuwenberg, Marieke D. Spreeuwenberg Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorJacopo Celli, Jacopo Celli Leiden Genome Technology Center, Human and Clinical Genetics, Leiden University Medical Center, The NetherlandsSearch for more papers by this authorJohan T. den Dunnen, Johan T. den Dunnen Leiden Genome Technology Center, Human and Clinical Genetics, Leiden University Medical Center, The NetherlandsSearch for more papers by this authorMarjo S. van der Knaap, Marjo S. van der Knaap Department of Child Neurology and VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorGajja S. Salomons, Corresponding Author Gajja S. Salomons [email protected] Metabolic Unit of the Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The NetherlandsDepartment of Clinical Chemistry, Metabolic Unit, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsSearch for more papers by this author First published: 26 March 2010 https://doi.org/10.1002/humu.21197Citations: 85 † Communicated by Ronald Wanders AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype–genotype relationship. Hum Mutat 30:1–11, 2010. © 2010 Wiley-Liss, Inc. References Abramson CJ, Platt SR, Jakobs C, Verhoeven NM, Dennis R, Garosi L, Shelton GD. 2003. L-2-hydroxyglutaric aciduria in Staffordshire Bull terriers. J Vet Intern Med 17: 551– 556. Aghili M, Zahedi Z, Rafiee E. 2009. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol 91: 233– 236. Barbot C, Fineza I, Diogo L, Maia M, Melo J, Guimarães A, Pires MM, Cardoso ML, Vilarinho L. 1997. L-2-Hydroxyglutaric aciduria: clinical, biochemical and magnetic resonance imaging in six Portuguese pediatric patients. Brain Dev 19: 268– 273. Barth PG, Hoffmann GF, Jaeken JJ, Lehnert W, Hanefeld F, van Gennip AH, Duran M, Valk J, Schutgens RB, Trefz FK, Reimann G, Hartung HP. 1992. L-2-Hydroxyglutaric aciduria: a novel inherited neurometabolic disease. Ann Neurol 32: 66– 71. Barth PG, Hoffmann GF, Jaeken J, Wanders RJA, Duran M, Jansen GA, Jakobs C, Lehnert W, Hanefeld F, Valk J, Schutgens RBH, Trefz FK, Hartung HP, Chamoles NA, Sfaello Z, Caruso U. 1993. L-2-Hydroxyglutaric acidaemia: clinical and biochemical findings in 12 patients and preliminary report on L-2-hydroxyacid dehydrogenase. J Inherit Metab Dis 16: 753– 761. Burge C, Karlin S. 1997. Prediction of complete gene structures in human genomic DNA. J Mol Biol 268: 78– 94. da Silva CG, Bueno ARF, Schuck PF, Leipnitz G, Ribeiro CAJ, Wannmacher CMD, Wyse ATS, Wajner M. 2003. L-2-Hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats. Int J Dev Neurosci 21: 217– 224. den Dunnen JT, Antonarakis SE. 2000. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15: 7– 12 D'Incerti L, Farina L, Moroni I, Uziel G, Savoiardo M. 1998. L-2-Hydroxyglutaric aciduria: MRI in seven cases. Neuroradiology 40: 727– 733. Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK. 1980. L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J Inherit Metab Dis 3: 109– 112. Fokkema IF, den Dunnen JT, Taschner PE. 2005. LOVD: easy creation of a locus-specific sequence variation database using an “LSDB-in-a-box” approach. Hum Mut 26: 63– 68. Fujitake J, Ishikawa Y, Fuji H, Nishimura K, Hayakawa K, Inoue F, Terada N, Okochi M, Tatsuoka Y. 1999. L-2-Hydroxyglutaric aciduria: two Japanese adult cases in one family. J Neurol 246: 378– 382. Garosi GS, Penderis J, McConnell JF, Jakobs C. 2005. L-2-Hydroxyglutaric aciduria in a West Highland white terrier. Vet Rec 156: 145– 147. Goffette SM, Duprez TP, Nassogne MCL, Vincent MFA, Jakobs C, Sindic CJ. 2006. L-2-Hydroxyglutaric aciduria: clinical, genetic, and brain MRI characteritics in two adult sisters. Eur J Neurol 13: 499– 504. Haliloglu G, Jobard F, Oguz KK, Anlar B, Akalan N, Coskun T, Sass JO, Fischer J, Topcu M. 2008. L-2-Hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings. Neuropediatrics 39: 119– 122. Hall TA. 1999. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41: 95– 98. Jequier Gygax M, Roulet-Perez E, Meagher-Villemure K, Jakobs C, Salomons GS, Boulat O, Superti-Furga A, Ballhausen D, Bonafé L. 2009. Sudden unexpected death in an infant with L-2-hydroxyglutaric aciduria. Eur J Pediatr 168: 957– 962. Junqueira D, Brusque AM, Porciúncula LO, Rotta LN, Ribeiro CAJ, Frizzo MES, Dutra Filho CS, Wannmacher CMD, Wyse ATS, Souza DO, Wajner M. 2003. Effects of L-2-hydroxyglutaric acid on various parameters of the glutamatergic system in cerebral cortex of rats. Metab Brain Dis 18: 233– 243. Larnaout A, Amouri R, Kefi M, Hentati F. 2008. L-2-Hydroxyglutaric aciduria: clinical and molecular study in three tunesian families. Identification of a new mutation and inter-familial phenotype variability. J Inherit Metab Dis [Epub ahead of print]. Latini A, Scussiato K, Rosa RB, Leipnitz G, Llesuy S, Belló-Klein A, Dutra-Filho CS, Wajner M. 2003. Induction of oxidative stress by L-2-hydroxyglutaric acid in rat brain. J Neurosci Res 74: 103– 110. Moroni I, Bugiani M, D'Incerti L, Maccagnano C, Rimoldi M, Bissola L, Pollo B, Inocchiaro G, Uziel G. 2004. L-2-Hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Neurology 62: 1882– 1884. Moroni I, D'Incerti L, Farina L, Rimoldi M, Uziel G. 2000. Clinical, biochemical and neuroradiological findings in L-2-hydroxyglutaric aciduria. Neurol Sci 21: 103– 108. O'Conner G, King M, Salomons G, Jakobs C, Hardiman O. 2009. A novel mutation as a cause of L-2-hydroxuglutaric aciduria. J Neurol [Epub ahead of print]. Penderis J, Calvin J, Abramson C, Jakobs C, Pettitt L, Binns MM, Verhoeven NM, O'Driscoll E, Platt SR, Mellersh CS. 2007. L-2-hydroxyglutaric aciduria: characterization of the molecular defect in a spontaneous canine model. J Med Genet 44: 334– 340. Reese MG, Eeckman FH, Kulp D, Haussler D. 1997. Improved splice site detection in genie. J Comp Biol 4: 311– 323. Rzem R, Van Schaftingen E, Veiga-da-Cunha M. 2006. The gene mutated in L-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie 88: 113– 116. Rzem R, Veiga-da-Cunha M, Noel G, Goffette S, Nassogne MC, Tabarki B, Schöller C, Marquardt T, Vikkula M, van Schaftingen E. 2004. A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci USA 101: 16849– 16854. Rzem R, Vincent MF, Van SE, Veiga-da-Cunha M. 2007. L-2-Hydroxyglutaric aciduria, a defect of metabolite repair. J Inherit Metab Dis 30: 681– 689. Samuraki M, Komai K, Hasegawa Y, Kimura M, Yamaguchi S, Terada N, Yamada M. 2008. A successfully treated adult patient with L-2-hydroxyglutaric aciduria. Neurology 70: 1051– 1052. Sass JO, Jobard F, Topcu M, Mahfoud A, Werle E, Cure S, Al-Sannaa A, Alshahwan SA, Bataillard M, Cimbalistiene L, Grolik C, Kemmerich V, Omran H, Sztriha L, Tabache M, Fischer J. 2008. L-2-Hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene. J Inherit Metab Dis [Epub ahead of print]. Seijo-Martinez M, Navarro C, Castro del Rio M, Vila O, Puig M, Ribes A, Butron M. 2005. L-2-Hydroxyglutaric aciduria: clinical, neuroimaging, and neuropathological findings. Arch Neurol 62: 666– 670. Steenweg ME, Salomons GS, Yapici Z, Uziel G, Scalais E, Zafeiriou DI, Ruiz-Falco ML, Mejaski-Bosnjak V, Augoustides-Savvopoulou P, Wajner M, Walter J, Verhoeven-Duif NM, Struys EA, Jakobs C, van der Knaap MS. 2009. L-2-Hydroxyglutaric aciduria: pattern of MR Imaging abnormalities in 56 patients. Radiology 251: 856– 865. Struys EA, Gibson KM, Jakobs C. 2007. Novel insights into L-2-hydroxyglutaric aciduria: mass isotopomer studies reveal 2-oxoglutaric acid as the metabolic precursor of L-2-hydroxyglutaric acid. J Inherit Metab Dis 30: 690– 693. Struys EA, Jansen EE, Verhoeven NM, Jakobs C. 2004. Measurement of urinary D- and L-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-L-tartaric anhydride. Clin Chem 50: 1391– 1395. Topcu M, Aydin OF, Yalcinkaya C, Haliloǧlu G, Aysun S, Anlar B, Topaloǧlu H, Turanli G, Yalnizogǧlu D, Kesimer M, Coşkun T. 2005. L-2-Hydroxyglutaric aciduria: a report of 29 patients. Turk J Pediatr 47: 1– 7. Topcu M, Jobard F, Halliez S, Coskun T, Yalçinkayal C, Ozbas Gerceker F, Wanders RJA, Prud'homme, Lathrop M, Özguc M, Fischer J. 2004. L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 13: 2803– 2811. Van Schaftingen E, Rzem R, Veigha-da-Cunha M. 2009. L-2-Hydroxyglutaric aciduria, a disorder of metabolite repair. J Inherit Metab Dis. 32: 135– 142. Vilarinho L, Cardoso ML, Gaspar P, Barbot C, Azevedo L, Diogo L, Santos M, Carrilho I, Fineza I, Kok F, Chorão R, Alegria P, Martins E, Teixeira J, Cabral Fernandes H, Verhoeven NM, Salomons GS, Santorelli FM, Cabral P, Amorim A, Jakobs C. 2005. Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin. Hum Mutat 26: 395– 396. Wilcken B, Pitt J, Heath D, Walsh P, Wilson G, Buchanan N. 1993. L-2-hydroxyglutaric aciduria: three Australian cases. J Inherit Metab Dis 16: 501– 504. Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE. 2008. Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mut 29: 6– 13. Yilmaz K. 2009. Riboflavin treatment in a case with L-2-hydroxyglutaric aciduria. Eur J Paediat Neurol 13: 57– 60. Zafeiriou DI, Ververi A, Salomons GS, Vargiami E, Haas D, Papadopoulou V, Kontopoulos E, Jakobs C. 2008. L-2-hydroxyglutaric aciduria presenting with severe autistic features. Brain Dev 30: 305– 307. Citing Literature Supporting Information Additional Supporting information may be found in the online version of this article Filename Description humu_21197_sm_SupplInfo1.pdf16.3 KB Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume31, Issue4April 2010Pages 380-390 ReferencesRelatedInformation

With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype.Retrospective study. Subjects A total of 63 patients with posteriorly predominant lissencephaly.Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined.Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly.Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.

Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine.We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate.Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura.We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutations.

Early onset epileptic encephalopathies (EOEEs) are dramatic heterogeneous conditions in which aetiology, seizures and/or interictal EEG have a negative impact on neurological development. Several genes have been associated with EOEE and a molecular diagnosis workup is challenging since similar phenotypes are associated with mutations in different genes and since mutations in one given gene can be associated with very different phenotypes. Recently, de novo mutations in KCNQ2, have been found in about 10% of EOEE patients. Our objective was to confirm that KCNQ2 was an important gene to include in the diagnosis workup of EOEEs and to fully describe the clinical and EEG features of mutated patients.We have screened KCNQ2 in a cohort of 71 patients with an EOEE, without any brain structural abnormality. To be included in the cohort, patient's epilepsy should begin before three months of age and be associated with abnormal interictal EEG and neurological impairment. Brain MRI should not show any structural abnormality that could account for the epilepsy.Out of those 71 patients, 16 had a de novo mutation in KCNQ2 (23%). Interestingly, in the majority of the cases, the initial epileptic features of these patients were comparable to those previously described in the case of benign familial neonatal epilepsy (BFNE) also caused by KCNQ2 mutations. However, in contrast to BFNE, the interictal background EEG was altered and displayed multifocal spikes or a suppression-burst pattern. The ongoing epilepsy and development were highly variable but overall severe: 15/16 had obvious cognitive impairment, half of the patients became seizure-free, 5/16 could walk before the age of 3 and only 2/16 patient acquired the ability to speak.This study confirms that KCNQ2 is frequently mutated de novo in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the neurological and epileptic evolution is variable.

Abstract Developmental and benign movement disorders are a group of movement disorders with onset in the neonatal period, infancy, or childhood. They are characterized by the absence of associated neurological manifestations and by their favorable outcome, although developmental abnormalities can be occasionally observed. Knowledge of the clinical, neurophysiological, and pathogenetic aspects of these disorders is poor. Based on a comprehensive review of the literature and our practical experience, this article summarizes current knowledge in this area. We pay special attention to the recognition and management of these movement disorders in children. © 2010 Movement Disorder Society

Heterozygous dominant mutations of PRRT2 have been associated with various types of paroxysmal neurological manifestations, including benign familial infantile convulsions and paroxysmal kinesigenic dyskinesia. The phenotype associated with biallelic mutations is not well understood as few cases have been reported.PRRT2 screening was performed by Sanger sequencing and quantitative multiplex PCR of short fluorescent fragments. A CGH array was used to characterise the size of the deletion at the 16p11.2 locus.Five patients with homozygous or compound heterozygous deleterious PRRT2 gene mutations are described. These patients differ from those with a single mutation by their overall increased severity: (1) the combination of at least three different forms of paroxysmal neurological disorders within the same patient and persistence of paroxysmal attacks; (2) the occurrence of uncommon prolonged episodes of ataxia; and (3) the association of permanent neurological disorders including learning difficulties in four patients and cerebellar atrophy in 2.Our observations expand the phenotype related to PRRT2 insufficiency, and highlight the complexity of the phenotype associated with biallelic mutations, which represents a severe neurological disease with various paroxysmal disorders and frequent developmental disabilities.

On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets.We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus.Patients with GLUT1-DS experienced a mean of 30.8 (± 27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (± 2.9, 76% motor events) during the treatment phase (p = 0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (± 21.9, 52% motor events; p = 0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p = 0.021), and deteriorated when triheptanoin was withdrawn.Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS.NCT02014883.

Rasmussen's encephalitis (RE) is a severe chronic inflammatory brain disease affecting one cerebral hemisphere and leading to drug-resistant epilepsy, progressive neurologic deficit, and unilateral brain atrophy. Hemispherotomy remains the gold standard treatment but causes permanent functional impairment. No standardized medical treatment protocol currently exists for patients prior to indication of hemispherotomy, although some immunotherapies have shown partial efficacy with functional preservation but poor antiseizure effect. Some studies suggest a role for tumor necrosis factor alpha (TNF-α) in RE pathophysiology.We report an open-label study evaluating the efficacy and the safety of anti-TNF-α therapy (adalimumab) in 11 patients with RE. The primary outcome criterion was the decrease of seizure frequency. The secondary outcome criteria were neurologic and cognitive outcomes and existence of side effects.Adalimumab was introduced with a median delay of 31 months after seizure onset (range 1 month to 16 years), and follow-up was for a median period of 18 months (range 9-54 months). There was a significant seizure frequency decrease after adalimumab administration (from a median of 360 to a median of 32 seizures per quarter, p ≤ 0.01). Statistical analysis showed that adalimumab had a significant intrinsic effect (p < 0.005) independent from disease fluctuations. Five patients (45%) were found to have sustained improvement over consecutive quarters in seizure frequency (decrease of 50%) on adalimumab. Three of these five patients also had no further neurocognitive deterioration. Adalimumab was well tolerated.Our study reports efficacy of adalimumab in terms of seizure frequency control. In addition, stabilization of functional decline occurred in three patients. This efficacy might be particularly relevant for atypical slowly progressive forms of RE, in which hemispherotomy is not clearly indicated. Due to our study limitations, further studies are mandatory to confirm these preliminary results.

Abstract We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in <i>TMEM126A</i> and <i>ACO2</i> are known. In four families with early-onset recessive optic neuropathy, we identified mutations in <i>RTN4IP1</i>, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in <i>C. elegans</i> is involved in UV light response. Analysis of fibroblasts from affected individuals with a <i>RTN4IP1</i> mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of <i>RTN4IP1</i> altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking <i>RTN4IP1</i> functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation.

Exacerbation of hyperkinesia is a life-threatening complication of dyskinetic movement disorders, which can lead to multi-organ failure and even to death. GNAO1 has been recently identified to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders. Patients with GNAO1 mutations can present with a severe, progressive hyperkinetic movement disorder with prolonged life-threatening exacerbations, which are refractory to most anti-dystonic medication.The objective was to investigate the evolution of symptoms and the response to deep brain stimulation of the globus pallidus internus (GPi-DBS) in patients with different GNAO1 mutations.We report six patients presenting with global motor retardation, reduced muscle tone and recurrent episodes of severe, life-threatening hyperkinesia with dystonia, choreoathetosis, and ballism since early childhood. Five of them underwent GPi-DBS.The genetic workup revealed mutations in GNAO1 for all six patients. These encompass a new splice site mutation (c.723+1G>T) in patient 1, a new missense mutation (c.610G>C; p.Gly204Arg) in patient 2, a heterozygous mutation (c.625>T; p.Arg209Cys) in patients 3 and 4, and a heterozygous mutation (c.709G>A; p.Glu237Lys) in patients 5 and 6. By intervention with GPi-DBS the severe paroxysmal hyperkinetic exacerbations could be stopped in five patients. One patient is still under evaluation for neuromodulation.In complex movement disorders of unsolved etiology clinical WES can rapidly streamline pathogenic genes. We identified two novel GNAO1 mutations. GPi-DBS can be an effective and life-saving treatment option for patients with GNAO1 mutations and has to be considered early.

Abstract Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

PurposeTo investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes.MethodsSingleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes.ResultsWe identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant.ConclusionSingleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).

Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations.We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing.Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes.Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.

Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders.

Abstract Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary.

In a retrospective study, 32 patients with myotonic dystrophy, including congenital (n=17) and infantile/juvenile forms (n=15) were studied during a long follow-up lasting 7-28 years (median: 17 years). The clinical presentation was extremely variable; however, a continuum did exist between severe and less severe congenital forms, and later-onset forms, without genotype-phenotype correlation. We observed some unusual presentations, such as 3 cases of isolated club-feet during the neonatal period, and 7 patients (23%) with a completely isolated mental deficiency, language delay and school failure, who only completed the clinical picture several years later. Wechsler scale testing was performed in all cases, and repeated with 8 patients. It demonstrated a decrease in intellectual abilities in 5 patients, suggesting the possibility of a degenerative cerebral process occurring in these children. This decrease has also been reported in some adult cases. This study illustrates the extremely heterogeneous clinical presentation of myotonic dystrophy in childhood.

Management of childhood dystonia differs in certain respects from that of adult dystonia: (i) childhood dystonia is more often secondary than primary; (ii) mixed motor disorders are frequent; (iii) in children, the course of dystonia may be influenced by ongoing brain maturation and by the remarkable plasticity of the young brain; (iv) drug tolerability and effectiveness can be different in children; (v) the therapeutic strategy must be discussed with both the patient and his or her parents; and (vi) the child's education must be taken into account. Based on a systematic review of the literature through June 2011 and on our personal experience, we propose a therapeutic approach to childhood dystonia. After a detailed clinical evaluation and a comprehensive work-up to rule out a treatable cause of dystonia, symptomatic treatment may include various drugs, local botulinum toxin injections, and deep brain stimulation, in addition to rehabilitation.

By family-based screening, first Fuchs and then many other authors showed that mutations in THAP1 (THAP [thanatos-associated protein] domain-containing, apoptosis-associated protein 1) account for a substantial proportion of familial, early-onset, nonfocal, primary dystonia cases (DYT6 dystonia). THAP1 is the first transcriptional factor involved in primary dystonia and the hypothesis of a transcriptional deregulation, which was primarily proposed for the X-linked dystonia-parkinsonism (DYT3 dystonia), provided thus a new way to investigate the possible mechanism underlying the development of dystonic movements. Currently, 56 families present with a THAP1 mutation; however, no genotype/phenotype relationship has been found. Therefore, we carried out a systematic review of the literature on the THAP1 gene to colligate all reported patients with a specific THAP1 mutation and the associated clinical signs in order to describe the broad phenotypic continuum of this disorder. To facilitate the comparison of the identified mutations, we created a Locus-Specific Database (UMD-THAP1 LSDB) available at http://www.umd.be/THAP1/. Currently, the database lists 56 probands and 43 relatives with the associated clinical phenotype when available. The identification of a larger number of THAP1 mutations and collection of high-quality clinical information for each described mutation through international collaborative effort will help investigating the structure-function and genotype-phenotype correlations in DYT6 dystonia.

