Imelda Hughes

Background Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. Methods We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7–16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487. Findings Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was −47·7 m (SE 9·3) for ataluren-treated patients and −60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI −7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was −7·7 m (SE 24·1, 95% CI −54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8–74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and −9·5 m (17·2, −43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment. Interpretation Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint. Funding PTC Therapeutics.

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

<h3>Objective</h3> To assess the current use of glucocorticoids (GCs) in Duchenne muscular dystrophy in the UK, and compare the benefits and the adverse events of daily versus intermittent prednisolone regimens. <h3>Design</h3> A prospective longitudinal observational study across 17 neuromuscular centres in the UK of 360 boys aged 3–15 years with confirmed Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off) prednisolone for a mean duration of treatment of 4 years. <h3>Results</h3> The median loss of ambulation was 12 years in intermittent and 14.5 years in daily treatment; the HR for intermittent treatment was 1.57 (95% CI 0.87 to 2.82). A fitted multilevel model comparing the intermittent and daily regiments for the NorthStar Ambulatory Assessment demonstrated a divergence after 7 years of age, with boys on an intermittent regimen declining faster (p&lt;0.001). Moderate to severe side effects were more commonly reported and observed in the daily regimen, including Cushingoid features, adverse behavioural events and hypertension. Body mass index mean z score was higher in the daily regimen (1.99, 95% CI 1.79 to 2.19) than in the intermittent regimen (1.51, 95% CI 1.27 to 1.75). Height restriction was more severe in the daily regimen (mean z score −1.77, 95% CI −1.79 to −2.19) than in the intermittent regimen (mean z score −0.70, 95% CI −0.90 to −0.49). <h3>Conclusions</h3> Our study provides a framework for providing information to patients with Duchenne muscular dystrophy and their families when introducing GC therapy. The study also highlights the importance of collecting longitudinal natural history data on patients treated according to standardised protocols, and clearly identifies the benefits and the side-effect profile of two treatment regimens, which will help with informed choices and implementation of targeted surveillance.

Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage.To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy.Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019).Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66).The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017.Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]).Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy.ClinicalTrials.gov Identifier: NCT01603407.

Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. Histopathological findings frequently feature central cores or multi-minicores, more rarely, type 1 predominance/uniformity, fiber-type disproportion, increased internal nucleation, and fatty and connective tissue. We describe 71 families, 35 associated with dominant RYR1 mutations and 36 with recessive inheritance. Five of the dominant mutations and 35 of the 55 recessive mutations have not been previously reported. Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability. As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. In conclusion, our study reports a large number of novel RYR1 mutations and indicates that recessive variants are at least as frequent as the dominant ones. Assigning pathogenicity to novel mutations is often difficult, and interpretation of genetic results in the context of clinical, histological, and muscle magnetic resonance imaging findings is essential.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Yanick Crow and colleagues report that biallelic mutations in SNORD118, which encodes the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. The mutations affect U8 expression, processing and protein binding and suggest a role for this snoRNA in cerebral vascular homeostasis. Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

<h3>Objective</h3> To evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1). <h3>Methods</h3> Patients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children9s Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32). <h3>Results</h3> We treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (<i>p</i> &lt; 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 (<i>SMN2</i>) gene. <h3>Conclusions</h3> Our results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease. <h3>ClinicalTrials.gov identifier:</h3> NCT02865109. <h3>Classification of evidence</h3> This study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.

Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups.To investigate outcomes after 30 months of open-label vamorolone treatment.This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021.Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d.Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone.Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time.This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD.ClinicalTrials.gov Identifier: NCT03038399.

Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6–89] months; median weight: 7.86 [range, 3.2–20.2] kg; duration of follow-up: 3–22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8–21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28–548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3–223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2–209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Novartis Innovative Therapies AG provided a grant for independent medical writing services.

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4–7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10 days on/10 days off). Boys are followed for a minimum of 3 years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.

ABSTRACT Introduction : X‐linked myotubular myopathy (XLMTM), characterized by severe hypotonia, weakness, respiratory distress, and early mortality, is rare and natural history studies are few. Methods : RECENSUS is a multicenter chart review of male XLMTM patients characterizing disease burden and unmet medical needs. Data were collected between September 2014 and June 2016. Results : Analysis included 112 patients at six clinical sites. Most recent patient age recorded was ≤18 months for 40 patients and &gt;18 months for 72 patients. Mean (SD) age at diagnosis was 3.7 (3.7) months and 54.3 (77.1) months, respectively. Mortality was 44% (64% ≤18 months; 32% &gt;18 months). Premature delivery occurred in 34/110 (31%) births. Nearly all patients (90%) required respiratory support at birth. In the first year of life, patients underwent an average of 3.7 surgeries and spent 35% of the year in the hospital. Discussion : XLMTM is associated with high mortality, disease burden, and healthcare utilization. Muscle Nerve 57 : 550–560, 2018

Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C.

ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process.Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021.Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint.Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

Abstract Extensive intracranial calcifications and leukoencephalopathy are seen in both Coats plus and leukoencephalopathy with calcifications and cysts (LCC; Labrune syndrome). Coats plus syndrome is additionally characterized by the presence of bilateral retinal telangiectasia and exudates while LCC shows the progressive formation of parenchymal brain cysts. Despite these apparently distinguishing features, recent evidence suggests that Coats plus and LCC represent the same clinical entity with a common primary pathogenesis involving a small vessel obliterative microangiopathy. Here, we describe eight previously unreported cases, and present an update on one of the original Coats plus patients to highlight the emerging core clinical features of the “cerebroretinal microangiopathy with calcification and cysts” (CRMCC) phenotype. © 2007 Wiley‐Liss, Inc.

Homoplasmic maternally inherited, m.14674T>C or m. 14674T>G mt-tRNA(Glu) mutations have recently been identified in reversible infantile cytochrome c oxidase deficiency (or 'benign COX deficiency'). This study sought other genetic defects that may give rise to similar presentations.Eight patients from seven families with clinicopathological features of infantile reversible cytochrome c oxidase deficiency were investigated.The study reviewed the diagnostic features and performed molecular genetic analyses of mitochondrial DNA and nuclear encoded candidate genes.Patients presented with subacute onset of profound hypotonia, feeding difficulties and lactic acidosis within the first months of life. Although recovery was remarkable, a mild myopathy persisted into adulthood. Histopathological findings in muscle included increased lipid and/or glycogen content, ragged-red and COX negative fibres. Biochemical studies suggested more generalised abnormalities than pure COX deficiency. Clinical improvement was reflected by normalisation of lactic acidosis and histopathological abnormalities. The m.14674T>C mt-tRNA(Glu) mutation was identified in four families, but none had the m. 14674T>G mutation. Furthermore, in two families pathogenic mutations were also found in the nuclear TRMU gene which has not previously been associated with this phenotype. In one family, the genetic aetiology still remains unknown.Benign COX deficiency is better described as 'reversible infantile respiratory chain deficiency'. It is genetically heterogeneous, and patients not carrying the m.14674T>C or T>G mt-tRNA(Glu) mutations may have mutations in the TRMU gene. Diagnosing this disorder at the molecular level is a significant advance for paediatric neurologists and intensive care paediatricians, enabling them to select children with an excellent prognosis for continuing respiratory support from those with severe mitochondrial presentation in infancy.

