Hubert Kwieciński

Treatment options for patients with secondary progressive multiple sclerosis are few. Encouraging results in open-label studies prompted this randomised trial of mitoxantrone in such patients.194 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis were assigned placebo or mitoxantrone (5 mg/m(2) [exploratory group] or 12 mg/m(2) intravenously) every 3 months for 24 months. Clinical assessments were made every 3 months for 24 months. The primary endpoint was a multivariate analysis of five clinical measures. Analyses of mitoxantrone 12 mg/m(2) versus placebo were based on patients who received at least one dose and returned for at least one assessment of efficacy.Of 194 patients enrolled, 188 were able to be assessed at 24 months. There were no drug-related serious adverse events or evidence of clinically significant cardiac dysfunction. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome (difference 0.30 [95% CI 0.17-0.44]; p<0.0001) and the preplanned univariate analyses of those measures: change in expanded disability status scale (0.24 [0.04-0.44]; p=0.0194), change in ambulation index (0.21 [0.02-0.40]; p=0.0306), adjusted total number of treated relapses (0.38 [0.18-0.59]; p=0.0002), time to first treated relapse (0.44 [0.20-0.69]; p=0.0004), and change in standardised neurological status (0.23 [0.03-0.43]; p=0.0268).Mitoxantrone 12 mg/m(2) was generally well tolerated and reduced progression of disability and clinical exacerbations. Further studies are needed to identify the patients with these forms of multiple sclerosis who are most likely to respond to therapy, the best treatment protocols, and the frequency of long-term drug-related side-effects.

Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K(+) channel Kir2.1. In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype. All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function. In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%. LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. While arrhythmias were common, none of our subjects suffered sudden cardiac death. To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K(+), induced Na(+)/Ca(2+) exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias. These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome.

This article represents the recommendations for the management of spontaneous intracerebral haemorrhage of the European Stroke Initiative (EUSI). These recommendations are endorsed by the 3 European societies which are represented in the EUSI: the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies.

Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease.To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease.The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations.Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide.Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.

Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by spontaneous hyperkinetic attacks that are precipitated by alcohol, coffee, stress and fatigue. We report mutations in the myofibrillogenesis regulator 1 (MR-1) gene causing PNKD in 50 individuals from eight families. The mutations cause changes (Ala to Val) in the N-terminal region of two MR-1 isoforms. The MR-1L isoform is specifically expressed in brain and is localized to the cell membrane while the MR-1S isoform is ubiquitously expressed and shows diffuse cytoplasmic and nuclear localization. Bioinformatic analysis reveals that the MR-1 gene is homologous to the hydroxyacylglutathione hydrolase (HAGH) gene. HAGH functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a by-product of oxidative stress. Our results suggest a mechanism whereby alcohol, coffee and stress may act as precipitants of attacks in PNKD. Stress response pathways will be important areas for elucidation of episodic disease genetics where stress is a common precipitant of many common disorders like epilepsy, migraine and cardiac arrhythmias.

<b>Background: </b> Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by episodic hyperkinetic movement attacks. We have recently identified mutations in the <i>MR-1</i> gene causing familial PNKD. <b>Methods: </b> We reviewed the clinical features of 14 kindreds with familial dyskinesia that was not clearly induced by movement or during sleep. Of these 14 kindreds, 8 had <i>MR-1</i> mutations and 6 did not. <b>Results: </b> Patients with PNKD with <i>MR-1</i> mutations had their attack onset in youth (infancy and early childhood). Typical attacks consisted of a mixture of chorea and dystonia in the limbs, face, and trunk, and typical attack duration lasted from 10 minutes to 1 hour. Caffeine, alcohol, and emotional stress were prominent precipitants. Attacks had a favorable response to benzodiazepines, such as clonazepam and diazepam. Attacks in families without <i>MR-1</i> mutations were more variable in their age at onset, precipitants, clinical features, and response to medications. Several were induced by persistent exercise. <b>Conclusions: </b> Paroxysmal nonkinesigenic dyskinesia (PNKD) should be strictly defined based on age at onset and ability to precipitate attacks with caffeine and alcohol. Patients with this clinical presentation (which is similar to the phenotype initially reported by Mount and Reback) are likely to harbor myofibrillogenesis regulator 1 (<i>MR-1</i>) gene mutations. Other “PNKD-like” families exist, but atypical features suggests that these subjects are clinically distinct from PNKD and do not have <i>MR-1</i> mutations. Some may represent paroxysmal exertional dyskinesia.

<h3>Abstract</h3> <h3>Background:</h3> Delayed-release dimethyl fumarate (DMF), indicated for the treatment of patients with relapsing-remitting multiple sclerosis (MS), is a disease-modifying therapy with potential immunomodulatory and neuroprotective effects. In clinical trials, DMF was associated with reduced white blood cell and absolute lymphocyte counts. Current US prescribing information recommends obtaining a complete blood count, including absolute lymphocyte count (ALC), before initiating and during DMF treatment. <h3>Methods:</h3> We conducted an integrated analysis of phase 2b/3/long-term extension studies of DMF in MS (N = 2,470) to characterize ALC profiles. <h3>Results:</h3> Mean ALCs decreased by 30% during the first year and then plateaued, remaining above the lower limit of normal (LLN). Among patients treated ≥6 months (N = 2,099), 2.2% experienced ALCs &lt;500 mm³ persisting ≥6 months. ALCs remained ≥LLN in 84% and 76% of patients during the first 6 and 12 months, respectively; of these, 0.1% and 0%, respectively, developed ALCs &lt;500 mm³ persisting ≥6 months at any time. Evidence of ALC improvement following DMF discontinuation was observed. DMF efficacy was not substantially different in patients with and without lymphopenia. <h3>Conclusion:</h3> Lymphocyte monitoring provides effective means for early identification of patients at risk for developing severe, prolonged lymphopenia.

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin‐containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of ‘myopathic’ changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM‐type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short‐term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin‐positive tau‐, α‐synuclein‐, polyglutamine repeat‐negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.

Abstract Clinical and electrophysiological data have outlined a spectrum of similar yet distinct periodic paralyses, including potassium‐sensitive (hyperkalemic periodic paralysis [HYPP]) and temperature‐sensitive (paramyotonia congenita [PC]) forms. Recent work has revealed that these disorders result from allelic defects in the x‐subunit of the adult, human skeletal muscle sodium channel. We report an additional mutation, a leucine ‐ arginine substirution in the ss segment of domain 4 (L1433R), that results in the PC phenotype. Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each. Characterization of these mutartions and phenotypic variations in such familes will contribute to the understanding of sodium channel structure and function relationships, as well as channel malfunction in the periodic paralyses.

The effects of disopyramide, phenytoin, mexiletine, and tocainide were compared in 30 patients with myotonic disorders. The severity of myotonia was assessed by clinical and electromyographic criteria at the end of each treatment phase lasting four weeks. Mexiletine (MXT) and tocainide (TCD) were found to be the most potent antimyotonic agents. The antimyotonic efficacy of MXT and TCD is explained by their fast-blocking effect on voltage-dependent sodium channels in the muscle membrane. The benefits of myotonia control with pharmacological agents must be weight against the risk of therapy in the individual patient. Because of the risks of hematologic problems, TCD is not recommended by us for the treatment of myotonia.

Background and purpose: Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We investigated the expression of MMPs and tissue inhibitors of matrix metalloproteinases (TIMPs) in serum and cerebrospinal fluid (CSF) correlating the results with age, disease duration and the clinical course. Methods: The material consisted of 30 ALS patients and 15 age‐matched healthy controls. ELISA method to determine the expression of MT‐MMP‐1, MMP‐2, MMP‐9, TIMP‐1 and TIMP‐2 in serum and CSF was used. MMP‐2 and MMP‐9 by zymography was also tested. Results: In serum MT‐MMP‐1, MMP‐2, MMP‐9 and TIMP‐1 expression was increased, especially in mild ALS cases. TIMP‐2 values were normal. In CSF MT‐MMP‐1, MMP‐2 and TIMP‐1 level was either increased or normal, that of MMP‐9 was decreased. TIMP‐2 did not change. No correlation of MMPs and TIMP‐1 expression in serum and CSF and the age of the patients was found. A correlation was observed between MMPs and TIMPs and disease duration. Conclusions: Increased level of MMPs and TIMP‐1 of ALS patients may reflect the degeneration process of motor neurons and skeletal muscles and/or is associated with tissues remodeling. The low level of MMP‐9 in CSF may result from impaired balance between MMP‐9 and TIMP‐1 and/or its increased intrathecal degradation and physical clearance. Although the role of changed MMPs/TIMPs level in the pathogenesis of ALS is not clear their analysis in serum may be used as prognostic factor and a potential marker for monitoring treatment effects.

A median safinamide (SAF) dose of 70 mg/day (range 40 to 90 mg/day) increased the percentage of parkinsonian patients improving their motor scores by ≥30% from baseline (responders) after 3 months from 21.4% (placebo) to 37.5% (p &lt; 0.05, calculated by logistic regression analysis). In a subgroup of 101 patients under stable treatment with a single dopamine agonist, addition of SAF magnified the response (47.1% responders, mean 4.7-point motor score decrease; <i>p</i> ≥ 0.05). These results suggest that doses of SAF exerting ion channel block and glutamate release inhibition add to its symptomatic effect and warrant exploration of higher doses.