Benign paroxysmal vertigo (BPV) is characterized by recurrent attacks of dizziness in a healthy child. Complete recovery typically takes place during childhood, and an epidemiological link with migraine has been pointed out. Nevertheless, data concerning long-term patient outcome are scarce.We analyzed the clinical data of 17 patients diagnosed with BPV between 1991 and 2008 in our neuropediatric department; we particularly focused on family medical history and long-term patient outcome by reviewing their medical files and by interviewing the families with a standardized questionnaire administered by phone.Thirteen families responded to the questionnaire, performed 1.1 to 24.5 years after onset. Among 10 patients older than 11 years of age, five continue to suffer attacks of vertigo. Median age at recovery was six years. Nine subjects exhibited migraine, including all six aged 15 years or older. There was a first-degree history of migraine in eight out of 13 children.BPV may not be a homogeneous condition, as some children have a poorer prognosis than others. The strong link with migraine, already noticed by previous authors, led us to discuss the pathophysiology of this condition.

BackgroundChildren with multiple café-au-lait macules (CALMs) may be followed for years before a second National Institutes of Health clinical criterion of neurofibromatosis type 1 (NF1) develops to confirm the diagnosis.ObjectiveWe sought to assess the prevalence of nevus anemicus (NA) in NF1 and its association with neuro-ophthalmologic complications.MethodsThis was a prospective multicenter case-control study of 210 consecutive patients with multiple CALMs. Patients with NF1 were matched for age, sex, and center with control subjects. We documented the number, location, and morphologic appearance of NA; dermatologic features of NF1; magnetic resonance imaging results; and family history.ResultsIn all, 77 (51%) patients with NF1 had NA compared with 6 (2%) control subjects. NA was not detected in 26 patients with other genodermatoses associated with CALMs. Patients with NF1 and NA were younger than those without NA (median age: 17 years) (P = .002). NA was mostly localized to the upper anterior aspect of the chest. NA was not significantly linked with other clinical manifestations of NF1, including optic glioma and unidentified bright objects.LimitationsA potential referral bias associated with tertiary care centers is a limitation.ConclusionsNA appears to have a high prevalence and specificity in NF1 and might serve as a marker for NF1 in children with multiple CALMs. Children with multiple café-au-lait macules (CALMs) may be followed for years before a second National Institutes of Health clinical criterion of neurofibromatosis type 1 (NF1) develops to confirm the diagnosis. We sought to assess the prevalence of nevus anemicus (NA) in NF1 and its association with neuro-ophthalmologic complications. This was a prospective multicenter case-control study of 210 consecutive patients with multiple CALMs. Patients with NF1 were matched for age, sex, and center with control subjects. We documented the number, location, and morphologic appearance of NA; dermatologic features of NF1; magnetic resonance imaging results; and family history. In all, 77 (51%) patients with NF1 had NA compared with 6 (2%) control subjects. NA was not detected in 26 patients with other genodermatoses associated with CALMs. Patients with NF1 and NA were younger than those without NA (median age: 17 years) (P = .002). NA was mostly localized to the upper anterior aspect of the chest. NA was not significantly linked with other clinical manifestations of NF1, including optic glioma and unidentified bright objects. A potential referral bias associated with tertiary care centers is a limitation. NA appears to have a high prevalence and specificity in NF1 and might serve as a marker for NF1 in children with multiple CALMs.

Purpose To search for WFS1 mutations in patients with optic atrophy (OA) and assess visual impairment. Design Retrospective molecular genetic and clinical study. Participants Patients with OA followed at a national referral center specialized in genetic sensory diseases. Methods Mutation screening in WFS1 was performed by Sanger sequencing. WFS1-positive patients were evaluated on visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness using time-domain (TD) or spectral-domain (SD) optical coherence tomography (OCT). Statistical analysis was performed. Main Outcome Measures Mutation identification, VA values, and RNFL thickness in sectors. Results Biallelic WFS1 mutations were found in 3 of 24 unrelated patients (15%) with autosomal recessive nonsyndromic optic atrophy (arNSOA) and in 8 patients with autosomal recessive Wolfram syndrome (arWS) associated with diabetes mellitus and OA. Heterozygous mutations were found in 4 of 20 unrelated patients (20%) with autosomal dominant OA. The 4 WFS1-mutated patients of this latter group with hearing loss were diagnosed with autosomal dominant Wolfram-like syndrome (adWLS). Most patients had VA decrease, with logarithm of the minimum angle of resolution (logMAR) values lower in arWS than in arNSOA (1.530 vs. 0.440; P = 0.026) or adWLS (0.240; P = 0.006) but not differing between arNSOA and adWLS (P = 0.879). All patients had decreased RNFL thickness that was worse in arWS than in arNSOA (SD OCT, 35.50 vs. 53.80 μm; P = 0.018) or adWLS (TD-OCT, 45.84 vs. 59.33 μm; P = 0.049). The greatest difference was found in the inferior bundle. Visual acuity was negatively correlated with RNFL thickness (r = −0.89; P = 0.003 in SD OCT and r = −0.75; P = 0.01 in TD-OCT). Conclusions WFS1 is a gene causing arNSOA. Patients with this condition had significantly less visual impairment than those with arWS. Thus systematic screening of WFS1 must be performed in isolated, sporadic, or familial optic atrophies. To search for WFS1 mutations in patients with optic atrophy (OA) and assess visual impairment. Retrospective molecular genetic and clinical study. Patients with OA followed at a national referral center specialized in genetic sensory diseases. Mutation screening in WFS1 was performed by Sanger sequencing. WFS1-positive patients were evaluated on visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness using time-domain (TD) or spectral-domain (SD) optical coherence tomography (OCT). Statistical analysis was performed. Mutation identification, VA values, and RNFL thickness in sectors. Biallelic WFS1 mutations were found in 3 of 24 unrelated patients (15%) with autosomal recessive nonsyndromic optic atrophy (arNSOA) and in 8 patients with autosomal recessive Wolfram syndrome (arWS) associated with diabetes mellitus and OA. Heterozygous mutations were found in 4 of 20 unrelated patients (20%) with autosomal dominant OA. The 4 WFS1-mutated patients of this latter group with hearing loss were diagnosed with autosomal dominant Wolfram-like syndrome (adWLS). Most patients had VA decrease, with logarithm of the minimum angle of resolution (logMAR) values lower in arWS than in arNSOA (1.530 vs. 0.440; P = 0.026) or adWLS (0.240; P = 0.006) but not differing between arNSOA and adWLS (P = 0.879). All patients had decreased RNFL thickness that was worse in arWS than in arNSOA (SD OCT, 35.50 vs. 53.80 μm; P = 0.018) or adWLS (TD-OCT, 45.84 vs. 59.33 μm; P = 0.049). The greatest difference was found in the inferior bundle. Visual acuity was negatively correlated with RNFL thickness (r = −0.89; P = 0.003 in SD OCT and r = −0.75; P = 0.01 in TD-OCT). WFS1 is a gene causing arNSOA. Patients with this condition had significantly less visual impairment than those with arWS. Thus systematic screening of WFS1 must be performed in isolated, sporadic, or familial optic atrophies.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia). The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort. 265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings. 53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p < 0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood. Our data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype–phenotype correlations.

Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening.We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH).We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%.Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening.

Background Data on long-term topical sirolimus treatment of the cutaneous manifestations of tuberous sclerosis complex are rare. Objective To evaluate the long-term benefit and tolerance of topical 1% sirolimus in tuberous sclerosis complex. Methods In this 18-month prospective single-center study, 1% sirolimus cream was applied daily to facial angiofibromas (FAs), fibrous cephalic plaques (FCPs), shagreen patches, hypomelanotic macules, and ungual fibromas. After complete clearance (CC) of FAs, we evaluated a maintenance protocol of 3 applications weekly. Results Twenty-five patients were enrolled. Fifty percent obtained CC of FAs within 9 months. Of 7 patients with CC (58%) who were following the maintenance protocol, 6 relapsed within 7 months and 1 was still responding at 1 year. Of 16 patients with FCPs, 7 (44%) remained stable at 12 months and 9 (56%) improved after 3 to 9 months of treatment. Only 1 of 5 patients treated for shagreen patches showed improvement at 12 months. Treatment was well tolerated with no serious adverse events. Limitations The small number of patients was a limitation. Conclusions Topical 1% sirolimus applied daily produced positive responses in treatment of FAs, FCPs, and facial hypomelanotic macules and was well tolerated. A 3-times-weekly maintenance protocol did not prevent FA relapses. Data on long-term topical sirolimus treatment of the cutaneous manifestations of tuberous sclerosis complex are rare. To evaluate the long-term benefit and tolerance of topical 1% sirolimus in tuberous sclerosis complex. In this 18-month prospective single-center study, 1% sirolimus cream was applied daily to facial angiofibromas (FAs), fibrous cephalic plaques (FCPs), shagreen patches, hypomelanotic macules, and ungual fibromas. After complete clearance (CC) of FAs, we evaluated a maintenance protocol of 3 applications weekly. Twenty-five patients were enrolled. Fifty percent obtained CC of FAs within 9 months. Of 7 patients with CC (58%) who were following the maintenance protocol, 6 relapsed within 7 months and 1 was still responding at 1 year. Of 16 patients with FCPs, 7 (44%) remained stable at 12 months and 9 (56%) improved after 3 to 9 months of treatment. Only 1 of 5 patients treated for shagreen patches showed improvement at 12 months. Treatment was well tolerated with no serious adverse events. The small number of patients was a limitation. Topical 1% sirolimus applied daily produced positive responses in treatment of FAs, FCPs, and facial hypomelanotic macules and was well tolerated. A 3-times-weekly maintenance protocol did not prevent FA relapses.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.