Genetic testing in the epilepsies is becoming an increasingly accessible clinical tool. Mutations in the sodium channel alpha 1 subunit (SCN1A) gene are most notably associated with Dravet syndrome. This is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives.Participants were identified prospectively from referrals to the Epilepsy Genetics Service in Glasgow and contacted via their referring clinicians. Questionnaires exploring the consequences of SCN1A genetic testing for each case were sent to carers and physicians.Of the 244 individuals contacted, 182 (75%) carried a SCN1A mutation. Carers of 187 (77%) patients responded (90 females, 97 males; mean age at referral 4 y 10 mo; interquartile range 9 y 1 mo). Of those participants whose children tested positive for a mutation, 87% reported that genetic testing was helpful, leading to treatment changes resulting in fewer seizures and improved access to therapies and respite care. Out of 187 physicians, 163 responded (87%), of whom 48% reported that a positive test facilitated diagnosis earlier than with clinical and electroencephalography data alone. It prevented additional investigations in 67% of patients, altered treatment approach in 69%, influenced medication choice in 74%, and, through medication change, improved seizure control in 42%.In addition to confirming a clinical diagnosis, a positive SCN1A test result influenced treatment choice and assisted in accessing additional therapies, especially in the very young.

We report here the first families carrying recessive variants in the MSTO1 gene: compound heterozygous mutations were identified in two sisters and in an unrelated singleton case, who presented a multisystem complex phenotype mainly characterized by myopathy and cerebellar ataxia. Human MSTO1 is a poorly studied protein, suggested to have mitochondrial localization and to regulate morphology and distribution of mitochondria. As for other mutations affecting genes involved in mitochondrial dynamics, no biochemical defects typical of mitochondrial disorders were reported. Studies in patients’ fibroblasts revealed that MSTO1 protein levels were strongly reduced, the mitochondrial network was fragmented, and the fusion events among mitochondria were decreased, confirming the deleterious effect of the identified variants and the role of MSTO1 in modulating mitochondrial dynamics. We also found that MSTO1 is mainly a cytosolic protein. These findings indicate recessive mutations in MSTO1 as a new cause for inherited neuromuscular disorders with multisystem features.

Spinal muscular atrophy (SMA) type 1, or early-onset SMA, is the most common and severe form of SMA 5q, an autosomal recessive neuromuscular disorder caused by bi-allelic deletions or pathogenic variants in the SMN1 gene. The resulting deficiency of the survival motor neuron (SMN) protein leads to degeneration of motor neurons in brainstem and spinal cord [1]. The median age of death is ∼12 months and most children do not survive into the second year of life if not on supportive care. In the last few years, three approved SMN-enhancing medications have dramatically improved the natural history of the disease, with most treated SMA 1 babies now surviving longer and a proportion achieving unprecedented motor milestones like sitting, standing, and walking with support [2].

A case of cytochrome c oxidase deficiency primarily affecting skeletal muscle is described. The child was admitted at 4 weeks due to failure to thrive and examination at that time revealed weakness and hypotonia. His condition deteriorated until at 11 weeks respiratory arrest necessitated artificial ventilation and death occurred at 14 weeks. Biochemical investigation showed lactic acidaemia and generalised aminoaciduria. Histochemical examination of muscle obtained at biopsy showed strong reactions for some oxidative enzymes, but by contrast cytochrome c oxidase could not be detected. Cytochrome c oxidase activity was less than 5% of control values in an extract of fresh muscle. The reduced-minus oxidised absorption spectra of muscle mitochondrial fractions prepared from post-mortem tissue showed an absence of cytochrome aa3 and a partial deficiency of cytochrome b. Ultra-structural examination showed abnormal mitochondria with loss of cristae and an abnormal granular matrix. The family history suggests autosomal recessive inheritance.

Distinct clinical syndromes have been associated with pathogenic MT‐ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty‐one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT‐ATP6 –related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310–315

Abstract Ezutromid (SMT C1100) is a small‐molecule utrophin modulator that was developed to treat Duchenne muscular dystrophy (DMD). Previous clinical trials of this agent revealed lower exposure in DMD patients compared with healthy volunteers, which may reflect differences in diet. This study evaluated the pharmacokinetics of ezutromid in patients with DMD who followed a balanced diet. This was a multicenter, double‐blind, placebo‐controlled, ascending single and multiple oral dose study. Twelve pediatric patients were randomly allocated to 1 of 3 treatment sequences within which were 3 treatment periods of 2 weeks each. Each patient received, in a dose‐escalating fashion, 1250 mg and 2500 mg twice daily (BID) of ezutromid administered orally as a microfluidized suspension (F3) with placebo in the other treatment period. Throughout the study, patients followed a balanced diet including recommended proportions of major food groups and administration of drug accompanied with 100 mL of full‐fat milk. This approach improved the absorption of ezutromid, resulting in higher systemic exposure, with considerable variability in exposure between patients at each dose level. Single and multiple oral doses of 1250 mg and 2500 mg BID were considered safe and well tolerated. No severe or serious adverse events and no study discontinuations due to adverse events were reported. This study provides assurance that, with the formulation tested (F3) and instructions regarding food (balanced diet and whole‐fat milk), 2500 mg BID of ezutromid achieves plasma concentrations that, based on preclinical studies, should be able to modulate utrophin expression in future clinical trials.

Purpose Individuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and associated mortality risk in RECENSUS, particularly among patients ≤5 years old who received respiratory support at birth; this subgroup closely matches patients in the ASPIRO trial of gene therapy for XLMTM. Design RECENSUS is an international, retrospective study of patients with XLMTM. Descriptive and time-to-event analyses examined survival on the basis of age, respiratory support, tracheostomy use, predicted mutational effects and life-sustaining care. Results Outcomes for 145 patients were evaluated. Among 126 patients with respiratory support at birth, mortality was 47% overall and 59% among those ≤5 years old. Median survival time was shorter for patients ≤5 years old than for those &gt;5 years old (2.2 years (IQR 0.7–5.6) vs 30.2 years (IQR 19.4–30.2)). The most common cause of death was respiratory failure (66.7%). Median survival time was longer for patients with a tracheostomy than for those without (22.8 years (IQR 8.7–30.2) vs 1.8 years (IQR 0.2–not estimable)). The proportion of patients living without a tracheostomy was 50% at age 6 months and 28% at age 2 years. Median survival time was longer with provision of life-sustaining care than without (19.4 years (IQR 3.1–not estimable) vs 0.2 years (IQR 0.1–2.1)). Conclusions High mortality, principally due to respiratory failure, among patients with XLMTM ≤5 years old despite respiratory support underscores the need for early diagnosis, informed decision-making and disease-modifying therapies. Trial registration number NCT02231697

Background Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen—an oestrogen receptor regulator—reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. Methods We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5–12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. Findings Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (–3·05%, 95% CI –7·02 to 0·91) and placebo (–6·15%, –9·19 to –3·11; 2·90% difference, –3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events. Interpretation Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence. Funding Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies.