Myotonia, defined as delayed relaxation of muscle after contraction, is seen in a group of genetic disorders that includes autosomal dominant myotonia congenita (Thomsen9s disease) and autosomal recessive myotonia congenita (Becker9s disease).Both disorders are characterized electrophysiologically by increased excitability of muscle fibers, reflected in clinical myotonia. These diseases are similar except that transient weakness is seen in patients with Becker9s, but not Thomsen9s disease. Becker9s and Thomsen9s diseases are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). Genetic screening of a panel of 18 consecutive myotonia congenita (MC) probands for mutation in CLCN1 revealed that a novel Gln-68-Stop nonsense mutation predicts premature truncation of the chloride channel protein. Four previously reported mutations, Arg-894-stop, Arg-338-Gln, Gly-230-Glu, and del 1437-1450, were also noted in our sample set. The Arg-338-Gln and Gly-230-Glu mutations were found in patients with different phenotypes from those of previous reports. Further study of the Arg-338-Gln and Gly-230-Glu alleles may shed light on variable modes of transmission (dominant versus recessive) in different families. Physiologic study of these mutations may lead to better understanding of the pathophysiology of myotonia in these patients and of voltage-gated chloride channel structure/function relationships in skeletal muscles. <b>NEUROLOGY 1996;47: </b> 993-998

<b>Background: </b> Previous studies have examined the role of <i>APOE</i> variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the <i>APOE</i> epsilon polymorphism. <b>Methods: </b> Studies of MS and <i>APOE</i> were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of <i>APOE</i> epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of <i>APOE</i> epsilon genotype on disease severity. <b>Results: </b> A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of ε2 or ε4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96–1.34 and OR 0.89, 95% CI 0.78–1.01). Results obtained from analyses of <i>APOE</i> genotypes in 1,279 MS families were also negative (<i>p</i> = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that <i>APOE</i> epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. <b>Conclusion: </b> Overall, these findings do not support a role for <i>APOE</i> in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

The authors analyzed the <i>CLCN2</i> chloride channel gene in 112 probands with familial epilepsy, detecting 18 common polymorphisms. Two brothers with generalized epilepsy and their asymptomatic father, and a father and son with focal epilepsy carried variants of possible functional significance that were not found in 192 controls. The authors conclude that <i>CLCN2</i> mutations may be a rare cause of familial epilepsy. Further studies are needed to test if polymorphisms in this gene are associated with epilepsy.

An autoimmune basis has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). This hypothesis is supported by the presence of antibodies that interact with motoneuron antigens in serum of these patients. Against autoimmunity are the discrepances in the frequency of the antibodies appearance and also failure of immunosuppression. The aim of our study was to evaluate the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and anti-sulfatides in paired serum and cerebrospinal fluid samples in the ALS patients.Serum of 103 and CSF of 79 patients with ALS was examined. The "disease controls" consisted of 22 cases of other motor neuron diseases and 50 healthy, age-matched normals. CSF was drawn at the same time from 79 ALS patients, 6 cases of the "disease controls" and 50 normals. To study the titer of antibodies against GM1-gangliosides, AGM1-gangliosides and sulfatides the ELISA technique has been applied.An increased titer against GM1-gangliosides, AGM1-gangliosides and sulfatides in ALS appeared in serum in 18%, 32%, and 11%, resp., in the "disease controls" the increased antibodies titer appeared in single cases. In CSF the appropriate values in ALS were 20%, 15%, 8%, resp. In the "disease controls" a high antibodies titer was a rare finding.It is concluded that in some ALS cases and also in some patients with other motor neuron diseases an autoimmune mechanism may contribute to motor neuron injury.

Ischemic stroke in young adults is a well-known disease, but despite extensive clinical and laboratory investigations, its etiology remains unclear in approximately half of the cases. We examined the prevalence of factor V Leiden, the prothrombin G20210A genotype, and the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in 100 patients (51 males and 49 females) who survived an ischemic stroke without a cardiac embolic source at an age < or = 45 years, and in 238 healthy control subjects from the same geographic area. The patients were selected for study only if the diagnosis of stroke was documented by computed tomography scan or nuclear magnetic resonance (NMR) of the brain, or both. Heterozygosity for the FV Leiden mutation was found in 3 patients (3.0%) and in 10 control subjects (4.2%). Two patients (2.0%) and five control subjects (2.1%) were heterozygous for the prothrombin G20210A mutation. The frequencies of the MTHFR 677TT, CT, and CC genotypes in the patient group were 12%, 37%, and 51%, respectively, and were not significantly different from those in control subjects (11%, 40%, and 49%, respectively). In conclusion, our results indicate that FV Leiden mutation, prothrombin G20210A genotype, and homozygosity for the C677T mutation in the MTHFR gene are not associated with an increased risk for ischemic stroke in young adults.

Guidelines| January 15 2004 Prevention Subject Area: Cardiovascular System , Neurology and Neuroscience Didier Leys; Didier Leys Search for other works by this author on: This Site PubMed Google Scholar Hubert Kwiecinski; Hubert Kwiecinski Search for other works by this author on: This Site PubMed Google Scholar Julien Bogousslavsky; Julien Bogousslavsky Search for other works by this author on: This Site PubMed Google Scholar Philip Bath; Philip Bath Search for other works by this author on: This Site PubMed Google Scholar Michael Brainin; Michael Brainin Search for other works by this author on: This Site PubMed Google Scholar Hans-Christoph Diener; Hans-Christoph Diener Search for other works by this author on: This Site PubMed Google Scholar Markku Kaste; Markku Kaste Search for other works by this author on: This Site PubMed Google Scholar Juhani Sivenius; Juhani Sivenius Search for other works by this author on: This Site PubMed Google Scholar Michael G. Hennerici; Michael G. Hennerici Search for other works by this author on: This Site PubMed Google Scholar Werner Hacke Werner Hacke Search for other works by this author on: This Site PubMed Google Scholar Cerebrovasc Dis (2003) 17 (Suppl. 2): 15–29. https://doi.org/10.1159/000074817 Article history Published Online: January 15 2004 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Didier Leys, Hubert Kwiecinski, Julien Bogousslavsky, Philip Bath, Michael Brainin, Hans-Christoph Diener, Markku Kaste, Juhani Sivenius, Michael G. Hennerici, Werner Hacke; Prevention. Cerebrovasc Dis 1 December 2003; 17 (Suppl. 2): 15–29. https://doi.org/10.1159/000074817 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsCerebrovascular Diseases Search Advanced Search Article PDF first page preview Close Modal This content is only available via PDF. © 2004 S. Karger AG, Basel2004Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.

The importance of apolipoprotein E (ApoE) and myeloperoxidase (MPO) genotypes in the clinical characteristics of multiple sclerosis (MS) has been recently emphasized. In a large group of Polish patients we have tested the hypothesis that polymorphism in ApoE and MPO genes may influence the course of the disease. G enotypes were determined in 117 MS patients (74 females and 43 males; 99 sporadic and 18 familial cases) with mean EDSS of 3.6, mean age of 44.1 years, mean duration of the disease 12.8 years and mean onset of MS at 31.2 years, and in 100 healthy controls. The relationship between ApoE and MPO genes’ polymorphism and the MS activity as well as the defect of remyelination (diffuse demyelination) and brain atrophy on MRI were analysed. The ApoE o4 allele was not related to the disease course or the ApoE o2 to the intensity of demyelination on MRI. The genotype MPO G/G was found in all familial MS and in 57% (56/99) of sporadic cases. This genotype was also related to more pronounced brain atrophy on MRI. The MPO G/G subpopulation was characterized by a significantly higher proportion of patients with secondary progressive MS (PB- 0.05) and by a higher value of EDSS. A ccording to our results the MPO G allele is frequently found (in 96% of cases) among Polish patients with MS. More severe nervous tissue damage in the MPO G/G form can be explained by the mechanism of accelerated oxidative stress. It seems that MPO G/G genotype may be one of the genetic factors influencing the progression rate of disability in MS patients.

Abstract Membrane parameters at the respective resting potentials in low, normal, and high extracellular potassium solutions were determined in intercostal muscle fibers from 15 patients with no known neuromuscular disease. In synthetic interstitial fluid (normal potassium concentration 3.5 mmol/liter), we found the following mean values: resting membrane potential RP = ‐−83.3 mV, space constant γLD = 2364 μm, fiber diameter d = 49.3 μm, fiber input resistance R in = 795 KΩ, specific membrane capacitance C m = 4.7 μF/cm 2 , and specific membrane resistance R m = 5970 Ω·cm 2 . The specific membrane conductance was g m = 168 m̈S/cm 2 , 76% of it being chloride conductance, 24% being potassium conductance. The dependence of the membrane parameters on the extracellular potassium concentration followed the predictions by the constant field theory. There was no indication of active chloride transport. The resting membrane conductance decreased with temperature with a Q 10 of 1.3. Excitability parameters were nearly independent of temperature between 37 and 27°C.