Data on KCNT1 epilepsy of infancy with migrating focal seizures are heterogeneous and incomplete. Kuchenbuch et al. refine the syndrome phenotype, showing a three-step temporal sequence, poor prognosis with acquired microcephaly, high prevalence of extra-neurological manifestations and early mortality, particularly due to SUDEP. Refining the electro-clinical spectrum should facilitate early diagnosis.

Abstract We report four patients from two families who presented attacks of childhood‐onset episodic ataxia associated with pathogenic mutations in the FGF14 gene. Attacks were triggered by fever, lasted several days, and had variable frequencies. Nystagmus and/or postural tremor and/or learning disabilities were noticed in individuals harboring FGF14 mutation with or without episodic ataxia. These cases and literature data delineate the FGF14‐ mutation‐related episodic ataxia phenotype: wide range of age at onset (from childhood to adulthood), variable durations and frequencies, triggering factors including fever, and association to chronic symptoms. We propose to add FGF14 ‐related episodic ataxia to the list of primary episodic ataxia as Episodic Ataxia type 9.

Abstract Background Aromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare, severe neurological disorder caused by pathogenic variants in the dopa decarboxylase ( DDC ) gene, resulting in a combined deficiency of monoamine neurotransmitters. Clinically, patients present with a range of dysfunctions that impact motor, autonomic, and cognitive development. The constellation of symptoms of AADC deficiency varies among patients, and clinical presentation falls across a wide spectrum. However, most patients with AADC deficiency experience significant impairments when compared with children with normal development, irrespective of genotype, phenotype, or disease severity. Further, AADC deficiency is associated with increased mortality. Methods In response to the recent approval of a disease‐modifying gene therapy for AADC deficiency, this review presents considerations for the selection of patients for treatment. Conclusion Suggested clinical criteria to determine whether a patient is a candidate for gene therapy are: (1) genetically and biochemically confirmed AADC deficiency; (2) lack of achievement of gross motor milestones and/or persistence of clinically significant movement disorders; (3) persistent neurocognitive or systemic symptoms secondary to AADC deficiency despite standard medical therapy; and (4) informed parental/guardian decision and consent to treatment.

Abstract Aim To compare the efficacy of intravenous clonazepam (CLZ) for the initial management of convulsive status epilepticus (CSE) in children as a function of the first‐line in‐hospital dose used. Method This monocentric retrospective study included children who received a first dose of CLZ for CSE at Montpellier University Hospital, France, between January 2016 and June 2019. Data from medical records (clinical, treatment, course) were collected and compared as a function of the first CLZ dose used. Results Among the 310 children treated for CSE, 105 received at least one CLZ dose (median age 3 years; quartile 1–quartile 3 [Q1–Q3] = 1 years 2 months–6 years 6 months). Among these 105 patients, 24 (22%) received a dose less than 0.03 mg/kg (low dose) and 69 (65%) received a dose of at least 0.03 mg/kg (high dose). Seizure cessation rate was not different between the low‐ and high‐dose groups (62.5% vs 76%; odds ratio 0.53, 95% confidence interval [CI] 0.19–1.44, p = 0.29). The administration of a second dose of CLZ was more frequent in the low‐ than the high‐dose group (37.5% vs 16%; odds ratio 3.2, 95% CI 1.1–9.1, p = 0.04). Interpretation Our study did not find any difference in seizure termination rate as a function of CLZ dose in children with CSE. However, a second CLZ dose was more frequently needed in the group receiving low (less than 0.03 mg/kg) CLZ.

Rasmussen encephalitis (RE) sera were screened for antibodies to human alpha7 nicotinic acetylcholine receptors (nAChRs) using electrophysiology, calcium imaging, and ligand binding assays. Sera from two of nine patients with RE blocked ACh-induced currents through alpha7 nAChRs and the ACh-induced rise in intracellular free calcium ([Ca2+]i) and inhibited (125)I-alpha-bungarotoxin binding in cells expressing alpha7 nAChRs. Thus, the alpha7 nAChR is a potential target for pathogenic antibodies in patients with RE.

Abstract Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder due to glutaryl CoA dehydrogenase deficiency. Comprehensive descriptions of GA1‐associated movement disorders are rare. In order to refine the description of the motor phenotype, we prospectively studied 16 consecutive pediatric and adult GA1 patients, focusing on the movement disorders and their time course. In most patients, generalized dystonia, superimposed on baseline axial hypotonia, remained the predominant feature throughout the disease course. With aging, it tended to evolve from mobile to fixed dystonia and to be associated with akinetic‐rigid parkinsonism. Prominent orofacial involvement was a consistent feature in GA1 patients with movement disorders, resulting in speech disorders with features of combined hyperkinetic dysarthria and speech apraxia. The types and outcome of movement disorders in this setting should be taken into consideration during rehabilitation and for patient selection and evaluation in therapeutic trials. © 2008 Movement Disorder Society

Mitochondrial complex I (CI) deficiencies are causing debilitating neurological diseases, among which, the Leber Hereditary Optic Neuropathy and Leigh Syndrome are the most frequent. Here, we describe the first germinal pathogenic mutation in the NDUFA13/GRIM19 gene encoding a CI subunit, in two sisters with early onset hypotonia, dyskinesia and sensorial deficiencies, including a severe optic neuropathy. Biochemical analysis revealed a drastic decrease in CI enzymatic activity in patient muscle biopsies, and reduction of CI-driven respiration in fibroblasts, while the activities of complex II, III and IV were hardly affected. Western blots disclosed that the abundances of NDUFA13 protein, CI holoenzyme and super complexes were drastically reduced in mitochondrial fractions, a situation that was reproduced by silencing NDUFA13 in control cells. Thus, we established here a correlation between the first mutation yet identified in the NDUFA13 gene, which induces CI instability and a severe but slowly evolving clinical presentation affecting the central nervous system.

Dominant optic neuropathies causing fiber loss in the optic nerve are among the most frequent inherited mitochondrial diseases. In most genetically resolved cases, the disease is associated to a mutation in OPA1, which encodes an inner mitochondrial dynamin involved in network fusion, cristae structure and mitochondrial genome maintenance. OPA1 cleavage is regulated by two m-AAA proteases, SPG7 and AFG3L2, which are, respectively involved in Spastic Paraplegia 7 and Spino-Cerebellar Ataxia 28. Here, we identified a novel mutation c.1402C>T in AFG3L2, modifying the arginine 468 in cysteine in an evolutionary highly conserved arginine-finger motif, in a family with optic atrophy and mild intellectual disability. Ophthalmic examinations disclosed a loss of retinal nerve fibers on the temporal and nasal sides of the optic disk and a red-green dyschromatopsia. Thus, our results suggest that neuro-ophthalmological symptom as optic atrophy might be associated with AFG3L2 mutations, and should prompt the screening of this gene in patients with isolated and syndromic inherited optic neuropathies.

Summary Mutations in the KCNQ 2 gene encoding the voltage‐gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy ( EOEE ). Most mutations have been shown to induce a loss of function or to affect the subcellular distribution of Kv7 channels in neurons. Herein, we investigated functional consequences and subcellular distribution of the p.V175L mutation of Kv7.2 (Kv7.2 V175L ) found in a patient presenting EOEE . We observed that the mutation produced a 25–40 mV hyperpolarizing shift of the conductance–voltage relationship of both the homomeric Kv7.2 V175L and heteromeric Kv7.2 V175L /Kv7.3 channels compared to wild‐type channels and a 10 mV hyperpolarizing shift of Kv7.2 V175L /Kv7.2/Kv7.3 channels in a 1:1:2 ratio mimicking the patient situation. Mutant channels also displayed faster activation kinetics and an increased current density that was prevented by 1 μ m linopirdine. The p.V175L mutation did not affect the protein expression of Kv7 channels and its localization at the axon initial segment. We conclude that p.V175L is a gain of function mutation. This confirms previous observations showing that mutations having opposite consequences on M channels can produce EOEE . These findings alert us that drugs aiming to increase Kv7 channel activity might have adverse effects in EOEE in the case of gain‐of‐function variants.

Aim To describe the clinico‐radiological phenotype of children with a CACNA 1A mutation and to precisely evaluate their learning ability and cognitive status. Method Children between the ages of 3 and 18 years harboring a pathogenic CACNA 1A mutation associated with episodic ataxia, hemiplegic migraine, benign paroxysmal torticollis, benign paroxysmal vertigo, or benign paroxysmal tonic upgaze, were enrolled in this cross‐sectional study. Data concerning psychomotor development, academic performance, educational management, clinical examination at inclusion, and brain imaging were collected. Cognitive assessment was performed using age‐standardized scales. Results Eighteen patients (nine males, nine females; mean age at inclusion: 11y 7mo [ SD 4y 5mo; range 3y–17y 11mo]) from 14 families were enrolled. Eleven patients displayed the coexistence or consecutive occurrence of more than one type of episodic event. Nine patients exhibited abnormal neurological examination at inclusion. Brain magnetic resonance imaging ( MRI ) showed cerebellar atrophy in five patients. Psychomotor development was delayed in nine patients and academic difficulties were reported by the parents in 15 patients; nine patients were in special education. Impairment of intellectual function was assessed in six of the 12 patients with interpretable Full‐scale IQ scores and was more frequent when cerebellar atrophy was present on MRI . Interpretation Cognitive impairment is commonly associated with CACNA 1A mutations. We suggest that CACNA 1A ‐associated phenotype should be considered a neurodevelopmental disorder. What this paper adds Cognitive disabilities and academic difficulties are common in children with CACNA1A mutations associated with episodic syndromes. Cognitive function ranges from normal to moderate intellectual disorder in wheelchair‐dependent children. Patients with vermian atrophy are at a higher risk of cognitive impairment.

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l-amino acid decarboxylase (AADC) deficiency and Parkinson's disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno-associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l-DOPA into dopamine in Parkinson's patients.

The main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicates that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans.We enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2 and their matched controls. Participants underwent a multimodal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state fMRI, during which we tested the aftereffects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified the structural integrity of gray matter using voxel-based morphometry, the structural integrity of white matter using fixel-based analysis, and the strength and direction of functional cerebellar connections using spectral dynamic causal modeling.Patients with PRRT2 had decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex, microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas, and dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks and tended to restore this communication to the level observed in healthy controls.Patients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output toward the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders.ClinicalTrials.gov identifier: NCT03481491.