Minicore myopathy is a congenital myopathy characterized by multifocal areas of degeneration in muscle fibres. Genetic heterogeneity expected on the basis of clinical variability awaits further resolution. We reviewed 19 cases in order to further delineate the phenotype. Marked hypotonia was the predominant presenting feature, with evidence of antenatal onset in 30% of cases. Weakness was most pronounced axially and proximally, often more severely affecting the shoulder girdle. Mild facial involvement was frequent. Varying degrees of scoliosis were obvious in all patients older than 10 years. In addition, two patients who were also the most severely affected had complete external ophthalmoplegia. One patient showed marked distal involvement. Respiratory failure developed in half of all patients after 10 years of age and correlated strongly with the degree of scoliosis. Cardiac involvement occurred mainly secondary to respiratory impairment. The course appeared static in most cases. Loss of independent walking was observed only in one case at the age of 10 years. On ultrasound scan, differential involvement within the quadriceps was documented in several patients. Variability in fibre size, type 1 predominance and atrophy with occasional type 2 hypertrophy were prominent but nonspecific histological changes. Apart from typical minicores, a marked increase in internal nuclei was the most prominent histological feature. With the exception of one family in which two generations were affected, inheritance appeared autosomal-recessive or sporadic in all cases.

<h2>Abstract</h2> Mitochondrial DNA depletion syndromes are a heterogeneous group of childhood neurological disorders characterised by a quantitative abnormality of mitochondrial DNA. We describe two siblings who presented at 8 months and 14 months with myopathy, which rapidly progressed and resulted in death by respiratory failure at age 14 and 18 months, respectively. Muscle biopsy revealed marked respiratory chain defects, with real-time PCR confirming a dramatic depletion of mitochondrial DNA. Sequencing of the thymidine kinase 2 (<i>TK2</i>) gene revealed two, novel heterozygous mutations (p.Q87X and p.N100S) with parental DNA analysis confirming the transmission of mutated alleles.

Abstract Post‐transplant lymphoproliferative disorder (PTLD) in the central nervous system (CNS) is a very rare complication of haematopoietic stem cell transplant (HSCT) and has a dismal prognosis. We report the successful treatment of this disorder with intrathecal rituximab therapy in two children who developed isolated CNS PTLD after HSCT. These children had failed to respond to standard chemotherapy, intravenous rituximab and EBV specific cellular therapy. Pediatr Blood Cancer 2012; 58: 459–461. © 2011 Wiley Periodicals, Inc.

Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Oral glucocorticoids (GC) preserve muscle strength and prolong walking in boys with Duchenne muscular dystrophy (DMD). Although vertebral fractures have been reported in boys taking GC, fracture rates for different GC regimes have not been investigated. The aim of this pragmatic longitudinal study was to compare growth, body mass, bone mineral density (BMD), vertebral fractures (VF) and ambulatory status in boys with DMD on daily (DAILY) or intermittent (INTERMITTENT), oral GC regimens. A convenience sample of 50 DMD boys from two centres was included in the study; 25 boys each were on the DAILY or INTERMITTENT regimen. Size adjusted lumbar spine BMD (LS BMAD), total body less head BMD (TBLH), by DXA and distal forearm bone densities by pQCT, GC exposure, VF assessment and ambulatory status were analysed at three time points; baseline, 1 and 2 years. At baseline, there were no differences in age, GC duration or any bone parameters. However, DAILY boys were shorter (height SDS DAILY = -1.4(0.9); INTERMITTENT = -0.8(1.0), p = 0.04) with higher BMI (BMI SDS DAILY = 1.5(0.9); INTERMITTENT = 0.8(1.0), p = 0.01). Over 2 years, DAILY boys got progressively shorter (delta height SDS DAILY = -0.9(1.1); INTERMITTENT = +0.1(0.6), p < 0.001). At their 2 year assessment, 5 DAILY and 10 INTERMITTENT boys were non-ambulant. DAILY boys had more VFs than INTERMITTENT boys (10 versus 2; χ2 p = 0.008). BMAD SDS remained unchanged between groups. TBLH and radius BMD declined significantly but the rate of loss was not different. In conclusion, there was a trend for more boys on daily GCs to remain ambulant but at the cost of more VFs, greater adiposity and markedly diminished growth. In contrast, boys on intermittent GCs had fewer vertebral fractures but there was a trend for more boys to loose independent ambulation.

Objective A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. Methods We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock‐in mouse were done. Results A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient‐derived myogenic cells, and a knock‐in mouse of one of the mutations (Y259C) resulted in prenatal lethality. Interpretation The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332–347.

Adrenal hypoplasia congenita (AHC) can occur due to deletions or mutations in the DAX 1 (NR0B1) gene on the X chromosome (OMIM 300200). This form of AHC is therefore predominantly seen in boys. Deletion of the DAX 1 gene can also be part of a larger contiguous deletion including the centromeric dystrophin and glycerol kinase (GK) genes. We report a girl with a de novo deletion at Xp21.2 on the maternal chromosome, including DAX1, the GK gene and 3' end of the dystrophin gene, who presented with salt losing adrenal insufficiency and moderate developmental delay, but relatively mild features of muscular dystrophy. Investigation using the androgen receptor as a marker gene identified skewed inactivation of the X chromosome. In the patient's leucocytes, the paternal X chromosome was completely inactive, but in muscle 20% of the active chromosomes were of paternal origin. Thus skewed X inactivation (deletion on the active maternal X chromosome with an inactive paternal X chromosome) is associated with AHC in a female. Variability in X inactivation between tissues may account for the pronounced salt loss and adrenal insufficiency but mild muscular dystrophy.

Between 1971 and 1989 measles encephalitis was identified in five children receiving chemotherapy for acute lymphoblastic leukaemia. Review of these and previously reported cases of measles encephalitis in immunosuppressed patients failed to identify any pathognomonic features in the history, the clinical presentation, or the results of electroencephalography or computed tomography. Detection of measles virus antigen in nasopharyngeal secretions or intrathecal synthesis of specific antibody was not possible in all instances. Early diagnosis by direct detection of viral antigen in the brain was confounded by difficulties in identifying areas of the brain suitable for biopsy. Increasing herd immunity to measles in the general population by vaccination is the only effective intervention against measles encephalitis in immunosuppressed children. Measles encephalitis must be remembered as a possible explanation of encephalopathy in the immunocompromised child: the benefits of early use of antiviral agents need to be evaluated.

Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the PLA2G6 gene. Direct gene sequencing detects ∼85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of PLA2G6 mutations. MLPA should thus be employed to detect CNVs of PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencing.