The mechanism of ion permeation through Na+ channels that have been modified by batrachotoxin (BTX) and inserted into planar bilayers has been generally described by models based on single-ion occupancy, with or without an influence of negative surface charge, depending on the tissue source. For native Na+ channels there is evidence suggestive of a multi-ion conduction mechanism. To explore the question of ion occupancy, we have reexamined permeation of Na+, Li+, and K+ through BTX-modified Na+ channels from rat skeletal muscle. Single-channel current-voltage (I-V) behavior was studied in neutral lipid bilayers in the presence of symmetrical Na+ concentrations ranging from 0.5 to 3,000 mM. The dependence of unitary current on the mole fraction of Na+ was also examined in symmetrical mixtures of Na(+)-Li+ and Na(+)-K+ at a constant total ionic strength of 206 and 2,006 mM. The dependence of unitary conductance on symmetrical Na+ concentration does not exhibit Michaelis-Menten behavior characteristic of single-ion occupancy but can be simulated by an Eyring-type model with three barriers and two sites (3B2S) that includes double occupancy and ion-ion repulsion. Best-fit energy barrier profiles for Na+, Li+, and K+ were obtained by nonlinear curve fitting of I-V data using the 3B2S model. The Na(+)-Li+ and Na(+)-K+ mole-fraction experiments do not exhibit an anomalous mole-fraction effect. However, the 3B2S model is able to account for the biphasic dependence of unitary conductance on symmetrical [Na+] that is suggestive of multiple occupancy and the monotonic dependence of unitary current on the mole fraction of Na+ that is compatible with single or multiple occupancy. The best-fit 3B2S barrier profiles also successfully predict bi-ionic reversal potentials for Na(+)-Li+ and Na(+)-K+ in both orientations across the channel. Our experimental and modeling results reconcile the dual personality of ion permeation through Na+ channels, which can display features of single or multiple occupancy under various conditions. To a first approximation, the 3B2S model developed for this channel does not require corrections for vestibule surface charge. However, if negative surface charges of the protein do influence conduction, the conductance behavior in the limit of low [Na+] does not correspond to a Gouy-Chapman model of planar surface charge.

1. Paramyotonia congenita is a temperature-sensitive skeletal muscle disorder caused by missense mutations that occur in the adult skeletal muscle voltage-gated sodium channel. We report here the identification of a new genetic mutation in a family with the paramyotonia congenita phenotype. 2. Single-strand conformation polymorphism analysis and DNA sequencing showed that the defect was linked to a single nucleotide substitution causing an amino acid change from an arginine to a serine at position 1448 in the human sodium channel alpha-subunit. 3. Expression of the altered protein in human embryonic kidney (HEK) 293 cells revealed several defects in channel function: (i) the rate of fast inactivation was slower in the mutant channel compared with wild-type, (ii) steady-state fast inactivation was shifted towards hyperpolarizing potentials, (iii) the R1448S channels deactivated much more slowly, and (iv) the mutant channels recovered from the fast inactivated state more rapidly. 4. By contrast, the activation curve, steady-state slow inactivation and the rate of onset and recovery from slow inactivation were not altered by the R1448S mutation. 5. These data show that the defects observed in the sodium channel function could well explain the onset of the paramyotonia congenita in this family and emphasize the role of segment S4 of domain IV in sodium channel inactivation.

The voltage-gated chloride channel ClC-1 is the major contributor of membrane conductance in skeletal muscle and has been associated with the inherited muscular disorder myotonia congenita. Here, we report a novel mutation identified in a recessive myotonia congenita family. This mutation, Gly-499 to Arg (G499R) is located in the putative transmembrane domain 10 of the ClC-1 protein. In contrast to normal ClC-1 channels that deactivate upon hyperpolarization, functional expression of G499R ClC-1 yielded a hyperpolarization-activated chloride current when measured in the presence of a high (134 mm) intracellular chloride concentration. Current was abolished when measured with a physiological chloride transmembrane gradient. Electrophysiological analysis of other Gly-499 mutants (G499K, G499Q, and G499E) suggests that the positive charge introduced by the G499R mutation may be responsible for this unique gating behavior. To further explore the function of domain 10, we mutated two charged residues near Gly-499 of ClC-1. Functional analyses of R496Q, R496Q/G499R, R496K, and E500Q mutant channels suggest that the charged residues in domain 10 are important for normal channel function. Study of these mutants may shed further light on the structure and voltage-gating of this channel.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which has been linked to the generation of free radicals and oxidative stress. Oxidative damage to spinal cord proteins is suggested to be a contributory factor to neuronal death in ALS. Since proteins are the major targets for free radicals and the so-called "reactive species", therefore the objective of our study was to identify oxidatively damaged spinal cord proteins. The material consisted of spinal cords of 8 sporadic ALS cases and 5 controls. We estimated the level of protein carbonyl moieties, which react quantitatively with 2,4-dinitrophenylhydrazine (DNPH). Afterwards proteins were separated by SDS-polyacrylamide gel electrophoresis and the protein bound DNPH moieties were detected immunochemically. We also morphologically examined spinal cords after immune staining against DNPH. The protein carbonyl content of the ALS spinal cords significantly increased in all examined cases. In most ALS patients, proteins with 125 kDa, 70 kDa and 36kDa were highly oxidized. The 70-kDa protein was identified immunochemically to be neurofilament 68. The morphological examination of ALS spinal cords indicated a pronounced anti-DNPH immune reaction in neurones of the anterior horns; the reaction in the posterior horns was less intense. Microglia in the white matter was immunoreactive; astroglia was DNPH-negative. Although the exact mechanism by which reactive oxygen species induce motor neurones to die is not known yet, the presented data indicate that they affect spinal cord cellular proteins, including neurofilament 68. In this study, we successfully examined the neurochemical features accompanying motor neuron injury in ALS, and the results may help to develop a rationale anti-oxidative neuroprotective strategy.

Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities.We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K + channel Kir2.1.In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype.All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function.In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%.LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%.While arrhythmias were common, none of our subjects suffered sudden cardiac death.To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model.A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K + , induced Na + /Ca 2+ exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias.These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome.

Background and purpose: MuSK‐positive myasthenia gravis (MG) is diagnosed in 0–48% of cases with generalized seronegative MG in different populations. The presence of anti‐MuSK antibodies generally relates to a severe course and lack of response to thymectomy. We analyzed for the first time the serology and clinical characteristics of MuSK‐positive MG in the Polish population. Methods: One hundred and fifty‐one patients were tested for the presence of anti‐AChR and anti‐MuSK antibodies: 62 with seronegative MG, including 14 with ocular seronegative MG, 48 age‐matched patients with seropositive MG and 41 controls. Results: All patients with seropositive MG and the disease controls were MuSK‐negative. Anti‐MuSK antibodies were detected only in four patients with seronegative MG (8.7% of generalized seronegative cases): three women and one man. All four had predominantly bulbar involvement, and underwent thymectomy, with no apparent benefit. All of them improved clinically after immunosuppressive treatment with remissions lasting up to 7 years. Conclusion: MuSK‐positive MG is rare in Polish population accounting for only 8.7% of seronegative cases with generalized MG. This is consistent with emerging evidence for lower MuSK antibodies at more northerly latitudes.

Polymorphic configurations of the coagulation factor VII gene (F7) are associated with plasma levels of FVII antigen (FVII:Ag) and FVII coagulant activity (FVII:C). Our aim was to determine whether F7 polymorphisms influence risk of ischemic stroke in young adults. One hundred and fifty survivors of ischemic stroke before the age of 45 and an equal number of age and sex-matched controls were genotyped for five F7 polymorphisms: the –A670C transversion, –323 decanucleotide insertion (P + 10), the number (which varies between five and eight) of a 37 base pair repeat polymorphisms in intron 7 (IVS7), amino acid substitution R353Q, and +154AA insertion. 353Q, P + 10 and +154AA were demonstrated to associate with significantly decreased plasma FVII:Ag, whereas −670C and IVS7 seven or higher were associated with a tendency towards increased plasma FVII:Ag. The former three polymorphisms were significantly more common in control individuals than in patients, whereas the latter two were significantly more common in patients than in control individuals. The multiple logistic regression analysis revealed that two F7 polymorphisms, −670C and IVS7 seven or higher, are independent risk factors for ischemic stroke in young adult patients.

Lower motor neuron syndromes (LMNS) are heterogenous conditions, which include patients with progressive lower motor neuron disease (LMND) and cases with the clinical phenotype of motor neuropathy (MN). The aim of this study was to estimate the IgM anti-GM1 ganglioside antibodies titer and the ratio of the light chains in order to define the presence of autoimmunity process in particular cases with LMNS. Twenty-eight patients were diagnosed with LMND and 15 patients were diagnosed with MN (10 patients with multifocal motor neuropathy with conduction block, five patients with MN without conduction block). Total of 103 patients with classical amyotrophic lateral sclerosis (ALS) and 50 healthy, age-matched persons were also tested. The IgM anti-GM1 ganglioside titer and the ratio of lambda/kappa light chains in serum were determined using the ELISA technique. High titer of IgM anti-GM1 antibodies were detected in serum of 46% LMND patients, 80% of MN patients, and 18% of the classical ALS cases. An elevated ratio of lambda/kappa light chains appeared in 18% of LMND patients, and in 67% of the MN cases. The lambda/kappa light chains ratio was normal in all ALS patients. The presence of elevated titer of IgM anti-GM1 ganglioside antibodies and the changed ratio of the light chains supports the presence of autoimmune process in LMNS and may provide clues for their management.

Data on the role of Chlamydia pneumoniae in patients with ischemic stroke are inconsistent. We investigated the presence of anti-C. pneumoniae antibodies in young adults with ischemic stroke.94 patients (<55 years) with ischemic stroke and 103 controls were enrolled. Indices of anti-C. pneumoniae IgA and IgG were assessed with an ELISA. We determined OR and 95% CI for the IgA and IgG seropositivity in stroke cases.Mean IgA and IgG indices were higher in stroke patients vs controls (IgA: 1.40 vs 0.56; P < 0.001; IgG: 0.85 vs. 0.78; P < 0.003). The IgA seropositivity was associated with stroke risk (11.92; 5.94-23.92; P < 0.001) as well as IgG seropositivity was (2.31; 1.15-4.61; P < 0.016). Seropositivity assessed with combined IgA and IgG indices was associated with increased stroke risk (OR 9.35; 95% CI 4.78-18.29; P < 0.0001). After controlling for age and sex, the IgA seropositivity yielded a significantly adjusted OR for stroke (8.95; 4.44-18.07; P < 0.002), while IgG seropositivity did not (0.85; 0.53-1.63).We find an increased risk of stroke in young patients seropositive to C. pneumoniae in the IgA antibody class. Further studies to explore this finding are warranted.