ABSTRACT Background Aromatic l ‐amino acid decarboxylase deficiency (AADCD) is a rare, early‐onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). Objective We describe the clinical, biological, and imaging evolution of two AADCD patients ages &gt;10 years after GD. Methods Eladocagene exuparvovec, a recombinant adeno‐associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Results Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l ‐6‐[ 18 F] fluoro‐3, 4‐dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Conclusion Two patients with a severe form of AADCD had an objective motor and non‐motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

Duplications in Xq28 involving the methyl CpG binding protein 2 gene (MECP2) have been described in male patients with severe mental disability, delayed milestones, absence of language, hypotonia replaced by spasticity and retractions, and recurrent and often severe infections. In a study involving five patients in two families, multiplex ligation-dependent probe amplification was used to screen the Xq28 region that includes MECP2, focusing on the presence of gene duplications. Some manifestations of the disease observed in these patients may occur less regularly than the classical abnormalities. Epilepsy with frequent seizures of the myoclonic-astatic type was observed in these patients and was associated with a slowing of the background electroencephalographic activity, rather than the generalized spike-waves or polyspike-waves usually observed in this type of seizure. In addition, cerebral abnormalities were observed with magnetic resonance imaging that were inconstant and nonspecific but that could nonetheless assist in diagnosis of this genetic pathology. Duplications in Xq28 involving the methyl CpG binding protein 2 gene (MECP2) have been described in male patients with severe mental disability, delayed milestones, absence of language, hypotonia replaced by spasticity and retractions, and recurrent and often severe infections. In a study involving five patients in two families, multiplex ligation-dependent probe amplification was used to screen the Xq28 region that includes MECP2, focusing on the presence of gene duplications. Some manifestations of the disease observed in these patients may occur less regularly than the classical abnormalities. Epilepsy with frequent seizures of the myoclonic-astatic type was observed in these patients and was associated with a slowing of the background electroencephalographic activity, rather than the generalized spike-waves or polyspike-waves usually observed in this type of seizure. In addition, cerebral abnormalities were observed with magnetic resonance imaging that were inconstant and nonspecific but that could nonetheless assist in diagnosis of this genetic pathology.

<h3>Objective</h3> To describe the clinico-radiological phenotype of 3 patients harboring a homozygous novel <i>AP4M1</i> pathogenic mutation. <h3>Methods</h3> The 3 patients from an inbred family who exhibited early-onset developmental delay, tetraparesis, juvenile motor function deterioration, and intellectual deficiency were investigated by magnetic brain imaging using T1-weighted, T2-weighted, T2*-weighted, fluid-attenuated inversion recovery, susceptibility weighted imaging (SWI) sequences. Whole-exome sequencing was performed on the 3 patients. <h3>Results</h3> In the 3 patients, brain imaging identified the same pattern of bilateral SWI hyposignal of the globus pallidus, concordant with iron accumulation. A novel homozygous nonsense mutation was identified in <i>AP4M1</i>, segregating with the disease and leading to truncation of half of the <i>adap</i> domain of the protein. <h3>Conclusions</h3> Our results suggest that <i>AP4M1</i> represents a new candidate gene that should be considered in the neurodegeneration with brain iron accumulation (NBIA) spectrum of disorders and highlight the intersections between hereditary spastic paraplegia and NBIA clinical presentations.

ABSTRACT Background : Status dystonicus (SD) is a life‐threatening condition. Objective and Methods : In a dystonia cohort who developed status dystonicus, we analyzed demographics, background dystonia phenomenology and complexity, trajectory previous to‐, via status dystonicus episodes, and evolution following them. Results : Over 20 years, 40 of 328 dystonia patients who were receiving DBS developed 58 status dystonicus episodes. Dystonia was of pediatric onset (95%), frequently complex, and had additional cognitive and pyramidal impairment (62%) and MRI alterations (82.5%); 40% of episodes occured in adults. Mean disease duration preceding status dystonicus was 10.3 ± 8 years. Evolution time to status dystonicus varied from days to weeks; however, 37.5% of patients exhibited progressive worsening over years. Overall, DBS was efficient in resolving 90% of episodes. Conclusion : Status dystonicus is potentially reversible and a result of heterogeneous conditions with nonuniform underlying physiology. Recognition of the complex phenomenology, morphological alterations, and distinct patterns of evolution, before and after status dystonicus, will help our understanding of these conditions. © 2018 International Parkinson and Movement Disorder Society

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.

Pallidal deep brain stimulation is an established treatment in dystonia. Available data on the effect in DYT-THAP1 dystonia (also known as DYT6 dystonia) are scarce and long-term follow-up studies are lacking. In this retrospective, multicenter follow-up case series of medical records of such patients, the clinical outcome of pallidal deep brain stimulation in DYT-THAP1 dystonia, was evaluated. The Burke Fahn Marsden Dystonia Rating Scale served as an outcome measure. Nine females and 5 males were enrolled, with a median follow-up of 4 years and 10 months after implant. All benefited from surgery: dystonia severity was reduced by a median of 58% (IQR 31-62, p = 0.001) at last follow-up, as assessed by the Burke Fahn Marsden movement subscale. In the majority of individuals, there was no improvement of speech or swallowing, and overall, the effect was greater in the trunk and limbs as compared to the cranio-cervical and orolaryngeal regions. No correlation was found between disease duration before surgery, age at surgery, or preoperative disease burden and the outcome of deep brain stimulation. Device- and therapy-related side-effects were few. Accordingly, pallidal deep brain stimulation should be considered in clinically impairing and pharmaco-resistant DYT-THAP1 dystonia. The method is safe and effective, both short- and long-term.

Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). Seventy-one patients were included (68% female, 32% male). The diagnosis was made in the context of (a) a metabolic decompensation (42%), (b) family history (55%), or (c) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16-86). Eighty-nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD-6 decompensations and 1 epilepsy secondary to inaugural decompensation. This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life-threatening condition. Physicians working in adult care must be aware of late-onset presentations given the implications for patients and their families.

Movement DisordersVolume 31, Issue 8 p. 1251-1252 Letters: New Observations Novel heterozygous mutation in ANO3 responsible for craniocervical dystonia Morgane Miltgen MS, Morgane Miltgen MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorArnaud Blanchard PhD, Arnaud Blanchard PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorHélène Mathieu MS, Hélène Mathieu MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorAlexandre Kreisler MD, PhD, Alexandre Kreisler MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, France INSERM UMR-S1172, Lille, FranceSearch for more papers by this author Jean-Pierre-Desvignes MS, Jean-Pierre-Desvignes MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorDavid Salgado PhD, David Salgado PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorAgathe Roubertie MD, PhD, Agathe Roubertie MD, PhD CHRU Montpellier, Service de Neuro-pédiatrie, Hôpital Gui de Chauliac, Montpellier, France; Institut des Neurosciences de Montpellier, U1051 de l'INSERM, Université de Montpellier, BP 74103 Montpellier, FranceSearch for more papers by this authorLaura Barre MS, Laura Barre MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorGhadi Rai MS, Ghadi Rai MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorVeronique Blanck MS, Veronique Blanck MS Département de Génétique Médicale, Hôpital La Timone, Marseille, FranceSearch for more papers by this authorMelissa Frederic PhD, Melissa Frederic PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorXavier Douay MD, PhD, Xavier Douay MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorRonald Mazzolenni MD, PhD, Ronald Mazzolenni MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorPierre Charpentier MD, PhD, Pierre Charpentier MD, PhD Service de Neurologie, CH Béthune, FranceSearch for more papers by this authorVictoria Gonzalez MD, Victoria Gonzalez MD CHU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, FranceSearch for more papers by this authorAlain Destée MD, PhD, Alain Destée MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, France INSERM UMR-S1172, Lille, FranceSearch for more papers by this authorChristophe Béroud PharmD, PhD, Christophe Béroud PharmD, PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France Département de Génétique Médicale, Hôpital La Timone, Marseille, FranceSearch for more papers by this authorGwenaelle Collod-Béroud PhD, Corresponding Author Gwenaelle Collod-Béroud PhD orcid.org/0000-0003-4098-6161 Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceCorrespondence to: Dr. Gwenaelle Collod-Béroud, INSERM UMR_S910, Medical Genetics and Functional Genomics, Faculté de Médecine la Timone, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France; E-mail: gwenaelle.collod-beroud@inserm.frSearch for more papers by this author Morgane Miltgen MS, Morgane Miltgen MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorArnaud Blanchard PhD, Arnaud Blanchard PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorHélène Mathieu MS, Hélène Mathieu MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorAlexandre Kreisler MD, PhD, Alexandre Kreisler MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, France INSERM UMR-S1172, Lille, FranceSearch for more papers by this author Jean-Pierre-Desvignes MS, Jean-Pierre-Desvignes MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorDavid Salgado PhD, David Salgado PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorAgathe Roubertie MD, PhD, Agathe Roubertie MD, PhD CHRU Montpellier, Service de Neuro-pédiatrie, Hôpital Gui de Chauliac, Montpellier, France; Institut des Neurosciences de Montpellier, U1051 de l'INSERM, Université de Montpellier, BP 74103 Montpellier, FranceSearch for more papers by this authorLaura Barre MS, Laura Barre MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorGhadi Rai MS, Ghadi Rai MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorVeronique Blanck MS, Veronique Blanck MS Département de Génétique Médicale, Hôpital La Timone, Marseille, FranceSearch for more papers by this authorMelissa Frederic PhD, Melissa Frederic PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorXavier Douay MD, PhD, Xavier Douay MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorRonald Mazzolenni MD, PhD, Ronald Mazzolenni MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorPierre Charpentier MD, PhD, Pierre Charpentier MD, PhD Service de Neurologie, CH Béthune, FranceSearch for more papers by this authorVictoria Gonzalez MD, Victoria Gonzalez MD CHU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, FranceSearch for more papers by this authorAlain Destée MD, PhD, Alain Destée MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, France INSERM UMR-S1172, Lille, FranceSearch for more papers by this authorChristophe Béroud PharmD, PhD, Christophe Béroud PharmD, PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France Département de Génétique Médicale, Hôpital La Timone, Marseille, FranceSearch for more papers by this authorGwenaelle Collod-Béroud PhD, Corresponding Author Gwenaelle Collod-Béroud PhD orcid.org/0000-0003-4098-6161 Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceCorrespondence to: Dr. Gwenaelle Collod-Béroud, INSERM UMR_S910, Medical Genetics and Functional Genomics, Faculté de Médecine la Timone, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France; E-mail: gwenaelle.collod-beroud@inserm.frSearch for more papers by this author First published: 09 July 2016 https://doi.org/10.1002/mds.26717Citations: 20 Relevant conflicts of interest/financial disclosures: : Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher's web-site. Filename Description mds26717-sup-0001-suppinfo.pdf112.1 KB Supporting Information mds26717-sup-0002-suppmovie1.mov54 MB Supporting Information Movie 1. mds26717-sup-0003-suppmovie2.mov54.3 MB Supporting Information Movie 2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume31, Issue8August 2016Pages 1251-1252 RelatedInformation