The hereditary sensory and autonomic neuropathies (HSANs) are a group of rare genetic disorders characterised by variable phenotypic expression affecting both sensory and autonomic dysfunction. Diagnosing these conditions can be a challenge as the presenting symptoms can be diverse and may overlap. This often leads to a delay in referral and diagnosis. Pain is often used by clinicians as a marker for systemic diseases. The key feature of HSAN conditions is the absence of pain perception and its consequences such as unexplained injuries. When a child presents with an unexplained injury, a diagnosis of non-accidental injuries must be considered, but rarely HSAN could be a possibility. The diagnosis of HSANs in children is both important and rare. This article aims to discuss an approach to the diagnosis and management of HSANs.

Developmental Medicine & Child NeurologyVolume 34, Issue 1 p. 80-86 Genetic Aspects of Cerebral Palsy Imelda Hughes, Imelda Hughes Department of Neurology, Royal Victoria Hospital, Belfast.Search for more papers by this authorRichard Newton, Richard Newton Department of Child and Adolescent Neurology, Royal Manchester Children's Hospital, Pendlebury, Manchester M27 1HA.Search for more papers by this author Imelda Hughes, Imelda Hughes Department of Neurology, Royal Victoria Hospital, Belfast.Search for more papers by this authorRichard Newton, Richard Newton Department of Child and Adolescent Neurology, Royal Manchester Children's Hospital, Pendlebury, Manchester M27 1HA.Search for more papers by this author First published: January 1992 https://doi.org/10.1111/j.1469-8749.1992.tb08568.xCitations: 29AboutPDF 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 Citing Literature Volume34, Issue1January 1992Pages 80-86 RelatedInformation

Mitochondrial respiratory chain disease represents one of the most common inborn errors of metabolism and is genetically heterogeneous, with biochemical defects arising from mutations in the mitochondrial genome (mtDNA) or the nuclear genome. As such, inheritance of mitochondrial respiratory chain disease can either follow dominant or recessive autosomal (Mendelian) inheritance patterns, the strictly matrilineal inheritance observed with mtDNA point mutations or X-linked inheritance. Parental consanguinity in respiratory chain disease is often assumed to infer an autosomal recessive inheritance pattern, and the analysis of mtDNA may be overlooked in the pursuit of a presumed nuclear genetic defect. We report the histochemical, biochemical and molecular genetic investigations of two patients with suspected mitochondrial disease who, despite being born to consanguineous first-cousin parents, were found to harbour well-characterised pathogenic mtDNA mutations, both of which were maternally transmitted. Our findings highlight that any diagnostic algorithm for the investigation of mitochondrial respiratory chain disease must include a full and complete analysis of the entire coding sequence of the mitochondrial genome in a clinically relevant tissue. An autosomal basis for respiratory chain disease should not be assumed in consanguineous families and that 'maternally inherited consanguineous' mitochondrial disease may thus be going undiagnosed.

Abstract Biallelic mutations in SNORD118 , encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118 . Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5′ end and 3′ extension of precursor‐U8. There was no obvious genotype–phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3′ end processing of precursor‐U8.

Abstract Objectives The objective of this study is to analyse retrospective, observational, longitudinal growth (weight, height and BMI) data in ambulatory boys aged 5–12 years with Duchenne muscular dystrophy (DMD). Background We considered glucocorticoids (GC) use, dystrophin isoforms and amenability to exon 8, 44, 45, 51 and 53 skipping drug subgroups, and the impact of growth on loss of ambulation. We analysed 598 boys, with 2604 observations. This analysis considered patients from the UK NorthStar database (2003–2020) on one of five regimes: “GC naïve”, “deflazacort daily” (DD), “deflazacort intermittent” (DI), “prednisolone daily” (PD) and “prednisolone intermittent” (PI). A random slope model was used to model the weight, height and BMI SD scores (using the UK90). Results The daily regime subgroups had significant yearly height stunting compared to the GC naïve subgroup. Notably, the average height change for the DD subgroup was 0.25 SD (95% CI − 0.30, − 0.21) less than reference values. Those with affected expression of Dp427, Dp140 and Dp71 isoforms were 0.77 (95% CI 0.3, 1.24) and 0.82 (95% CI 1.28, 0.36) SD shorter than those with Dp427 and/or Dp140 expression affected respectively. Increased weight was not associated with earlier loss of ambulation, but taller boys still ambulant between the age of 10 and 11 years were more at risk of losing ambulation. Conclusion These findings may provide further guidance to clinicians when counselling and discussing GCs commencement with patients and their carers and may represent a benchmark set of data to evaluate the effects of new generations of GC.

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by mutations in Survival motor neuron 1 (SMN1) gene, leading to reduction in survival motor neuron protein (SMN), key for motor neuron survival and function in the brainstem and spinal cord. Risdiplam is an orally administered SMN2-splicing modifier which increases production of functional SMN protein. Risdiplam was offered in the UK under early access to medicines scheme (EAMS) to SMA type 1 and 2 patients aged 2 months and older, not suitable for authorised treatments from September 2020 to December 2021.To describe the largest paediatric European real-world set of data on patients' characteristics and short-term safety for risdiplam in Great Britain through EAMS.We collated data from SMA REACH UK a national clinical and research network for all patients enrolled onto EAMS and assessed all submitted adverse events.Of the 92 patients; 78% were Type 2 SMA, mean age 10.9 years, range 0-17 years. 56 were treatment naïve, 33 previously treated; of these 25 had received nusinersen, 3 previous treatment unknown. Sixty adverse events (AEs) were reported occurring in 34 patients. The commonest were respiratory tract infections and gastrointestinal disturbance. Four life-threatening events were reported with 2 deaths and permanent cessation of risdiplam in 3 patients.Overall, 38/60 AEs were considered unrelated to risdiplam, 10/60 related to risdiplam and for 12/60 causality not specified.This study found a safety profile similar to clinical trials with no new safety concerns identified. With the restricted eligibility of onasemnogene abeparvovec and complications of nusinersen administration, EAMS allowed access or continued treatment to naïve patients or patients no longer suitable for approved medications. Collection of longitudinal data for this complex population is needed, to provide greater insights into risdiplam's role in addressing patients' needs into the future.