Introduction: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological disorders, affecting approximately half a million people worldwide. Currently there is no cure or prevention for ALS. Although ALS is a rare condition, it places a tremendous socioeconomic burden on patients, family members, caregivers and health systems.

The aim of this study was applications of cerebrospinal fluid (CSF) NMR-based metabolic fingerprinting to amyotrophic lateral sclerosis (ALS) as possible early diagnostic tool. Two CSF sample categories were collected: 9 ALS patients and 13 age-matched control patients (without neurological disease). Metabolic profile of the CSF was determined by high resolution proton NMR spectroscopy. For statistical analysis magnitudes of 33 signals of the NMR spectrum were selected. Partial least square discriminant analysis (PLS-DA) and orthogonal PLS-DA (OPLS-DA) modeling were used to find potential biomarkers of the disease. Those analyses showed that it was possible to distinguish the ALS patients from the control ones on the basis of the CSF metabolic profile. Significantly higher levels of metabolites observed in the patients with ALS may represent the state of anaerobic metabolism and excitotoxicity.

There is evidence that an imbalance between glutamatergic and inhibitory neurotransmission may contribute to selective neurodegeneration in amyotrophic lateral sclerosis (ALS). The efficacy of Riluzole in prolonging the survival of patients with ALS has been demonstrated in two large controlled trials. It is believed that Riluzole is a glutamate antagonist, but the exact mode of its action is not known. Data on the effects of Riluzole treatment on excitotoxic amino acid levels in serum are not available.We prospectively studied 17 patients with ALS (diagnosed according to the El Escorial criteria), who received long-term treatment with Riluzole (100 mg/day). The subjects were evaluated at baseline (before treatment) and after 6, 12 and 18 months on drug. Assessments included the functional status of the patients and serum levels of amino acids. Analysis of the serum amino acids was performed using high performance liquid chromatography techniques at baseline, and after 6, 12 and 18 months of the treatment.At baseline, glutamate, GABA and total amino acid concentration in serum of the ALS patients, mainly in those with severe course of the disease, were increased. During the first 6 months of Riluzole treatment there was a significant decrease of glutamate and total amino acids, afterwards the values returned to the initial high values, or even an 'overshooting' in their levels appeared. We did not observe a similar effect of Riluzole on glutamate and other amino acids in patients with less advanced ALS.It is suggested that the positive clinical effect of Riluzole in ALS patients may be related, at least partly, to its influence on amino acid metabolism in neural tissues.

It is known that mutations of CACNA1A, which encodes a neuronal P/Q Ca 2+ channel, are present in patients with familial hemiplegic migraine, and possibly in other types of migraine as well. This calcium channel is also involved in neuromuscular transmission. To assess if the single-fibre EMG (SFEMG) method can demonstrate a neuromuscular transmission deficit in migraine, a group of 26 patients with different types of migraine and 20 healthy control subjects were studied. The migraine patients were divided into three groups: 8 patients with migraine without aura (MoA), 12 with migraine with aura excluding visual aura (MA) and 6 with visual aura (VA). A SFEMG of the voluntarily activated extensor digitorum communis muscle was performed. The SFEMG results were normal in the healthy controls and the MoA group (migraine without aura). Slight neuromuscular transmission disturbances were present in 6/12 (50%) of patients with MA and in 1/6 (17%) of patients with VA. We suggest that abnormal neuromuscular transmission detectable by SFEMG may reflect a genetically determined dysfunction of the P/Q Ca 2+ channels in a subgroup of migraineurs with aura.

In the present study, morphological examination of patients from two unrelated Polish families with CADASIL was performed. Using light microscopy, there were evident changes characteristic to the disease. On electron microscopy, deposits of granular osmiophillic material (GOM) were found not only in cerebral arteries and veins but also in cerebral capillaries and vessels of the internal organs. These findings indicate that pathological process in CADASIL is generalized and involves also small vessels devoid of smooth muscle cells. Therefore, we propose to consider a replacement for the name CADASIL that better reflects the morphological picture of the disease like, for example, cerebral autosomal dominant vasculopathy with subcortical infarcts and leukoencephalopathy (CADVaSIL) or, to preserve the commonly known acronym, cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, which are present in central and peripheral nervous system. They are considered to be involved in the pathogenesis of several neurological diseases, as multiple sclerosis, Alzheimer disease, and amyotrophic lateral sclerosis (ALS). The aim of the present study was to evaluate the application of the pattern recognition methods for the assessment of MMPs in serum of patients with ALS. Thirty patients with amyotrophic lateral sclerosis (ALS), in two subgroups: (i) with mild and (ii) severe progressing ALS, and 15 control healthy subjects were studied. The metalloproteinases MT-MMP-1, MMP-2, MMP-9 were examined. Additional variables (age of subjects and disease duration) were also analyzed by using a standard, parallel and hierarchical classifiers. Our results indicate that: (i) MMP-2 in serum may be an important marker for the evaluation of ALS progress; (ii) the set of two features {MT-MMP-1, MMP-9} may be helpful in differentiation between ALS and healthy subjects; (iii) the error rates obtained for the pair-wise linear classifier were similar to those received for the classifiers (standard, parallel, and hierarchical) based on k-NN rule. We conclude that the pattern recognition methods may be useful for the evaluation of significance MMPs as markers in neurodegenerative diseases, such as ALS.

Metabolic disturbances of excitatory and inhibitory neurotransmitters are implicated in pathogenesis of Tourette syndrome (TS). The aim of the study was to measure serum concentrations of glutamic acid, g-aminobutyric acid (GABA) and glycine in TS patients and evaluate any correlation between neurotransmitter levels and age at onset, actual age, gender, tic severity, duration of the disease and concomitant psychiatric disorders.Sixty-seven TS patients, aged 16-59, and 57 healthy controls, aged 19-37, were enrolled in the study. Information regarding medical history and physical investigation was collected using a short questionnaire. Sixty-seven percent of patients were medication-free at the time of examination and the rest had withheld treatment for 24 hours before. Blood samples were taken after a 12-hour fasting period. HPLC technique was used.The TS group had higher glutamic acid and lower GABA levels. Glycine concentrations were comparable. No differences regarding neurotransmitter concentrations between treated and non-treated patients were found. Patients with concomitant obsessive-compulsive disorder and severe tics had higher glutamate levels. Glutamate concentrations correlated positively with the number of comorbid psychiatric disorders and GABA concentrations correlated negatively with the number of behavioural problems in patients with comorbidities. There was no correlation between analysed neurochemicals and age, gender, age at onset or disease duration.Imbalance between excitatory and inhibitory systems in the brains of TS patients may be reflected by glutamate and GABA serum level changes. Glutamate and GABA may be biomarkers of the disease and high concentration of glutamate may indicate more severe course of TS.

Myotonic dystrophy (DM) is the most common muscular dystrophy in adults. Two known genetic subtypes include DM1 (myotonic dystrophy type 1) and DM2 (myotonic dystrophy type 2). Genetic testing is considered as the only reliable diagnostic criterion in myotonic dystrophies. Relatively little is known about DM1 and DM2 myopathology. Thus, the aim of our study was to characterise light and electron microscopic features of DM1 and DM2 in patients with genetically proven types of the disease. We studied 3 DM1 cases and 15 DM2 cases from which muscle biopsies were taken for diagnostic purposes during the period from 1973 to 2006, before genetic testing became available at our hospital. The DM1 group included 3 males (age at biopsy 15-19). The DM2 group included 15 patients (5 men and 10 women, age at biopsy 26-60). The preferential type 1 fibre atrophy was seen in all three DM1 cases in light microscopy, and substantial central nucleation was present in two biopsies. Electron microscopy revealed central nuclei in all three examined muscle biopsies. No other structural or degenerative changes were detected, probably due to the young age of our patients. Central nucleation, prevalence of type 2 muscle fibres, and the presence of pyknotic nuclear clumps were observed in DM2 patients in light microscopy. Among the ultrastructural abnormalities observed in our DM2 group, the presence of internal nuclei, severely atrophied muscle fibres, and lipofuscin accumulation were consistent findings. In addition, a variety of ultrastructural abnormalities were identified by us in DM2. It appears that no single ultrastructural abnormality is characteristic for the DM2 muscle pathology. It seems, however, that certain constellations of morphological changes might be indicative of certain types of myotonic dystrophy.

Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome are classified as transmissible cerebral amyloidoses, in contrast to the non-transmissible amyloidoses of Alzheimer's disease type. While the aetiologies of Creutzfeldt-Jakob disease and Alzheimer's disease and the molecular composition of their amyloids are different, similar basic pathogenetic mechanisms operate in both diseases through synthesis and processing of amyloid precursor proteins, to produce an accumulation of amyloid deposits. We report here a case of Creutzfeldt-Jakob disease exhibiting numerous diffuse A beta immunoreactive plaques, thus presenting features of both Creutzfeldt-Jakob disease and Alzheimer's disease. The existence of such cases underlines the existence of a 'grey' area between the two types of amyloidoses.