<h2>Abstract</h2><h3>Background</h3> <i>CACNA1A-</i>related disorders present with persistent progressive and non-progressive cerebellar ataxia and paroxysmal events: epileptic seizures and non-epileptic attacks. These phenotypes overlap and co-exist in the majority of patients. <h3>Objective</h3> To describe phenotypes in infantile onset <i>CACNA1A-</i>related disorder and to explore intra-familial variations and genotype-phenotype correlations. <h3>Material and methods</h3> This study was a multicenter international collaboration. A retrospective chart review of <i>CACNA1A</i> patients was performed. Clinical, radiological, and genetic data were collected and analyzed in 47 patients with infantile-onset disorder. <h3>Results</h3> Paroxysmal non-epileptic events (PNEE) were observed in 68% of infants, with paroxysmal tonic upward gaze (PTU) noticed in 47% of infants. Congenital cerebellar ataxia (CCA) was diagnosed in 51% of patients including four patients with developmental delay and only one neurological sign. PNEEs were found in 63% of patients at follow-up, with episodic ataxia (EA) in 40% of the sample. Cerebellar ataxia was found in 58% of the patients at follow-up. Four patients had epilepsy in infancy and nine in childhood. Seven infants had febrile convulsions, three of which developed epilepsy later; all three patients had CCA. Cognitive difficulties were demonstrated in 70% of the children. Cerebellar atrophy was found in only one infant but was depicted in 64% of MRIs after age two. <h3>Conclusions</h3> Nearly all of the infants had CCA, PNEE or both. Cognitive difficulties were frequent and appeared to be associated with CCA. Epilepsy was more frequent after age two. Febrile convulsions in association with CCA may indicate risk of epilepsy in later childhood. Brain MRI was normal in infancy. There were no genotype-phenotype correlations found.

Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.

GM1 gangliosidosis is a rare lysosomal storage disorder associated with β-galactosidase enzyme deficiency. There are three types of GM1 gangliosidosis based on age of symptom onset, which correlate with disease severity. In 2019, we performed a retrospective multicentric study including all patients diagnosed with GM1 gangliosidosis in France since 1998. We had access to data for 61 of the 88 patients diagnosed between 1998 and 2019. There were 41 patients with type 1 (symptom onset ≤6 months), 11 with type 2a (symptom onset from 7 months to 2 years), 5 with type 2b (symptom onset from 2 to 3 years), and 4 with type 3 (symptom onset >3 years). The estimated incidence in France was 1/210000. In patients with type 1, the first symptoms were hypotonia (26/41, 63%), dyspnea (7/41, 17%), and nystagmus (6/41, 15%), whereas in patients with type 2a, these were psychomotor regression (9/11, 82%) and seizures (3/11, 27%). In types 2b and 3, the initial symptoms were mild, such as speech difficulties, school difficulties, and progressive psychomotor regression. Hypotonia was observed in all patients, except type 3. The mean overall survival was 23 months (95% confidence interval [CI]: 7, 39) for type 1 and 9.1 years (95% CI: 4.5, 13.5) for type 2a. To the best of our knowledge, this is one of the largest historical cohorts reported, which provides important information on the evolution of all types of GM1 gangliosidosis. These data could be used as a historical cohort in studies assessing potential therapies for this rare genetic disease.

Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity, and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. Eight of 14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for six novel mutations and two haplotypes. The c.1331G>A, p.G444D allele has a drastic effect, whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity <50%. Eight out of nine subjects with a predicted residual activity > or = 50% bore at least one c.824C>A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia.

We hypothesized that cryptogenic forms of arterial ischemic stroke (AIS) in children may present better outcomes than symptomatic ones.We conducted a single-centered retrospective cohort study using chart reviews of all inpatients aged 0.25-16 years and admitted for AIS or TIA between 1994 and 2007. Sixty-three consecutive children with AIS were divided into 2 stroke categories: first, AIS with an established cause, considered as symptomatic (S), and second, AIS only associated with risk factors, and considered as cryptogenic (C). AIS were further subclassified according to the CASCADE stroke classification system. We measured long-term outcome with 2 endpoints: recurrence rate and neurologic impairment score (NIS). We used univariate analysis to compare the clinical and radiologic characteristics of both groups.AIS were cryptogenic in 28 patients (44%) and symptomatic in 35 (56%). Compared to patients in group S, patients in group C showed an absence of stroke recurrence under prolonged aspirin treatment (0% vs 30.3%; p < 0.01), a predominance of nonprogressive arteriopathies (p = 0.02), unilateral infarcts (p = 0.01), M1 segment stenosis (p = 0.02), and better stroke outcomes (mean NIS 2.7 vs 4.2; p = 0.04). Within group C, patients with post-varicella arteriopathy (PVA) had a profile comparable to that of patients with non-PVA strokes in terms of infarct topography, localization of vascular lesions, recurrence rate, and neurologic outcome.Cryptogenic AIS during childhood is a homogeneous clinical and radiologic entity, likely reflecting similar underlying pathophysiologic mechanisms. Under early and prolonged treatment with aspirin, cryptogenic AIS does not recur.

We report on clinical, genetic and metabolic investigations in a family with optic neuropathy, non-progressive cardiomyopathy and cognitive disability. Ophthalmic investigations (slit lamp examination, funduscopy, OCT scan of the optic nerve, ERG and VEP) disclosed mild or no decreased visual acuity, but pale optic disc, loss of temporal optic fibers and decreased VEPs. Mitochondrial DNA and exome sequencing revealed a novel homozygous mutation in the nuclear MTO1 gene and the homoplasmic m.593T>G mutation in the mitochondrial MT-TF gene. Muscle biopsy analyses revealed decreased oxygraphic Vmax values for complexes I+III+IV, and severely decreased activities of the respiratory chain complexes (RCC) I, III and IV, while muscle histopathology was normal. Fibroblast analysis revealed decreased complex I and IV activity and assembly, while cybrid analysis revealed a partial complex I deficiency with normal assembly of the RCC. Thus, in patients with a moderate clinical presentation due to MTO1 mutations, the presence of an optic atrophy should be considered. The association with the mitochondrial mutation m.593T>G could act synergistically to worsen the complex I deficiency and modulate the MTO1-related disease.

We describe 14 patients with 12 novel missense mutations in ASPA, the gene causing Canavan disease (CD). We developed a method to study the effect of these 12 variants on the function of aspartoacylase-the hydrolysis of N-acetyl-l-aspartic acid (NAA) to aspartate and acetate. The wild-type ASPA open reading frame (ORF) and the ORFs containing each of the variants were transfected into HEK293 cells. Enzyme activity was determined by incubating cell lysates with NAA and measuring the released aspartic acid by LC-MS/MS. Clinical data were obtained for 11 patients by means of questionnaires. Four patients presented with a non-typical clinical picture or with the milder form of CD, whereas seven presented with severe CD. The mutations found in the mild patients corresponded to the variants with the highest residual enzyme activities, suggesting that this assay can help evaluate unknown variants found in patients with atypical presentation. We have detected a correlation between clinical presentation, enzyme activity, and genotype for CD.

Aromatic l-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism, affecting catecholamines and serotonin biosynthesis. Cardinal signs consist in psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms. Patients and methods: We present a retrospective descriptive multicentric study concerning ten French children with a biochemical and molecular confirmed diagnosis of AADC deficiency. Results: Clinical presentation of most of our patients was consistent with the previous descriptions from the literature (hypotonia (nine children), autonomic signs (nine children), sleep disorders (eight children), oculogyric crises (eight children), motor disorders like hypertonia and involuntary movements (seven children)). We described however some phenotypic particularities. Two patients exhibited normal intellectual abilities (patients already described in the literature). We also underlined the importance of digestive symptoms like diarrhea, which occurred in five among the ten patients. We report in particular two children with chronic diarrhea, complicated by severe failure to thrive. Vanillactic acid (VLA) elevation in urines of one of these two patients led to suspect the diagnosis of AADC deficiency, as in two other patients from our population. Conclusion: Some symptoms like chronic diarrhea were atypical and have been poorly described in the literature up to now. Diagnosis of the AADC deficiency is sometimes difficult because of the phenotypic heterogeneity of the disease and VLA elevation in urines should suggest the diagnosis.

Aim Benign paroxysmal torticollis (BPT), benign paroxysmal vertigo (BPV), and benign tonic upward gaze (BTU) are characterized by transient and recurrent episodes of neurological manifestations. The purpose of this study was to analyse the clinical relationships between these syndromes, associated comorbidities, and genetic bases. Method In this cross‐sectional study, clinical data of patients with BPT, BPV, or BTU were collected with a focus on developmental achievements, learning abilities, and rehabilitation. Neuropsychological assessment and genetic testing were performed. Results Fifty patients (median age at inclusion 6y) were enrolled. Psychomotor delay, abnormal neurological examination, and low or borderline IQ were found in 19%, 32%, and 26% of the patients respectively. Cognitive dysfunction was present in 27% of the patients. CACNA1A gene mutation was identified in eight families, and KCNA1 and FGF14 mutation in one family respectively. The identification of a CACNA1A mutation was significantly associated with BTU ( p =0.03) and with cognitive dysfunction ( p =0.01). Patients with BPV were less likely to have cognitive dysfunction. Interpretation Children with BPT, BPV, or BTU are at high risk of impaired psychomotor and cognitive development. These syndromes should not be regarded as benign and should be considered as part of the spectrum of a neurodevelopmental disorder. What this paper adds OK Patients with benign paroxysmal torticollis (BPT), benign paroxysmal vertigo (BPV), and benign tonic upward gaze (BTU) have an increased risk of psychomotor delay. These patients also have an increased risk of abnormal neurological examination and cognitive dysfunction. Gene mutations, especially in CACNA1A , were identified in 21% of the families. BPT, BTU, and BPV should not be regarded as benign. BPT, BTU, and BPV should be considered as part of the spectrum of a neurodevelopmental disorder.