Journal of Inherited Metabolic DiseaseVolume 5, Issue S1 p. 27-28 Short Communication Mitochondrial myopathy with skeletal muscle cytochrome oxidase deficiency D. Stansbie, D. Stansbie Departments of Medical Biochemistry and Child Health, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XNSearch for more papers by this authorR. L. Dormer, R. L. Dormer Departments of Medical Biochemistry and Child Health, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XNSearch for more papers by this authorI. A. Hughes, I. A. Hughes Departments of Medical Biochemistry and Child Health, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XNSearch for more papers by this authorP. E. Minchom, P. E. Minchom Departments of Medical Biochemistry and Child Health, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XNSearch for more papers by this authorG. A. F. Hendry, G. A. F. Hendry Department of Biochemistry, University of Bristol, Medical School, University Walk, Bristol, BS8 1TDSearch for more papers by this authorO. T. G. Jones, O. T. G. Jones Department of Biochemistry, University of Bristol, Medical School, University Walk, Bristol, BS8 1TDSearch for more papers by this authorA. R. Cross, A. R. Cross Department of Biochemistry, University of Bristol, Medical School, University Walk, Bristol, BS8 1TDSearch for more papers by this authorH. S. A. Sherratt, H. S. A. Sherratt Departments of Pharmacological Sciences and Neurology, The University of Newcastle upon Tyne, The Medical School, Newcastle upon Type, NE1 7RUSearch for more papers by this authorD. M. Turnbull, D. M. Turnbull Departments of Pharmacological Sciences and Neurology, The University of Newcastle upon Tyne, The Medical School, Newcastle upon Type, NE1 7RUSearch for more papers by this authorM. A. Johnson, M. A. Johnson Departments of Pharmacological Sciences and Neurology, The University of Newcastle upon Tyne, The Medical School, Newcastle upon Type, NE1 7RUSearch for more papers by this author D. Stansbie, D. Stansbie Departments of Medical Biochemistry and Child Health, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XNSearch for more papers by this authorR. L. Dormer, R. L. Dormer Departments of Medical Biochemistry and Child Health, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XNSearch for more papers by this authorI. A. Hughes, I. A. Hughes Departments of Medical Biochemistry and Child Health, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XNSearch for more papers by this authorP. E. Minchom, P. E. Minchom Departments of Medical Biochemistry and Child Health, Welsh National School of Medicine, Heath Park, Cardiff, CF4 4XNSearch for more papers by this authorG. A. F. Hendry, G. A. F. Hendry Department of Biochemistry, University of Bristol, Medical School, University Walk, Bristol, BS8 1TDSearch for more papers by this authorO. T. G. Jones, O. T. G. Jones Department of Biochemistry, University of Bristol, Medical School, University Walk, Bristol, BS8 1TDSearch for more papers by this authorA. R. Cross, A. R. Cross Department of Biochemistry, University of Bristol, Medical School, University Walk, Bristol, BS8 1TDSearch for more papers by this authorH. S. A. Sherratt, H. S. A. Sherratt Departments of Pharmacological Sciences and Neurology, The University of Newcastle upon Tyne, The Medical School, Newcastle upon Type, NE1 7RUSearch for more papers by this authorD. M. Turnbull, D. M. Turnbull Departments of Pharmacological Sciences and Neurology, The University of Newcastle upon Tyne, The Medical School, Newcastle upon Type, NE1 7RUSearch for more papers by this authorM. A. Johnson, M. A. Johnson Departments of Pharmacological Sciences and Neurology, The University of Newcastle upon Tyne, The Medical School, Newcastle upon Type, NE1 7RUSearch for more papers by this author First published: 01 March 1982 https://doi.org/10.1007/BF01799812Citations: 24AboutPDF 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 No abstract is available for this article.Citing Literature Volume5, IssueS1March 1982Pages 27-28 RelatedInformation

SLC5A7 encodes the presynaptic sodium-dependant high-affinity choline transporter 1 (CHT), which uptakes choline to the presynaptic nerve terminal following the breakdown of acetylcholine by the acetylcholinesterase within the synaptic cleft. We report 5 patients from three consanguineous families with congenital myasthenic syndrome type 20 caused by novel mutations in SLC5A7. The individuals from family 1 and 2 were homozygous for c.320G>A; (p.Arg107His) and c.886G>A (p.Ala296Thr), respectively, and their phenotype was characterised by recurrent apnoeic attacks early after birth and learning and speech difficulties in childhood. Individuals from family 3 were homozygous for c.1240T>A (p.Tyr414Asn) and suffered from more severe central and peripheral manifestations with lack of spontaneous movements and respiratory drive and overall minimal response to external stimuli. All individuals tested showed neurophysiological defects compatible with impaired neuromuscular transmission. Combined treatment with cholinesterase inhibitors and β2-adrenergic agonists was beneficial in patients from family 1 and 2. Affected individuals from family 3 died from complications directly related to their underlying genetic condition. This report provides three novel pathogenic variants in SLC5A7 and highlights the variability in the clinical phenotype, severity and prognosis of this syndrome.

Twenty participants from 9 countries, Australia, Denmark, France, Germany, Italy, The Netherlands, Switzerland, UK and the USA, met in Hoofddorp, the Netherlands from 1 to 3 March 2019. This group included adult and paediatric neurologists, neurophysiologists and a patient representative from the European Myasthenia Gravis Association. The goals were to develop international consensus on the diagnosis and management of juvenile myasthenia gravis. A pre-workshop questionnaire (see supplementary material) was circulated to all participants to gather information on current diagnostic and management practice across the centres.

Acute disseminated encephalomyelitis associated with optic neuritis and marked peri-papillary hemorrhages

(The American Journal of Human Genetics 103, 666–678; November 1, 2018) In the version of this article originally published online, Qinghe Xing’s name was misspelled as Qinghe Xin. Also, Azita Sadeghpour, Erica E. Davis, and Nicholas Katsanis (all at Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA) and the Task Force for Neonatal Genomics were omitted from the author list. The members of the Task Force for Neonatal Genomics are as follows: Alexander Allori, Misha Angrist, Patricia Ashley, Margarita Bidegain, Brita Boyd, Eileen Chambers, Heidi Cope, C. Michael Cotten, Theresa Curington, Erica E. Davis, Sarah Ellestad, Kimberley Fisher, Amanda French, William Gallentine, Ronald Goldberg, Kevin Hill, Sujay Kansagra, Nicholas Katsanis, Sara Katsanis, Joanne Kurtzberg, Jeffrey Marcus, Marie McDonald, Mohammed Mikati, Stephen Miller, Amy Murtha, Yezmin Perilla, Carolyn Pizoli, Todd Purves, Sherry Ross, Azita Sadeghpour, Edward Smith, and John Wiener. The authors apologize for these omissions. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and DyskinesiasHelbig et al.The American Journal of Human GeneticsOctober 18, 2018In BriefDevelopmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Full-Text PDF Open Archive