Africa's history of neurology remains largely undiscovered and unwritten, except in countries like Egypt. The more modern history of neurology has been peppered with remarkable people such as Osuntokun in the latter part of the 20th century, followed by an unedifying gap in training and development in the specialty. Neurological morbidity, especially from human immunodeficiency virus (HIV) related neurological disease and stroke, is rising in much of the continent including Kenya.

Migraine is a common neurologic disorder whose etiology remains unknown. Migraine has been reported as a possible risk factor for ischemic stroke, especially in young women. The relationship between migraine and stroke is stronger in patients suffering from migraine with aura compared to those with common migraine. Coexistence of migraine and patent foramen ovale (PFO) should be also considered. The aim of our study was to evaluate the frequency of PFO in patients with migraine with aura (MA) and compare it with the prevalence of PFO in migraine patients without aura (M) and in a healthy age-matched control group.We assessed 62 patients (48 females) suffering from migraine with aura, 60 without aura (53 females) and 65 normal controls (51 females). In order to detect PFO the contrast transcranial Doppler was performed during Valsalva maneuver.The presence of PFO was found in 33/62 (53%) patients with MA compared to 15/60 (25%) without aura, and in 16/65 (25%) control subjects. The difference in PFO prevalence between MA patients and M patients and the difference between MA patients and the control group was statistically significant (p<0.05).Our findings suggest that at least some attacks of migraine with aura may be associated with paradoxical embolism.

Mitoxantrone (MTX) has been shown to reduce progression of disability and number of clinical exacerbations in patients with progressive multiple sclerosis (MS). Prolonged administration of MTX, however, is limited by the risk of cardiotoxicity. Cardiac monitoring in MTX-treated patients includes usually measurement of left ventricular ejection fraction (LVEF) by means of echocardiography. The N-terminal pro-brain natriuretic peptide (NT-proBNP) represents a novel diagnostic tool in the assessment of heart failure. This study was aimed to evaluate the usefulness of NT-proBNP for early detection of MTX-induced cardiotoxicity in MS patients.We measured the NT-proBNP plasma levels in 45 MS patients who completed 24-month MTX therapy and in 37 MS patients of control group.The median NT-proBNP plasma value was 15.12pg/mL. In 12 MTX-treated patients (27%), NT-proBNP plasma values were elevated, though this subgroup of patients neither clinical showed evidence of myocardial damage nor had the LVEF value <50%. In five patients with normal NT-proBNP, we observed LVEF decline >10%. We did not observe correlations between the NT-proBNP levels and patient age, MS duration, relapses index, Extended Disability Status Scale (EDSS), MTX single dose and the total cumulative dose of MTX. In 8 patients (22%) from control group, NT-proBNP plasma levels were also elevated.The results of our study confirm that MTX therapy is safe for carefully selected and closely monitored MS patients. We believe that serial evaluation of NT-proBNP levels (before, during and after MTX therapy) can identify MS patients at high risk for MTX-induced cardiotoxicity.

Abstract Hyperpolarizing and depolarizing square steps were imposed on the membrane potential of excised human intercostal muscle fibers by means of a 3‐microelectrode voltage clamp. The steady‐state amplitudes of the membrane currents inducing such steps were investigated as a function of the membrane potential, while the muscle was bathed in solutions varying in potassium content (K e = 1, 3.5, 7, 20, and 60 m M ). At all potassium concentrations, the membrane acted as a rectifier, both in the inward‐ and outward‐going directions. Inward currents were much reduced when K e was lowered from 3.5 to 1 m M , and were increased when K e was raised beyond 3.5 m M . The delayed outward current was reduced when K e was increased from 3.5 m M to 7 m M and higher potassium concentration. The results were qualitatively similar to those reported for rat skeletal muscle.

Mutations in NADH dehydrogenase (ND) subunits of complex I lead to mitochondrial encephalomyopathies associated with various phenotypes. This report aims to present the patient's clinical symptomatology in the context of a very rare 13042G>A de novo mutation and with an emphasis on changing phenotypic expression and pronounced, long-standing response to levetiracetam.

Cu/Zn superoxide dismutase (SOD1) gene mutations are the most frequently reported genetic causes of amyotrophic lateral sclerosis (ALS). The objective of the study was to describe a clinical phenotype and haplotype background of Polish and Japanese ALS patients harbouring the K3E SOD1 mutation. The K3E mutation was identified by direct sequencing, high resolution melting analysis or high-throughput microarray-based resequencing system. Microsatellite polymorphic markers flanking SOD1 were genotyped in members of six kindreds and two SALS patients. Results demonstrated that the K3E mutation was responsible for classic ALS. The median age of onset was 54 years. The clinical phenotype did not substantially differ between SALS and FALS cases of either ethnic origin, with some intrafamiliar variabilities. There was a limb onset in 92% of patients. In patients with bulbar syndrome, dysphagia predominated over dysarthria. Respiratory insufficiency was found in 61.1% of patients (19–84 months after the first symptoms onset). Median survival was 101 months with age of death ranging from 45 to 77 years. K3E was the most frequent SOD1 mutation among Polish FALS patients. It originated independently, on different haplotype background in the Polish and Japanese populations. In conclusion, recurrent K3E mutation results in a relatively slowly progressing limb onset ALS with classic phenotype.

Paroxysmal non-kinesigenic dyskinesia (PNKD) is a clinical syndrome of sudden involuntary movements, mostly of dystonic type, which may be triggered by alcohol or coffee intake, stress and fatigue. The attacks of PNKD may consist of various combinations of dystonia, chorea, athetosis and balism. They can be partial and unilateral, but mostly the hyperkinetic movements are bilateral and generalized. We present a large Polish family with 7 symptomatic members of the family in 6 generations. In all affected persons, the onset of clinical symptoms was in early childhood. All male cases showed an increase in severity and frequency of the attacks with ageing, while the only living female patient noticed an improvement of PNKD during both her pregnancies and also after menopause. In addition, at the age of 55 years, she developed symptoms of Parkinson’s disease with good response to levodopa treatment.

This paper concerns the analysis and interpretation of results obtained from biomedical experiments. The biomedical approach allows differentiating patients by testing their EPO concentration in serum and cerebrospinal fluids. The diagnostic tests can be applied in patient monitoring, or future therapeutic research. The paper presents the possibility of recognition of the clinical status of patients with Amyotrophic Lateral Sclerosis (ALS) by the use of parallel and hierarchical classifiers. The proposed method can be used in biometric identification of ALS patients. The results demonstrate that the pattern recognition methods may be helpful in evaluation of the clinical progress of ALS.

Paradoxical embolism due to the presence of patent foramen ovale (PFO) is a well-established possible mechanism of ischaemic stroke of unknown origin. Mechanical sealing of the interatrial septum seems to be the most effective method for the prevention of stroke recurrences.To assess prospectively the short- and mid-term results of transcatheter closure of PFO in consecutive patients with a history of cryptogenic ischaemic stroke.Between March 1999 and December 2002, thirty two patients with PFO (15 males, age from 19 to 55 years, mean 41 years) with a history of documented ischaemic stroke of unknown origin underwent transcatheter closure of PFO using an Amplatzer occluder. All procedures were performed under general anaesthesia and with transesophageal echocardiographic guidance.In all patients the procedure was effective and no complications were observed. During the follow-up period of a mean of 25.9 months (>12 months in 22 patients), no new neurological events were recorded. Control transesophageal echocardiography was performed in 28 patients mean 22.3 months after the procedure and confirmed the correct positioning of the occluder. A significant (>30 bubbles of contrast) residual shunt was detected in two patients. One patient developed episodes of paroxysmal supraventricular tachycardia which were effectively cured by radiofrequency ablation.Transcatheter closure of PFO is safe, effective and devoid of side effects connected with extracorporeal circulation. This procedure may become the treatment of choice in patients with the highest risk of recurrent ischaemic stroke.

We investigated the susceptibility of the dinucleotide polymorphism A0 in the tau gene to amyotrophic lateral sclerosis (ALS). In 416 unrelated patients with ALS and 242 control subjects the A0/A0 genotype was not associated with the pooled sample of ALS cases. Subgroup analysis revealed that in sporadic ALS the A0 polymorphism was significantly overrepresented. There was no association of the A0/A0 genotype with the age and site of disease onset or the presence of dementia. The studied tau genotype may contribute to the multifactorial genetic background of ALS.

Mitochondrial cytopathies are heterogeneous disorders affecting multiple systems but most commonly involving the skeletal muscle and central nervous system. The variety of symptoms and signs requires biochemical, morphological and genetic evaluation. The results of genetic studies indicate that there is no direct correlation between genotype and phenotype in mitochondrial cytopathies. This study is the first such analysis of a group of Polish patients with mitochondrial cytopathies. Its aim is to define the clinical features of mitochondrial cytopathies in relation to their genetic defects.In a retrospective study, 46 patients with final diagnosis of mitochondrial cytopathy were evaluated clinically and electrophysiologically. Each patient underwent electromyography, electroneurography, and some patients were also assessed using electroencephalography. Clinical diagnoses were confirmed through the histopathological evaluation of muscle biopsies. In 36 cases mitochondrial DNA (mtDNA) testing was performed.Eight different clinical syndromes were diagnosed among the evaluated patients. In the skeletal muscle biopsy, ragged-red fibres, which are a significant symptom for these disorders, were present in the majority of cases (93%). The presence of specific gene mutations was confirmed in 9 out of the 36 cases in which mtDNA was examined.The results of our study confirm the remarkable clinical heterogeneity of mitochondrial cytopathies. Final diagnosis in many cases could only be confirmed by detection of the genetic defects. Molecular diagnosis may in the future have a significant impact on new therapeutic approaches.