Dystonia musculorum deformans is an inherited severe disease, with a wide clinical polymorphism. The most severe clinical forms with early onset carry a high risk of life-threatening complications. In the absence of any efficient medical treatment, bilateral pallidotomy has previously been reported to be of value in the management of this disease. We report the first clinical case of a severe early-onset generalized dystonia dramatically improved by a bilateral stimulation of the internal globus pallidus. In November 1996, we proposed this neurosurgical procedure for a 8-year-old girl, who had suffered since the age of 3 from severe generalized dystonia, and who progressively became totally dependent and bedridden. She had been under sedation and permanent controlled respiratory assistance for the last two months. The etiology of the disease remained unknown (the DYT1 mutation was absent). Under general anesthesia, we bilaterally implanted a four-contacts electrode in the internal globus pallidus, using the Leksell's stereotactic frame and a 1.5 tesla MRI control. A dramatic improvement was noted 6 weeks later and led us to connect the two electrodes to neurostimulators inserted under the abdominal skin.

Over a period of ten years, a boy had several episodes of coma, lasting three to five days. Each episode was preceded by hemiparesis or paresthesias, aphasia, headaches and behavioural changes, with subsequent loss of consciousness. Partial seizures occurred during the first episode. A history of migraine or hemiplegic migraine was found in several members of the family. Linkage to chromosome 1q21-23, where a gene for familial hemiplegic migraine has been mapped, was shown in this family.

Sepiapterin reductase deficiency has recently been recognized as a treatable, inborn error of pterin metabolism. This investigation is the first long-term clinical study demonstrating impressive positive, long-term effects of treatment in two cases of sepiapterin reductase deficiency after 2 and 5 years of treatment respectively. The two patients were not diagnosed before 7 and 13 years of age. These results highlight the importance of cerebrospinal fluid neurotransmitter investigations in childhood encephalopathy, in cases of unexplained early-onset neurologic handicap. Such a widened approach to the diagnostic efforts in early-onset encephalopathy with motor delay during childhood is important, as we have at our disposal a simple and effective treatment.

Objective OPA1 mutations are responsible for more than half of autosomal dominant optic atrophy (ADOA), a blinding disease affecting the retinal ganglion neurons. In most patients the clinical presentation is restricted to the optic nerve degeneration, albeit in 20% of them, additional neuro-sensorial symptoms might be associated to the loss of vision, as frequently encountered in mitochondrial diseases. This study describes clinical and neuroradiological features of OPA1 patients. Methods Twenty two patients from 17 families with decreased visual acuity related to optic atrophy and carrying an OPA1 mutation were enrolled. Patients underwent neuro-ophthalmological examinations. Brain magnetic resonance imaging (T1, T2 and flair sequences) was performed on a 1.5-Tesla MR Unit. Twenty patients underwent 2-D proton spectroscopic imaging. Results Brain imaging disclosed abnormalities in 12 patients. Cerebellar atrophy mainly involving the vermis was observed in almost a quarter of the patients; other abnormalities included unspecific white matter hypersignal, hemispheric cortical atrophy, and lactate peak. Neurological examination disclosed one patient with a transient right hand motor deficit and ENT examination revealed hearing impairment in 6 patients. Patients with abnormal MRI were characterized by: (i) an older age (ii) more severe visual impairment with chronic visual acuity deterioration, and (iii) more frequent associated deafness. Conclusions Our results demonstrate that brain imaging abnormalities are common in OPA1 patients, even in those with normal neurological examination. Lactate peak, cerebellar and cortical atrophies are consistent with the mitochondrial dysfunction related to OPA1 mutations and might result from widespread neuronal degeneration.

To assess nonparoxysmal movement disorders in ATP1A3 mutation-positive patients with alternating hemiplegia of childhood (AHC).Twenty-eight patients underwent neurologic examination with particular focus on movement phenomenology by a specialist in movement disorders. Video recordings were reviewed by another movement disorders specialist and data were correlated with patients' characteristics.Ten patients were diagnosed with chorea, 16 with dystonia (nonparoxysmal), 4 with myoclonus, and 2 with ataxia. Nine patients had more than one movement disorder and 8 patients had none. The degree of movement disorder was moderate to severe in 12/28 patients. At inclusion, dystonic patients (n = 16) were older (p = 0.007) than nondystonic patients. Moreover, patients (n = 18) with dystonia or chorea, or both, had earlier disease onset (p = 0.042) and more severe neurologic impairment (p = 0.012), but this did not correlate with genotype. All patients presented with hypotonia, which was characterized as moderate or severe in 16/28. Patients with dystonia or chorea (n = 18) had more pronounced hypotonia (p = 0.011). Bradykinesia (n = 16) was associated with an early age at assessment (p < 0.01). Significant dysarthria was diagnosed in 11/25 cases. A history of acute neurologic deterioration and further regression of motor function, typically after a stressful event, was reported in 7 patients.Despite the relatively limited number of patients and the cross-sectional nature of the study, this detailed categorization of movement disorders in patients with AHC offers valuable insight into their precise characterization. Further longitudinal studies on this topic are needed.

Objective Riboflavin transporter deficiencies (RTDs), involving SLC52A3 and SLC52A2 genes, have recently been related to Brown-Vialetto-Van Laere (BVVL) syndrome, a hereditary paediatric condition associating motor neuropathy (MN) and deafness. BVVL/RTD has rarely been reported in adult patients, but is probably underdiagnosed due to poor knowledge and lack of awareness of this form of disease among neurologists. In this study, we aimed to investigate the phenotype and prognosis of RTD patients with late-onset MN. Methods We retrospectively collected clinical, biological and electrophysiological data from all French RTD patients with MN onset after 10 years of age (n=6) and extracted data from 19 other similar RTD patients from the literature. Results Adult RTD patients with MN had heterogeneous clinical presentations, potentially mimicking amyotrophic lateral sclerosis or distal hereditary motor neuropathy (56%), multinevritis with cranial nerve involvement (16%), Guillain-Barré syndrome (8%) and mixed motor and sensory neuronopathy syndromes (20%, only in SLC52A2 patients). Deafness was often diagnosed before MN (in 44%), but in some patients, onset began only with MN (16%). The pattern of weakness varied widely, and the classic pontobulbar palsy described in BVVL was not constant. Biochemical tests were often normal. The majority of patients improved under riboflavin supplementation (86%). Interpretation Whereas late-onset RTD may mimic different acquired or genetic causes of motor neuropathies, it is a diagnosis not to be missed since high-dose riboflavin per oral supplementation is often highly efficient.

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Abstract Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8–16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation ( n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy.

Alternating hemiplegia of childhood (AHC) is an early-onset neurodevelopmental disorder caused by pathogenic variants of ATP1A3, which encodes for a subunit of a neuronal Na+/K+ ATPase.1 Patients present various forms of paroxysmal manifestations associated with nonparoxysmal motor disorder and intellectual disability.2 Dystonic attacks are often the most disabling manifestation, and their pharmacological treatment is very disappointing. We report the case of a 25-year-old man with typical AHC attributed to a p.Glu815Lys variant in ATP1A3. He had an early psychomotor retardation. The hemiplegic episodes began at 3 months, and by 18 months he began having dystonic attacks. With aging, the dystonic attacks have become the predominant type of paroxysmal event. The dystonic attacks usually involve one or two limbs on the same side and occasionally progress toward generalized dystonia. They result in considerable pain and fatigue, with major consequences on daily activities. The patient has an intellectual disability, epilepsy, psychotic symptoms, and insomnia. His treatment comprises flunarizine, valproate, prazosin, bisoprolol, and fluoxetine. During the past 18 months, he has been experiencing up to eight dystonic attacks in a single day, which could last from 30 minutes to several hours, with an average duration of 1 hour. Acute treatment consists of a 10-mg dose of midazolam, with a maximum of two doses per day, and he used an average of 40 doses per month. Midazolam usually stops the episodes because it makes him fall asleep, but they often resume within 30 minutes after waking up. One year ago, he incidentally received a single administration of an equimolar mix of nitrous oxide/oxygen (O2) for 5 minutes during a dystonic attack, which resolved rapidly. Based on this observation, we decided to introduce high-flow oxygen inhalation (100% O2 at a flow rate of 12 L/min) as an acute treatment for the patient's dystonic events. O2 is administered as soon as the dystonic attack begins and for a duration of 15 minutes. Most attacks stop within 15 minutes after the beginning of the O2 administration. We have not changed the recommendation regarding the use of midazolam, but midazolam consumption has decreased from 40 doses per month on average to four after the introduction of O2. Oxygen therapy has not changed the frequency of the dystonic attacks, but it has led to a significant improvement in the quality of life by shortening the duration of the attacks and reducing midazolam consumption. Cortical spreading depression (CSD) may be an important mechanism for paroxysmal movement disorders in ATP1A3-related AHC3 and in ATP1A2-related hemiplegic migraine.4 CSD is associated with tissue hypoxia, and increasing O2 availability can shorten its duration.5 Therefore, high-flow oxygen inhalation could be expected to reduce the duration of paroxysmal events in AHC. We suggest that high-flow oxygen inhalation may be considered to treat dystonic attacks in AHC given the (1) safety of oxygen therapy, (2) rationale behind this therapeutical approach, (3) negative impact of dystonic attacks on quality of life, and (4) absence of an alternative pharmacological solution. The parents of the patient and the patient have given written consent for the publication. The authors declare no conflict of interest related to this research. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. Q.W.: 1C, 2A, 2B D.G.: 1C, 2B A.R.: 1C, 2B M.T.P.: 1C, 2B E.P.: 1C, 2B E.R.: 1A, 1B, 1C, 2A, 2B Q.W., D.G., and M.T.P. have no disclosure to declare. A.R. received honorarium for a speech from PTC Therapeutics. E.P. received honoraria for a speech from EISAI and for participating in an advisory board for StrideBio. She also received research support from the Association Française de l'Hémiplégie Alternante and from Fundacio La Marato de TV3 (Spain). E.R. received honoraria for speeches from Orkyn, Aguettant, and Elivie and for participating in an advisory board for Merz-Pharma. He received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Everpharma, Enjoysharing, Fondation Desmarest, AMADYS, ADCY5.org, Fonds de dotation Patrick Brou de Laurière, Agence Nationale de la Recherche, Societé Française de Médecine Esthétique, and the Dystonia Medical Research Foundation. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Abstract Background Classical infantile‐onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long‐term outcomes. Methods We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. Results Sixty‐four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty‐seven (58%) patients died during follow‐up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow‐up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross‐reactive immunologic material (CRIM)‐negative status ( n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors. Conclusions This study reports the long‐term follow‐up of one of the largest cohorts of classical IOPD patients and demonstrates high long‐term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.