Aim: Compare efficacies of deflazacort and prednisone/prednisolone in providing clinically meaningful delays in loss of physical milestones in patients with nonsense mutation Duchenne muscular dystrophy. Materials & methods: Placebo data from Phase IIb (ClinicalTrials.gov Identifier: NCT00592553) and ACT DMD (ClinicalTrials.gov Identifier: NCT01826487) ataluren nonsense mutation Duchenne muscular dystrophy clinical trials were retrospectively combined in meta-analyses (intent-to-treat population; for change from baseline to week 48 in 6-min walk distance [6MWD] and timed function tests). Results: Significant improvements in change in 6-min walk distance with deflazacort versus prednisone/prednisolone (least-squares mean difference 39.54 m [95% CI: 13.799, 65.286; p = 0.0026]). Significant and clinically meaningful improvements in 4-stair climb and 4-stair descend for deflazacort versus prednisone/prednisolone. Conclusion: Deflazacort provides clinically meaningful delays in loss of physical milestones over 48 weeks compared with prednisone/prednisolone for patients with nonsense mutation Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a pediatric neuromuscular disorder caused by mutations in the dystrophin gene. Genotype-phenotype associations have been examined in glucocorticoid-treated boys, but there are few data on the young glucocorticoid-naive DMD population. A sample of young glucocorticoid-naive DMD boys is described, and genotype-phenotype associations are investigated.Screening and baseline data were collected for all the participants in the Finding the Optimum Corticosteroid Regime for Duchenne Muscular Dystrophy (FOR-DMD) study, an international, multicenter, randomized, double-blind, clinical trial comparing 3 glucocorticoid regimens in glucocorticoid-naive, genetically confirmed boys with DMD between 4 and <8 years of age.One hundred ninety-six boys were recruited. The mean ± SD age at randomization was 5.8 ± 1.0 years. The predominant mutation type was out-of-frame deletions (67.4%, 130 of 193), of which 68.5% (89 of 130) were amenable to exon skipping. The most frequent mutations were deletions amenable to exon 51 skipping (13.0%, 25 of 193). Stop codon mutations accounted for 10.4% (20 of 193). The mean age at first parental concerns was 29.8 ± 18.7 months; the mean age at genetic diagnosis was 53.9 ± 21.9 months; and the mean diagnostic delay was 25.9 ± 18.2 months. The mean diagnostic delay for boys diagnosed after an incidental finding of isolated hyperCKemia (n = 19) was 6.4 ± 7.4 months. The mean ages at independent walking and talking in sentences were 17.1 ± 4.2 and 29.0 ± 10.7 months, respectively. Median height percentiles were below the 25th percentile regardless of age group. No genotype-phenotype associations were identified expect for boys with exon 8 skippable deletions, who had better performance on time to walk/run 10 m (p = 0.02) compared to boys with deletions not amenable to skipping.This study describes clinical and genetic characteristics of a sample of young glucocorticoid-naive boys with DMD. A low threshold for creatine kinase testing can lead to an earlier diagnosis. Motor and speech delays were common presenting symptoms. The effects of low pretreatment height on growth and adult height require further study. These findings may promote earlier recognition of DMD and inform study design for future clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01603407.

<h2>Abstract</h2> Knowledge of health related quality of life (HRQOL) in the immediate phase following DMD diagnosis has not been well-characterized. It is important to understand HRQOL early in disease for both clinical care and studies of treatment. The relationship between parent-proxy and child self-report HRQOL and their associations with medical, psycho-social and behavioral symptoms deserve study. In this study HRQOL was measured using the PedsQL inventory in parent/caregiver and corticosteroid-naïve boys (ages 4 to 7 years) participating in the FOR-DMD study. Agreement between the parent-proxy report and the boys' self-report HRQOL was measured using intraclass correlation coefficients (ICCs). Factors associated with HRQOL, including standardized psychosocial and behavioral measures in this cross-sectional sample, were explored using correlations. The results showed that the level of agreement between 70 dyads of child self-report and parent-proxy ratings of HRQOL was poor for the generic PedsQL total score (ICC=0.48, 95% CI (0.23, 0.66)) and its subscale scores, and was similarly low for the neuromuscular disease module (ICC=0.24, 95% CI (0.00, 0.45)). Parents rated their child's HRQOL as poorer than the children rated themselves in all scales. Psychosocial outcome measures were more highly associated with HRQOL measures than disease severity or patient demographic variables. In the early phases of DMD, child and parent-proxy HRQOL ratings were discordant. In early DMD, psychosocial and behavioral aspects appear to be more relevant to HRQOL than disease severity factors.

Retrospective review of referrals to the National-Multidisciplinary-Team (NMDT) in England (&amp; Wales), and of the clinical records of SMAtype1 patients included for Zolgensma® therapy in the UK. Data was available for 42 patients: 13, 12, 10, 6, 1 from Evelina-London, Sheffield, Bristol, Manchester and Belfast centres respectively. Patients’ age ranged from 2-months to 46-months and weights from 4.44kg to 13.5kg. Post-Zolgensma-infusion monitoring: Most patients had asymptomatic thrombocytopaenia in week-1, resolving by week-2. No thrombotic microangiopathy was reported. Majority developed transient transaminitis with mild/moderate elevation of AST/ALT. Some had more severe/prolonged transaminitis – Liver ultrasound, coagulation-studies and clinical examination remained normal: 11 (weight&gt;7.5kg) had ALT-peaks of &gt;100 IU/L; 22 (15/22 weighed &gt;7.5kg) had AST-peaks of &gt;100 IU/L – good response seen to doubling Prednisolone, where indicated. Echocardiograms remained normal in patients with elevated Troponin-I levels; 4 had levels &gt;100ng/l, prednisolone doubled in one, with good response. 13/42 needed doubling of Prednisolone; 12/13 had weight &gt;7.5kg. CHOP-INTEND scores post gene-therapy were available for 22/42. Scores improved in all patients except one (difficult assessment). Improvement ranged from 2-24 points. Conclusion All patients tolerated the Zolgensma®-therapy well and have recovered well from any transient issues. No persistent complications from gene-therapy or steroid-cover were reported.

Nat. Genet.; 10.1038/ng.3661; corrected online 19 September 2016 In the version of this article initially published, the names of authors Geraldine Aubert, Gerardine Quaghebeur and Yoann Rose were misspelled. The error has been corrected in the print, HTML and PDF versions of the article.

Disorders of central and peripheral nervous system should be considered in floppy infants with ventilator dependence. Workup for neuromuscular disorders should be undertaken in infants with hypotonia, weakness, contractures, feeding difficulties, or failed attempts at extubation. We present the case of a preterm infant with hypotonia and ventilator dependence where despite a positive result, further investigations were undertaken because of lack of clinical correlation. The infant had a rare combination of 2 neuromuscular conditions: X-linked myotubular myopathy and Duchenne muscular dystrophy. One was the reason for immediate clinical manifestation and the other influenced the prognosis and decision-making in determining reorientation of care. This case demonstrates the value of interpretation of a positive result that did not explain the clinical picture and warranted consideration of further diagnosis. This case also emphasizes the importance of discussions with family about the prognosis of 2 conditions that influenced decision making.

Sir, Idiopathic orbital inflammatory syndrome (IOIS) is a heterogeneous group of disorders characterized by orbital inflammation without any identifiable cause.1, 2 It commonly affects the EOMs, particularly the lateral rectus,3 lacrimal gland,4 and cavernous sinus.5 Classically it presents with unilateral pain, swelling, proptosis, diplopia, and reduced vision. We report the first case of bilateral IOIS involving all EOMs with an unusually grossly elevated creatinine kinase (CK) level and with a favourable response to steroids.

The original article to which this Erratum refers was published in Human Mutation 33(6):981–988 (DOI 10.1002/humu.22056). The authors noted some errors in the Supporting Information for this article: In Supp. Table S1b, it is family 42 instead of 41 that has previously been published by Zhou and in family 42, the previously published mutation c.325C>T; p.Arg109Trp was found in addition to the three mutations that we have reported. These changes are in trans. There is also a nomenclature error in (misspelling of) one mutation in patient 48: it is c.3196delT; p.Ser1066fs. The authors regret the errors.