Niemann-Pick disease type C is a rare hereditary disorder caused by mutation-disrupted metabolism of cholesterol and low-density lipoprotein (LDL). In most patients, symptoms begin in childhood with severe clinical progression. We present a patient with heterozygote mutations 3001A>G and 3019C>G with late onset of the disease and positive response to treatment with miglustat. Behaviour and educational problems in childhood were probably related to the disease diagnosed later. Choroba Niemanna-Picka typu C jest rzadkim schorzeniem dziedziczonym autosomalnie recesywnie, spowodowanym zaburzeniem metabolizmu i transportu cholesterolu i LDL. Zachorowanie w większości przypadków dotyczy okresu dziecięcego i ma ciężki przebieg kliniczny. W artykule przedstawiono przypadek pacjenta z potwierdzoną złożoną mutacją 3001A>G i 3019C>G o późnym początku wystąpienia zaburzeń neurologicznych i korzystną odpowiedzią na leczenie miglustatem. Zaburzenia zachowania w wieku dziecięcym i trudności w nauce są najprawdopodobniej związane przyczynowo z później zdiagnozowaną chorobą.

Mutations in the superoxide dismutase-1 (SOD1) gene have been found in 12-23% of patients with a diagnosis of ALS. Here we describe a large ALS Polish family with a branch in France, carrying a G41S mutation in the SOD1, and characterized by an early onset of the disease and extremely short survival time. The mutation has been initially detected in Italian ALS families with common founder effect. However, in the Polish population the G41S mutation most probably originated from an independent mutation event, as indicated by haplotype analysis. Collected data support the hypothesis that a SOD1 mutation is not the sole factor determining the clinical ALS phenotype.

Familial partial lipodystrophy (FPLD) belongs to the family of laminopathies – disorders associated with mutation in the lamin A/C gene (LMNA). FPLD is characterized by loss of subcutaneous adipose tissue from the limbs, trunk and buttocks, with its concomitant accumulation on the face, neck and intra-abdominal region, and by metabolic disorders. We present the first Polish family with FPLD confirmed genetically. A 34-year-old woman admitted with myalgia and cushingoid appearance was found to have a round face with double chin, neck bump, and loss of fat on extremities. Diagnostic tests revealed impaired glucose tolerance and increased levels of liver enzymes, and ultrasonography revealed hepatic steatosis. Her 9-year-old daughter presented a similar phenotype, but no fat loss. A genetic test revealed the presence of a heterozygous LMNA gene mutation: c.1445G>A, consistent with the “hot spot” for FPLD. Treatment with metformin to improve insulin resistance and address the diabetes proved successful. Rodzinna częściowa lipodystrofia (familial partial lipodystrophy – FPLD) należy do laminopatii – chorób związanych z mutacjami genu laminy A/C (LMNA). Charakteryzuje się utratą podskórnej tkanki tłuszczowej na kończynach, tułowiu i pośladkach z jednoczesnym jej przemieszczeniem na twarz, szyję i do przestrzeni wewnątrzbrzusznej oraz zaburzeniami metabolicznymi. Prezentujemy pierwszą polską rodzinę z genetycznie potwierdzoną FPLD. Trzydziestoczteroletnia chora została przyjęta do szpitala z powodu bólów mięśni oraz cushingoidalnego wyglądu. Klinicznie stwierdzono zaokrąglenie twarzy, podwójny podbródek, nagromadzenie tkanki tłuszczowej na karku oraz zanik tkanki tłuszczowej na kończynach. Badania wykazały nieprawidłową tolerancję glukozy i zwiększoną aktywność enzymów wątrobowych, zaś USG – cechy stłuszczenia wątroby. Dziewięcioletnia córka chorej prezentuje podobieństwo fenotypowe do matki, jednakże obecnie bez zaniku tkanki tłuszczowej. W badaniu genetycznym u chorej i jej córki stwierdzono heterozygotyczną substytucję w genie LMNA: c.1445G>A (p.Arg482Gln), która znajduje się w miejscu „hot spot” dla FPLD w 8. eksonie. Chorej podano metforminę w celu leczenia insulinooporności i zaburzeń gospodarki węglowodanowej.

A role for oxidative stress in the etiology or progression of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases has been recently proposed. We conducted the 18-month, randomized treatment trial with oral vitamin E (600 IU daily) and selegiline (10 mg daily) in 67 patients with sporadic ALS. Thirty five patients were randomly assigned to receive antioxidative therapy (vitamin E plus selegiline) and the remaining 32 patients were the ALS controls who received symptomatic treatment. The primary end point was survival and functional status. At the end of 18-month study, 13 patients in the treatment group and 14 in the control group died or were tracheostomized. A decline in functional disability was also similar in both groups. Long-term antioxidative treatment did not benefit patients with ALS.

There has been lively discussion about neurological education in different countries in the past decade.1–3 However, there have been no data on what those being trained think of their training programmes. We think that the opinions of neurology trainees and recent graduates from around the world regarding their training programmes will be an important addition to the ongoing discussion about the relative merits of international neurological training guidelines.

Mitochondrial DNA point mutations are associated with various syndromes, among which mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS) and myoclonic epilepsy with ragged red fibres (MERRF) are the most common.1 Here we present a case report of a young man with a mitochondrial encephalomyopathy caused by a mutation in the ND5 gene (13042A>G), which has been described previously.1 A 21-year-old man presented with a 2-year history of recurrent generalised epileptic seizures and myoclonus with no family history. Neurological examination revealed discrete nystagmus and multifocal myoclonus in the upper limbs, ataxia and focal dystonia presenting as writer's cramp. Neuropsychological examination showed slight working memory impairment and slowed learning of both verbal and visual material. Follow-up examinations conducted 18 and 33 months later did not show evidence of progression of the deficits. The patient exhibited anosodiaphoria throughout the observation period. Laboratory studies showed a normal serum lactic acid level of 9.45 mg% with an abnormal lactic acid curve during ischaemic muscle exercise. Creatine kinase activity was within the normal range. A 50 min video EEG disclosed a pattern characteristic of myoclonic epilepsy. Visual evoked potentials showed delayed P100 responses. Electromyography and nerve conduction studies were within normal ranges. MRI showed hyperintensive lesions on T2 and FLAIR images in the right cerebral peduncle, close to the occipital horns of the lateral ventricles, in the left temporal lobe as well as …

Experimental myotonia was induced in rats by long-term administration of 20,25-diazacholesterol. Electrophysiological, morphological and biochemical investigations were carried out on m. soleus, m. extensor digitorum longus and m. gastrocnemius. The effect of 20,25-diazacholesterol administration on myofibrillar proteins was studied and a significant rise in the concentration of a protein presumed to be α-actinin was demonstrated in m. gastrocnemius. A change of the same character, not statistically significant, was observed in the m. extensor digitorum longus.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder of still unknown aetiology and pathogenesis. It is characterized by a progressive and selective loss of motor neurons in the brain and spinal cord. The majority of ALS cases (90%) are sporadic and in approximately 10% the disorder is familial. In the light of recent studies, the familial forms might however be more frequent. The article describes mutations of genes linked to both sporadic and familial ALS and the role of the proteins they encode.

Myotonia-like activity was recorded from various muscles of rats treated with 25-azacholesterol for a period of 2-8 weeks. 50% of myotonic rats showed a decline of amplitude of the evoked muscle potentials of the flexor digitorum muscle on stimulation of the median nerve with supramaximal stimuli at frequencies of 3, 5, 8, 15 or 50 cps. Administration of prostigimine increased neuromuscular failure. This temporary paresis of myotonic muscle resembles the transient impediment of motility of myotonic patients and it is entirely different from myasthenic transmission defect.

We present a 43-year-old man with recurrent episodes of Hashimoto's encephalopathy who was diagnosed with autoimmune thyroiditis in childhood. Encephalopathy started with subacute dementia followed by extrapyramidal and psychiatric symptoms of insidious onset. He had also status epilepticus which occurred within the first year of the disease. The patient was in euthyreosis, but increased levels of antithyroid antibodies were found. MRI of the brain was normal. Electroencephalography was initially normal and later showed diffuse slowing with generalized theta/delta activity. The cerebrospinal fluid examination revealed a high level of protein which decreased when remission of the disease was achieved. After other etiology was excluded Hashimoto's encephalopathy was diagnosed. Almost complete clinical recovery after steroid administration was observed. Attempts of prednisone withdrawal led to recurrence of neurological and psychiatric symptoms. The diagnosis of Hashimoto's encephalopathy should be considered in each case with subacute encephalopathy associated with high levels of antithyroid antibodies (despite normal thyroid function) and in the absence of other brain diseases.

A possibility of recognition of the clinical status of patients with amyotrophic lateral sclerosis (ALS) in relation to severity of the disease was investigated. Three groups: (i) healthy controls (n=15) and two subgroups of ALS patients (ii) mild (n=15) and (iii) severe (n=15) were considered as classes. Four features of the subjects: (i) their age (AGE) (ii) erythropoietin concentration in serum (SERUM), (iii) in cerebrospinal fluid (CSF), and (iv) duration time of the disease (Tdis) were used for classifier construction based on the k Nearest Neighbours (k-NN) rule, known from pattern recognition theory. The presented results demonstrate that the pattern recognition approach may be useful for the evaluation of the severity of the ALS disease.