Niemann-Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (Clinical Trials.gov ID: NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians' rating of four participants via video recordings, repeated after ≥ 3 weeks. Intraclass correlation coefficients (ICCs) were calculated.Of the 36 individuals with NPC (2-18 years) enrolled, 31 (86.1%) completed the 6-14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (± SD) increase in 5-domain NPCCSS scores of 1.4 (± 2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (± SD) progression of 2.7 (± 4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p < 0.0001), HSP70 (p < 0.0001) and skin unesterified cholesterol (p = 0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p = 0.008) and correlated with the 5-domain NPCCSS (Spearman's correlation coefficient = 0.265, p = 0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC = 0.995) and intra-rater reliability (ICC = 0.937).Progression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030 ; EudraCT 2014-005,194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE . OR-REL-NPC-01: Unregistered.

Background and purpose Childhood‐onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. Methods We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion &gt; 100 CAG. Results We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. Conclusion SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

Chromosome 22q11 deletion (CATCH 22 syndrome or velocardiofacial syndrome) is one of the most frequent chromosomal syndromes. Neurological features other than cognitive disorders are probably the least-described part of the expanding phenotype of the 22q11 deletion. We report the neurological features of three unrelated children with a de novo deletion: one patient with an autistic disorder, a second patient with hypocalcaemic neonatal seizures and unusual persistent epileptic focus at electroencephalographic follow-up, and a third patient with atypical absence epilepsy. These observations enlarge the clinical and neurological spectrum of the 22q11 deletion. Awareness of such cases is necessary, and a diagnosis of the 22q11 deletion should be suspected in children with common neurological features associated with severe or mild dysmorphism. Diagnosis of the 22q11 deletion should be confirmed by fluorescence in situ hybridization analysis associated with standard chromosomal analysis.

Mutation of the gene for alpha-tocopherol transfer protein causes ataxia with isolated vitamin E deficiency, a disorder usually stabilized or improved after vitamin E supplementation. Dystonia has rarely been described in ataxia with isolated vitamin E deficiency (AVED) patients. We present the case of a young boy with AVED, whose neurological and extra-neurological cardinal symptoms of the disease improved after vitamin E supplementation but who progressively developed generalized dystonia.

HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC.We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs.The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants.Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.

Hyperprolinemia type I is a deficiency of proline oxidase (McKusick 23950), leading to hyperprolinemia and iminoglycinuria, usually with renal involvement. Hyperprolinemia type I is considered a benign trait. We reported a case of hyperprolinemia type I with a severe neurologic disorder and without renal involvement. The patient had marked psychomotor delay and right hemiparesis. Epilepsy was characterized by status epilepticus or a cluster of seizures. Laboratory findings revealed elevated levels of proline in the serum, urine, and cerebrospinal fluid without delta1-pyrroline 5-carboxylate dehydrogenase in the plasma or urine. Fluorescence in situ hybridization excluded a chromosome 22q11 deletion. Vigabatrin inhibits ornithine transaminase. Thus, vigabatrin could lead to a depletion of the normal pool of pyrroline 5-carboxylate dehydrogenase and could aggravate the clinical condition of the child. In this study, vigabatrin was discontinued. In the following months, the patient had marked psychomotor improvement, without modification of the epilepsy. We suggest that vigabatrin should be avoided in hyperprolinemia type I.

Parry-Romberg's syndrome or progressive facial hemiatrophy is a rare disorder of unknown etiology which may be accompanied by neurological complications, frequently epilepsy, usually focal refractory epilepsy. The associated brain lesions are located on the same side as the half face atrophy and may progress.We report the cases of two patients with Parry-Romberg's syndrome and epilepsy. Neurosurgery was performed in one patient, enabling a histological study.The link between Parry-Romberg's syndrome and epilepsy is discussed and the neurodevelopmental theory with vascular dysgenesis is suggested.

<h2>Abstract</h2> Propofol is a widely used hypnotic agent for induction and maintenance of pediatric anesthesia with a well known safety profile. Experimental <i>in vitro</i> studies suggest that propofol may be toxic to developing neurons. We report the cases of three infants who underwent surgery before 2 months of age for different benign pathologies. Propofol was used for induction and maintenance of anesthesia in all cases. The three patients developed convulsions with similar clinical characteristics (cluster of recurrent clinical and subclinical seizures) between the 23th and 30th hours following anesthesia. Clinical and electroencephalographic improvement was obtained between the third and fourth day of management in pediatric intensive care unit. The seizures never recurred, and the three patients underwent further uneventful general anesthesia without propofol. Follow-up of the three patients disclosed unexpected neurological dysfunction: progressive microcephaly (head circumferences were normal at birth), developmental impairment with cognitive and behavioural disturbances in two cases, and bilateral symmetrical white-matter abnormalities on cerebral magnetic resonance imaging. <i>Conclusion:</i> The causal relationship between propofol anesthesia and the neurological symptoms of our patients remains difficult to ascertain, but we believe that pediatricians, anesthetists and intensive care-givers should be aware of this possible adverse reaction that has never been described before.

Background: Acute transverse myelitis (ATM) in children is a rare and often severe disease for which there are few known prognostic factors, particularly the subsequent risk of multiple sclerosis (MS) diagnosis. Objectives: To determine the clinical course and prognostic factors after a first episode of ATM in children. Methods: Thirty children below 16 years of age diagnosed with a first neurological episode of ATM were included retrospectively. Clinical evaluation, treatment, laboratory, and MRI data were collected. Results: Median age at onset was 11 years (range 3–15 years). Follow-up data were available for a median of 4 years (range 0.5–16.7 years). Five patients subsequently had a diagnosis of MS (17%), which was associated with acute partial transverse myelitis (odds ratio 5; 95% confidence interval 2.3–11), with a 60% probability of having a relapse at five years ( p &lt; 0.01). The 2011 Verhey criteria correctly identified MS in children with the highest specificity (96%) and sensitivity (80%). Conclusion: Acute partial transverse myelitis and brain MRI abnormalities at initial presentation are significantly predictive of a subsequent diagnosis of MS in children with ATM. These findings suggest that closer brain MRI monitoring after acute partial transverse myelitis might make the earlier introduction of disease-modifying therapies possible.

We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy.EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence.In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10 Hz). Inter- and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%.We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis.

Background Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP. Methods Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role. Results Exome sequencing of a family with RP revealed a splice variant in IMPG1 . Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1 . In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments. Conclusion This study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2 .

Objective: To characterize the electro-clinical presentation of patients with pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate (PLP)-dependent epilepsy in order to determine whether some of them could be diagnosed as de novo West syndrome, i. e., West syndrome that starts after the age of 2 months without other types of seizures (focal seizures for instance) before the onset of epileptic spasms. Methods: We analyzed data from an unpublished cohort of 28 genetically confirmed cases of PDE with antiquitine (ATQ) deficiency and performed a review of the literature looking for description of West syndrome in patients with either PDE with ATQ deficiency or PLP-dependent epilepsy with Pyridox(am)ine phosphate oxidase (PNPO) deficiency. Results: Of the 28 cases from the ATQ deficiency French cohort, 5 had spasms. In four cases, spasms were associated with other types of seizures (myoclonus, focal seizures). In the last case, seizures started on the day of birth. None of these cases corresponded to de novo West syndrome. The review of the literature found only one case of PNPO deficiency presenting as de novo West syndrome and no case of ATQ deficiency. Significance: The presentation of PDE- and PLP-dependent epilepsy as de novo West syndrome is so exceptional that it probably does not justify a systematic trial of pyridoxine or PLP. We propose considering a therapeutic trial with these vitamins in West syndrome if spasms are associated with other seizure types or start before the age of 2 months.

Bilateral facial nerve palsy is a rare and sometimes difficult diagnosis. We describe a case of bilateral simultaneous facial nerve palsy associated with Epstein-Barr virus (EBV) infection in a 3-year-old boy. Several symptoms led to the diagnosis of EBV infection: the clinical situation (fever, stomachache, and throat infection), white blood cell count (5300/mm3 with 70% lymphocyte count), seroconversion with EBV-specific antibodies, lymphocytic meningitis, and a positive blood EBV polymerase chain reaction (9.3×103 copies of EBV-DNA). An MRI brain scan showed bilateral gadolinium enhancement of the facial nerve. A treatment plan with IV antibiotics (ceftriaxone) and corticosteroids was implemented. Antibiotics were stopped after the diagnosis of Lyme disease was ruled out. The patient's facial weakness improved within a few weeks. Bilateral facial nerve palsy is rare and, unlike unilateral facial palsy, it is idiopathic in only 20% of cases. Therefore, it requires further investigation and examination to search for the underlying etiology. Lyme disease is the first infectious disease that should be considered in children, especially in endemic areas. An antibiotic treatment effective against Borrelia burgdorferi should be set up until the diagnosis is negated or confirmed. Further examination should include a blood test (such as immunologic testing, and serologic testing for viruses and bacterium with neurological tropism), a cerebrospinal fluid test, and an MRI brain scan to exclude any serious or curable underlying etiology. Facial bilateral nerve palsy associated with EBV is rarely described in children. Neurological complications have been reported in 7% of all EBV infections. The facial nerve is the most frequently affected of all cranial nerves. Facial palsy described in EBV infections is bilateral in 35% of all cases. The physiopathology is currently unknown. Prognosis is good most of the time.

Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. The interictal electroencephalogram (EEG) shows a “suppression burst” (SB) pattern. The prognosis is usually poor and most children die within the first two years or survive with very severe intellectual disabilities. EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). We report a family with a less severe phenotype of EIEE type 3. We performed exome sequencing and identified two unreported variants in SLC25A22 in the compound heterozygous state: NM_024698.4: c.[813_814delTG];[818 G>A] (p.[Ala272Glnfs*144];[Arg273Lys]). Functional studies in cultured skin fibroblasts from a patient showed that glutamate oxidation was strongly defective, based on a literature review. We clustered the 18 published patients (including those from this family) into three groups according to the severity of the SLC25A22-related disorders. In an attempt to identify genotype–phenotype correlations, we compared the variants according to the location depending on the protein domains. We observed that patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. These data are suggestive of a continuum of disorders related to SLC25A22 that could be called SLC25A22-related disorders. This might be a first clue to enable geneticists to outline a prognosis based on genetic molecular data regarding the SLC25A22 gene.