Objective: Utrophin modulation is a putative therapeutic approach for Duchenne muscular dystrophy (DMD) regardless of the underlying dystrophin mutation. Ezutromid is a small-molecule utrophin modulator. Phase 1 trials with ezutromid's first formulation F2 revealed substantially lower exposure in DMD boys than healthy volunteers. A further trial using slightly modified F2 (F3) with a balanced diet enabled most DMD patients to achieve drug levels estimated to induce ≥30% increases in utrophin protein from in vitro data. This Phase 1 trial investigated whether a new ezutromid formulation (F6), given with a balanced diet, offers further PK improvements. Methods: The dose-escalating open-label trial enrolled eight DMD boys, 5–9 years old, and comprised three 7-day treatment periods and ≥7 day washouts Results: On day 7, geometric mean AUC (0–24) for 0.25 g bid and 0.5 g bid demonstrated near dose proportionality (528.6 ng h/mL, n=7; 1015 ng h/mL, n=5, respectively). AUC (0–24) for 1.0 g bid was 3855 ng h/mL (n=4). One patient's data were unevaluable due to protocol deviations. One patient withdrew after Period 1 due to clinical need to start a restricted medication. At 1.0 g bid, all evaluable patients achieved drug levels above those producing a 50% increase in utrophin in vitro. Final day maximum mean plasma concentration was around six times that observed previously with 2.5 g bid F3. F6 thus expands the range of blood concentrations attainable in DMD patients. F6 was generally safe and well tolerated. One patient withdrew at the 0.25 g dose, having developed conjugated hyperbilirubinaemia, which resolved within 10 days of stopping ezutromid. Another withdrew due to abdominal pain. Conclusion: Ezutromid's Phase 1 programme employed multiple approaches to address early PK issues. Potential for low-fat diets to affect absorption was addressed by diet modification; additionally, reformulation markedly increased exposure. A Phase 2 trial is now evaluating and comparing the F3 and F6 formulations of ezutromid, each with a balanced diet.

We previously showed that treatment by nusinersen in spinal muscular atrophy (SMA) type 1 patients older than 7 months may have comparable effects to those observed in the younger population, but the response to the treatment is highly variable. In our cohort, median improvement in the modified motor milestones Hammersmith infant neurological exam (HINE-2) score was 1.5 points after 6 months of treatment and 2 points after 10 months. We still lack long-term clinical data and predictive factors for clinical benefit in this cohort. We present 14-months' follow-up data (corresponding to 7 injections of nusinersen) of 40 patients with SMA type 1 (21 boys and 19 girls) treated by nusinersen at the median age of 22 months (8.3-113). Patients' data are recorded in an ERB-approved registry (NCT03339830) at the following time points – before treatment, at two months of treatment (end of the loading dose) and at each injection every 4 months subsequently. Our analysis will focus on the level of respiratory and nutritional support, and on the motor function assessed by the HINE-2 evaluation. We will test the correlation between the HINE-2 score changes after 14 months of treatment and the scores before treatment, after two and after six months of treatment. We will also study the influence of the age at the beginning of the treatment and of the SMN2 copies status on the Hine-2 changes at month 14. The objective of this work is to present longitudinal data and to pre-identify predictive factors for the 14 months clinical benefit of nusinersen treatment in SMA type 1 patients older than 7 months.

guidelines and best practices for paper use, establishing a vendor code of ethics, and engaging our colleagues and other stakeholders in our efforts.

Objective To describe age and time at key stages in the Duchenne muscular dystrophy (DMD) prediagnosis pathway at selected centres to identify opportunities for service improvement. Design A multicentre retrospective national audit. Setting Nine tertiary neuromuscular centres across the UK and Ireland. A prior single-centre UK audit of 20 patients with no DMD family history provided benchmark criteria. Patients Patients with a definitive diagnosis of DMD documented within 3 years prior to December 2018 (n=122). Main outcome measures Mean age (months) at four key stages in the DMD diagnostic pathway and mean time (months) of presentational and diagnostic delay, and time from first reported symptoms to definitive diagnosis. Type of symptoms was also recorded. Results Overall, mean age at definitive diagnosis, age at first engagement with healthcare professional (HCP) and age at first reported symptoms were 53.9±29.7, 49.9±28.9 and 36.4±26.8 months, respectively. The presentational delay and time to diagnosis were 21.1 (±21.1) and 4.6 (±7.9) months, respectively. The mean time from first reported symptoms to definitive diagnosis was 24.2±20.9. The percentages of patients with motor and/or non-motor symptoms recorded were 88% (n=106/121) and 47% (n=57/121), respectively. Conclusions Majority of data mirrored the benchmark audit. However, while the time to diagnosis was shorter, a presentational delay was observed. Failure to recognise early symptoms of DMD could be a contributing factor and represents an unmet need in the diagnosis pathway. Methods determining how to improve this need to be explored.

April 21, 2015April 6, 2015Free AccessUtrophin modulators to treat Duchenne muscular dystrophy (DMD): Phase 1b Clinical Trial Results of SMT C1100 (P2.006)Jon Tinsley, Francesco Muntoni, Stefan Spinty, Helen Roper, Imelda Hughes, Valeria Ricotti, Alison Bracchi, Bina Tejura, David Roblin, Gary Layton, and Kay DaviesAuthors Info & AffiliationsApril 6, 2015 issue84 (14_supplement)https://doi.org/10.1212/WNL.84.14_supplement.P2.006 Letters to the Editor

The continual expression of utrophin protein by pharmacological maintenance of utrophin transcription in dystrophin deficient muscle fibres is a potential disease modifying treatment for Duchenne muscular dystrophy (DMD). SMT C1100 is a small molecule utrophin modulator demonstrating significant benefit on the muscular dystrophy in the dystrophin deficient mdx mouse. Assessment of the in vitro and in vivo pharmacology plus the clean toxicology and safety data from the pre-clinical work led to the nomination of SMT C1100 as the first candidate for evaluation in DMD clinical trials. We previously reported that SMT C1100 successfully completed a Phase 1 healthy volunteer trial in which an oral paediatric formulation was deemed safe and well tolerated with plasma levels above those determined to be effective to modulate utrophin levels ex-vivo in DMD myoblasts and dystrophin deficient mdx mice. The first DMD paediatric patient trials of SMT C1100 started with an open-label, single and multiple oral dose finding Phase 1b study in DMD boys earlier this year. The purpose of the study was to determine whether increasing doses of SMT C1100 were safe, well tolerated and to understand the pharmacokinetic properties in patients with DMD. The boys were studied in 3 groups (Groups A to C), with each group consisting of 4 patients aged between 5 to 11 years. The doses for Groups A to C were administered in an escalating manner after safety review for each dose group. We will present the summary data from this trial.