Joseph Babinski pioneered development of French neurosurgery and world clinical neurology. Although he was best known for his discovery of the extensor plantar response, his foundations in the modern semiology of neurology are unequivocal. He introduced the concepts and terminology of cerebellar symptoms and discovered a reflex asymmetry as the sign of organic disease. Although he considered the development of French neurosurgery by his pupils as his greatest accomplishment, it is ‘the sign’ that has dominated his legacy over the years. This sign will also celebrate a centenary in 1996.

Determination of enzymatic activity, protein profile and phospholipid composition of muscle plasma membranes and sarcoplasmic reticulum in rats were carried out after clofibrate injections in a dose of 0.4 g/kg body weight. In the plasma membranes, the activity of Na+ + K+, Mg2+ ATPase was insignificantly decreased, and that of 5'-nucleotidase significantly diminished. A non-significant change was observed in the total amount of phopholipids. The amount of phosphoethanolamine appeared to be lower. Changes in the protein profile were seen. In the sarcoplasmic reticulum, the major abberation was the decrease of Mg2+ ATPase activity. No evident changes were observed in the phospholipid behaviour. Abnormalities in the protein profile appeared. In the myofibrillar proteins, increases of alpha-actinin and troponin at the expense of myosin were observed. In the clofibrate model of myotonia in rats, the changes in the biochemical parameters were less pronounced as compared to the previously tested 20,25-diazacholesterol model.

Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively.Molecular analyses were performed by PCR and the modified RP-PCR in patients, in their at-risk relatives and prenatal cases.The analysis of Polish controls revealed the range of 5-31 CTG repeats for DM1 and 110-228 bp alleles for DM2. Among 318 confirmed probands - 196 (62%) were DM1 and 122 (38%) - DM2. Within DM1families, 10 subjects carried a low expanded CTG tract (< 100 repeats), which resulted in a full mutation in subsequent generations. Two related individuals had unstable alleles-188 bp and 196 bp without common interruptions.The relative frequencies of DM1/DM2 among Polish patients were 68% and 32%, respectively, with a relatively high proportion of DM2 mutations (1.6:1).

Glycoconjugates in the serum of 73 patients with amyotrophic lateral sclerosis (ALS), 21 cases of other motor neuron diseases and 20 healthy controls were determined. Cerebrospinal fluid (CSF) was studied in 64, 7 and 10 of these subjects. respectively. The level of sialic acid containing glycoconjugates, detected by Maakia amurensis agglutinin (M.AA), was decreased in the serum of 61.6% of the ALS patients, while in the CSF it was decreased, on average, in 75% of these cases. Only in single ALS cases was the concentration of these glycoconjugates increased. There was no correlation between the content of MAA‐labelled glycoconjugates both in serum and CSF and the titre of sialic acid containing antiGMI gangliosides. The glycoconjugates, detected by peanut agglutinin (PNA) which recognizes the disaccharide galactose β(1‐3)N‐acetylgalactosamine (GGN), were decreased in the serum of 78.1% of ALS patients, while in CSF they were increased in 54.7% of these cases. There was no correlation between the concentration of PNA‐labelled glycoconjugates both in serum and CSF as well as the titre of antibodies against GGN‐containing anti‐GM1 and anti‐AGM1 gangliosides. Changes in the level of the MAA‐ and PNA‐labelled glycoconjugates, as well as the titre of anti‐GM1 and anti‐AGM1 gangliosides antibodies were not specific for ALS. They were also observed in some cases of other motor neuron diseases. The low level of the lectin‐labelled glycoconjugates in serum and party in CSF of the majority of ALS patients is possibly the consequence of their accelerated clearance and/or specific inactivation by the formation of immune complexes or epitope binding. Degeneration of neurons and muscle cells could also be responsible. The relatively low incidence of high anti‐glycolipids antibodies titre may be, at least partly, connected with the low concentration of the appropriate antigens. The increased content of PNA‐labelled glycoconjugates in the CSF of the majority of ALS patients, together with the low incidence of high titre of antibodies against the appropriate glycolipids, could indicate that in CSF this lectin binds to the GGN epitope of glycoproteins rather than to the GGN epitope of glycolipids.

Progressive supranuclear palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, is a rare form of parkinsonism characterised by abundant tau pathology. Only a few familial cases have been reported, therefore PSP can be considered as a sporadic tauopathy. Recent case-control studies of patients with sporadic PSP suggest that PSP has a recessive pattern of inheritance. Strong genetic evidences for the involvement of the tau gene variability in the pathogenesis of PSP have been demonstrated in several Caucasian populations. We review the most important DNA polymorphisms (e.g.: A0 polymorphism and H1 haplotype) contributing to the risk of PSP. Moreover, we discuss how these DNA polymorphisms may influence the exon 10 splicing, and thus the proportion of 4R/3R tau isoforms, leading to a class II tau pathology in PSP patients.

BACKGROUND AND PURPOSE Oculopharyngeal muscular dystrophy (OPMD) is mostly an autosomal dominant myopathic disorder, characterized by progressive bilateral ptosis, dysphagia and proximal muscle weakness, appearing usually in the fifth to sixth decade of life. The underlying cause of OPMD is an expanded GCG repeat in the first exon of the gene encoding poly (A)-binding protein nuclear 1 (PABPN1) localized on chromosome 14.q11.2-q13. The number of GCG expansion ranges from 8 to 13 repeats. PABPN1 is a nuclear multifunctional protein which is involved in transcription regulation and post-transcriptional processes. MATERIAL AND METHODS We report on clinical characteristics in 9 Polish patients with genetically confirmed OPMD. RESULTS The expanded repeat ranged from (GCG)8 to (GCG)11. Ptosis and dysphagia were present in all examined cases. In 4 patients weakness of extraocular muscle was found and two of them experienced transient diplopia. Mild limb-girdle weakness was observed in 6 patients. Muscle biopsy performed in all cases showed myopathic changes with rare rimmed vacuoles. Strikingly, despite thorough examination on electron microscopy, intranuclear inclusions typical for OPMD were found only in one patient. CONCLUSIONS Genetic testing is necessary to confirm the diagnosis of OPMD, especially in cases with ptosis and external ophthalmoparesis, which may be initially diagnosed as mitochondrial myopathy.

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and might be potential markers of d iagnosis, prognosis and monitoring treatment effect s. The aim of the present study was evaluation of the MMPs significance in ce rebrospinal fluid (CSF MMPs) of patients with ALS in relation to severity of the disease. Metalloproteinases MT-MMP-1, MMP-2, MMP-9 and additionally age of subjects and disease durati on were analyzed. The results demonstrate that the error of different iation between healthy subjects and ALS patients (f or MMP-2 feature) as well as between mild and severe ALS states (for CSF MMPs set) equalled to 0.033. In conclusion, the pattern rec ognition approach may be useful for differentation of ALS progressing on the basis of CSF MMPs features.

Cerebro-vascular accidents are the third most common cause of death. The most frequent localisation of lesions responsible for stroke are bifurcation of the common carotid artery or the proximal internal carotid artery (ICA). Surgical carotid endarterectomy (CEA) and carotid artery stenting (CAS) are the non-pharmacological methods used to treat carotid artery stenosis.To assess the efficacy and safety of CAS of ICA.CAS was performed in 75 patients (49 males, 26 females) with a mean age of 65.2+/-9.1 years. Twenty (26.7%) patients underwent CAS with the use of the central nervous system (CNS) protective devices. The immediate, mid-term, and long-term results were analysed.In total, 84 stents were implanted to 80 ICA in 73 patients. In two patients stent implantation was not possible. In 7 (9%) patients with a stenosis of both ICA, a bilateral procedure was performed. In two patients concomitant dilatations of the vertebral artery, and in the other two - of subclavian artery, were performed. In 38 patients coronary angiography was performed directly before CAS; one patient underwent coronary angioplasty. In 20 patients protective CNS devices were used. During the procedure four patients developed ischaemic stroke on the side of CAS. In one patient neurological symptoms completely disappeared within 48 hours. The type of technique used during CAS did not influence the frequency of ischaemic complications. Four patients developed hyperperfusion syndrome which disappeared after a few days. There were fire deaths during follow-up: three due to myocardial infarction (MI), one - after urgent CABG, and one due to pulmonary embolism. There were no deaths due to stroke. No new ischaemic changes in CNS nor significant changes in the neurological status, using the UNSS or Barthel scales, were observed. Asymptomatic restenosis was documented in six patients whereas one patient developed symptomatic restenosis due to stent deformation.Percutaneous angioplasty of an internal carotid artery carries a risk not exceeding that of surgical endarterectomy. In our study, a one-year follow-up revealed a minor risk of ischaemic stroke. Percutaneous angioplasty with the use of protective devices should be tested in larger groups of patients in order to establish the real clinical usefulness and improved safety of this technique.

Mitochondrial diseases may cause a wide range of central and peripheral nervous system disorders, as well as muscle disorders. The diagnostic workup routinely includes electrophysiological, morphological, neuroimaging and genetic studies. In some cases, the diagnosis may be ascertained only when mitochondrial DNA (mtDNA) examination in the muscle is performed. We report on a case of a 24-year-old woman, with a 7-year history of slowly progressive cerebellar syndrome and bilateral ptosis. Mitochondrial encephalomyopathy was suspected, based on the clinical picture and results of examinations, but the typical red ragged fibers were not found in the muscle biopsy. The results of molecular analysis of mtDNA showed a mtDNA deletion in the muscle and, on a level detectable only with polymerase chain reaction method, in blood leukocytes. This case emphasizes the important role of mtDNA studies in muscle in nonspecific multisystem mitochondrial disorders, even without clinical muscle involvement.

Interactions of transcriptions factors Nurr1, Pitx3, and EN1 are involved in the maturation and survival of adult midbrain dopaminergic neurons during a lifetime. The aim of the study was to evaluate the presence of mutations and single nucleotide polymorphisms in PITX3 gene in clinically diagnosed multisystem atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). In the group of 77 patients with MSA, 44 with PSP, and 6 with CBD, no pathogenic mutations were identified.

Poisoning with ethylene glycol is the most frequent poisoning in our country. Acute encephalopathy during this poisoning may be a cause of important diagnostic difficulties, especially in the initial phase of the poisoning, due to the variety of symptoms and signs. Three cases of this poisoning are reported. All patients were erroneously referred and admitted to neurological hospital department. It is postulated that in each case of coma of unknown aetiology with signs suggesting damage to the brain stem and hyperventilation arterial blood gasometric examination should be done and blood and urine should be taken for toxicological investigations. In the treatment of glycol poisoning the most important task is to correct metabolic acidosis and to apply early dialysis treatment in serious intoxication.

Mutations of CACNA1A, which encodes a neuronal P/Q Ca2+ channel, are present in patients with familial hemiplegic migraine, and possibly in other types of migraine as well. This calcium channel is also involved in neuromuscular transmission. In our previous study we confirmed that the single-fibre electromyography (SFEMG) method can demonstrate a neuromuscular transmission deficit in migraine with aura. The aim of our present study was to estimate the neurotransmitter dysfunction in cluster headache and to compare the results between patients with cluster headache and those with migraine with aura.We selected 6 patients with cluster headache and 6 patients with migraine with typical aura. SFEMG of the voluntarily activated extensor digitorum communis muscle was performed.The SFEMG results were in the normal range in the cluster headache group and in the healthy controls. Slight neuromuscular transmission disturbances were present in patients with migraine with aura.The abnormal neuromuscular transmission detectable by SFEMG may reflect a genetically determined dysfunction of the P/Q Ca2+ channels in a group of migraineurs with aura. Conversely, absence of neuromuscular abnormalities in cluster headache patients could be explained by different aetiology not resulting in channelopathy. Single-fibre electromyography could be a helpful tool in clinically questionable cases in differentiating between cluster headache and migraine with aura.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, affecting upper and lower motor neurons, which eventually progresses to respiratory deterioration and death in most of the patients. Only one drug, riluzole, has been approved for the treatment of ALS. The drug has a benefit, prolonging life by 3-6 months, but the disease progresses inexorably, with no better quality of life. The fundamental role of medicine is sometimes to cure, but always to bring comfort. In current situation, ALS patients need adequate palliative care more than anything else. Prognosis and treatment options should be discussed with the patient and the relatives, but full information about the prognosis may deprive the patient of hope. However, disclosure of the prognosis is necessary to obtain informed consent for management decisions such as tracheostomy and artificial ventilation. Nasal positive-pressure ventilation (BiPAP) is an alternative to tracheostomy, at least for some patients without advanced bulbar impairment. Nutritional status in patients who cannot swallow can be efficiently improved by a percutaneous endoscopic gastrostomy. (PEG).

One of the hypotheses in amyotrophic lateral sclerosis (ALS) indicates on excitatory amino acids as the cause of neuronal death. Changes in their concentration in the tissues and body fluids may be the consequence of a defect in their transport, as well as abnormal activities of glutamate metabolizing enzymes. Abnormal synthesis/degradation of these enzymes and/or influence of activators/inhibitors should be taken into account. The activity of enzymes of glutamate metabolism of rat spinal cord in vitro in the presence of serum and cerebrospinal fluid (CSF) of 20 patients with ALS and 20 healthy controls was tested. In the presence of serum of the ALS patients glutaminase was significantly stimulated, instead of being inhibited; the inhibition of GABA aminotransferase, glutamate decaboxylase and aspartate aminotransferase was less evident than in the controls, glutamate dehydrogenase lost its activity more than in control conditions, the inhibition of glutamine synthetase was comparable to that when normal serum was applied. The activity of the enzymes in the presence of CSF of ALS patients was generally similar to that of normal CSF, except of glutaminase which was stimulated and GABA aminotransferase, which was inhibited stronger than in the presence of normal CSF. This study indicates, that changes in glutamate concentration in tissues and body fluids in ALS may be caused, at least partly, by abnormalities in the activity of glutamate metabolism enzymes, which are in turn induced by neurotoxic agents present in body fluids of ALS patients.

Over the past 15 years an increasing awareness of the role of mutant ion channels in the pathogenesis of episodic neurological disorders has emerged. Molecular characteristic of genetic channelopathies, that are rare and monogenic, contributed to a better understanding of abnormalities in common episodic diseases such as migraine and epilepsy. Familial hemiplegic migraine, a rare autosomal dominant subtype of migraine with aura, is the first evidence implicating migraine as a neuronal channelopathy.

Disorders of neuromuscular transmission include a heterogenous group of diseases affecting the neuromuscular junction. The most important clinical syndrome is idiopathic myasthenia gravis. As a group, these disorders exhibit several common features, the essential one being a fluctuating fatigability and weakness of muscles. In this short review the molecular pathogenesis of different myasthenic syndromes is discussed.

Objective To assess the effect of interferon-beta 1A (IFNb 1A, Avonex) treatment on magnetic resonance (MR) image in patients with remitting-relapsing multiple sclerosis (RR MS) who participated in the Polish Avonex trial. Patients and methods RR MS patients (N = 126) participated in a two-year randomized open trial of Avonex treatment administered in the dose of 30 mcg once a week. MRI was performed twice in each case: shortly before the patient's enrollment in the study and within a month from the study completion. Changes in T2-weighted lesion volume and T1-weighted gadolinium-enhanced lesion volume, as well as the number of new T2-weighted and T1-weighted gadolinium-enhanced lesions were measured. Results Over the two-year treatment period the mean volume of T2-weighted lesions decreased by 3.9% (p = 0.83) while that of T1-weighted gadolinium-enhanced lesions decreased by 79% (p = 0.084%) as compared to the baseline MRI evaluation. The mean number of enhanced lesions after two years of Avonex therapy was reduced by 46.1% (p = 0.0035). The total number of enhanced lesions decreased by 49.8% (p = 0.0078). Both the number of new T2-weighted lesions, 3.7 per patient, and that of new T1-weighted gadolinium-enhanced lesions, 0.7 per patient, were comparable with the results obtained in other Avonex trials. Conclusion The results confirmed that interferon beta-1a (Avonex) has a significant effect in MS patients, slowing down the progress of their disease. This effect is particularly visible in T1-weighted contrast-enhanced images, indicating an impact of the treatment particularly on the inflammatory stage of the demyelination process.

A sporadic case of a 31 year-old woman with genetically confirmed diagnosis of LHON was presented. Both her optic nerves were affected, with a 5-year interval between the onset in one eye and the loss of vision in the second one. Besides optic atrophy clinical and laboratory signs of multiple sclerosis were found. A review of the literature suggests that the G3460A mutation present in this case rarely coexists with a MS-like clinical phenotype.

Glycoproteins in cerebrospinal fluid of 55 patients with amyotrophic lateral sclerosis (ALS), six disease controls (multifocal motor neuropathy, sensorimotor neuropathy, Guillain–Barré syndrome, spinal muscular atrophy type II, motor neuropathy with monoclonal gammopathy) and 20 healthy controls were separated by PAGE electrophoresis and then detected immunochemically with peanut agglutinin (PNA). In 36 amyotrophic lateral sclerosis patients the 262 kDa glycoprotein was significantly increased (over the normal mean ± SD × 2), which was associated with a decrease in the 114 kDa fraction. In the remaining patients, both fractions were either equal in concentration or the 114 kDa glycoprotein predominated. In normal cerebrospinal fluid, the 114 kDa glycoprotein predominated over the other glycoproteins. The total amount of separated glycoproteins was increased in 15 amyotrophic lateral sclerosis patients. In 12 of them it was followed by an increase in the percentage of the 262 kDa glycoprotein. There was no correlation between the content of the peanut agglutinin‐labelled glycoproteins and the patients' age, duration and severity of the disease. There was a correlation between the 262 kDa glycoprotein being increased in cerebrospinal fluid and the electrophysiological pattern of denervation seen in electromyographic study. The glycoproteins change, similar to that occurring in amyotrophic lateral sclerosis patients, was also observed in one case of multifocal motor neuropathy (MMN). We suggest that in amyotrophic lateral sclerosis and multifocal motor neuropathy, the peanut agglutinin‐labelled glycoproteins are released in excess from the nervous tissues into the cerebrospinal fluid as a result of neuronal degeneration. The question to be answered is, whether the released glycoproteins are becoming targets for auto‐antibodies.

Kennedy's disease is a rare X-linked spinal and bulbar muscular atrophy (SBMA). A degenerative process of the motor neurons is associated with an increase in the number of CAG repeats encoding a polyglutamine stretch within the androgen receptor. Despite a distinctive clinical phenotype, SBMA can be misdiagnosed, usually due to the lack of clear family history. Accurate diagnosis is important for genetic counseling and because alternative diagnosis of amyotrophic lateral sclerosis usually means much worse prognosis. We report 2 unrelated patients with Kennedy's disease in whom the clinical diagnosis was confirmed by showing the CAG repeat expansion.