In DMD, skeletal muscle is lost due to an inability to produce dystrophin. During foetal muscle development utrophin takes the functional role of dystrophin. Continuous muscle expression of utrophin could functionally replace dystrophin and potentially overcome the dystrophin deficit in DMD. In dystrophic animal studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. Data from a recently completed Phase 1b study in DMD subjects suggest that diet is able to influence absorption of SMT C1100. This study aims to investigate this further. Twelve boys with DMD were enrolled into this Phase 1b placebo-controlled study of single and multiple oral doses of SMT C1100. Boys were randomly allocated to the three treatment sequence groups. Each patient received both doses of SMT C1100 (1250 mg twice daily (BID) and 2500 mg BID) in a dose escalating fashion, with placebo in the other study period. A minimum two week washout was included between each Treatment Period to allow for study drug washout and safety review. One of the secondary objectives of this study was to evaluate reductions in creatine phosphokinase (CPK). With 12 patients this study had 80% power of demonstrating a statistically significant reduction in CPK compared to placebo with a two-sided, 5% confidence level, if SMT C1100 reduced CPK 30% more than placebo. Data from this trial will be presented and will assist in designing future Phase 2 studies that will include functional and biomarker endpoints.

Objective: The poor cognitive, psychiatric, and social outcome to infantile spasms is well described.The term 'epileptic encephalopathy' is used to describe the process whereby high rates of epileptic activity, clinical or subclinical, appear to cause temporary or permanent loss of skills.The mechanism for this process of cognitive deterioration is unknown.We hypothesized that decreased efficacy for retrieving formed memories is a predominating feature.Method: Non-invasive event-related potentials to auditory stimuli were applied to infants with newly diagnosed cryptogenic West syndrome and healthy infants.Results: We demonstrated that patients are able to form memories to presented stimuli, as assessed by the mismatch negativity (MMN); MMN amplitude was increased in patients (Mann-Whitney p=0.035).The most striking feature of information processing in patients' cortical networks is the inability to suppress ongoing activity.Frequency spectrum analysis reveals that this is due a low damping capability of the network compared with healthy comparisons (F=7.735,p=0.009).This results in a network with a lower resonance frequency (F=7.169,p=0.011) and a higher power output at its resonance frequency (F=4.56,p=0.039) in West syndrome.Conclusion: Taken together, these features are consistent with a qualitative change in connection topology in West syndrome, rather than merely a quantitative difference from controls.The most likely explanation is an augmentation of the probability of recurrent intracortical excitation

XLMTM is a rare, inherited centronuclear myopathy caused by pathogenic variants in the MTM1 gene resulting in severe hypotonia, weakness, respiratory failure, and early mortality. We examined disease burden and unmet medical need in patients with XLMTM from the RECENSUS study. RECENSUS is an ongoing, multicenter, retrospective chart review of male patients with XLMTM. Data reported here were collected from Sept. 10, 2014 to Jun. 16, 2016 from 6 international sites. Data collection was standardized across sites, performed by trained data extractors, and included demographics, diagnosis, gestation, pulmonary function, hospitalizations, surgeries, motor function, and more. A total of 112 patients were included in the analysis. The most recent age recorded was ≤18 months for 40 patients and >18 months for 72 patients. Mean (SD) age at diagnosis was 3.7 (3.7) months and 54.3 (77.1) months, respectively. From 1996–2000 (the first 4 years after discovery of MTM1) to 2011–2014, average age at genetic diagnosis declined from 35.1 months to 4.4 months. Overall mortality was 44% (64% of patients ≤18 months; 32% of patients >18 months). Premature delivery (<36 weeks) occurred in 31% of births at a mean 32.4 (2.3) weeks' gestation. Respiratory support at birth was nearly universal (97% ≤ 18 months; 86% > 18 months). In the first 24 hours after birth, 60% required ventilator support (68% ≤ 18 months; 56% > 18 months). Thereafter, 48% were ventilator-dependent 24 hours per day (58% ≤ 18 months; 43% > 18 months). Patients were hospitalized a mean 35% of the first year of life and underwent a mean 3.7 surgeries in that first year. While motor milestone data were limited, motor development was generally delayed. RECENSUS is one of the largest cohorts of XLMTM patients and provides a unique opportunity to examine the disease's natural history. Findings show that XLMTM is associated with high mortality, disease burden, and healthcare utilization.

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

(The American Journal of Human Genetics 103, 666–678; November 1, 2018) In the version of this article originally published online, Qinghe Xing's name was misspelled as Qinghe Xin. Also, Azita Sadeghpour, Erica E. Davis, and Nicholas Katsanis (all at Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA) and the Task Force for Neonatal Genomics were omitted from the author list. The members of the Task Force for Neonatal Genomics are as follows: Alexander Allori, Misha Angrist, Patricia Ashley, Margarita Bidegain, Brita Boyd, Eileen Chambers, Heidi Cope, C. Michael Cotten, Theresa Curington, Erica E. Davis, Sarah Ellestad, Kimberley Fisher, Amanda French, William Gallentine, Ronald Goldberg, Kevin Hill, Sujay Kansagra, Nicholas Katsanis, Sara Katsanis, Joanne Kurtzberg, Jeffrey Marcus, Marie McDonald, Mohammed Mikati, Stephen Miller, Amy Murtha, Yezmin Perilla, Carolyn Pizoli, Todd Purves, Sherry Ross, Azita Sadeghpour, Edward Smith, and John Wiener. The authors apologize for these omissions.

XLMTM is a rare, inherited myopathy caused by mutations in the MTM1 gene resulting in severe hypotonia, weakness, respiratory failure, and early mortality. RECENSUS is an ongoing, international, multicenter, retrospective medical record review of male patients with XLMTM. The primary objective is to characterize disease manifestations and recorded medical management. In the current analysis of 136 patients, we describe mortality and respiratory support (RS). Data are described for the total cohort and the group that most closely matches the recently initiated ASPIRO gene therapy clinical trial (≤5 years old and RS at birth). Mortality among boys with genetically confirmed XLMTM was 44% overall, but 60% in patients ≤5 years old who required RS at birth. As a medical decision in line with perceived futility of treatment, life-sustaining therapy was withheld in 25/60 (42%) of patients with reported data. Respiratory failure was highly prevalent and was the cause of patient death in 23/37 (62%) of cases with documented information. Most patients (84%) required some form of RS at birth (54% received invasive RS, 24% non-invasive RS and 6% supplemental oxygen); of these, median time to death in those ≤5 years old was 2.2 years vs. 30.2 years in those >5 years old. Tracheostomies were placed at a mean age of 12.5 months overall and by 5.2 months in patients ≤5 years old who required RS at birth. Overall, tracheostomy-free survival decreased rapidly over time, and only 21% of patients who remained alive were tracheostomy-free by 4 years of age. Ventilator dependence >16 h/day was reported in 67/132 (51%) patients overall and 44/77 (57%) patients ≤5 years old who required RS at birth. The RECENSUS data show high mortality in young XLMTM patients despite RS and substantial disease burden (i.e. tracheostomy and ventilator use) in those who survive. These retrospective data support the significant unmet need in XLMTM patients ≤5 years of age, who are now the initial focus of the ASPIRO gene therapy trial.