Changing phenotypic expression in a patient with a mitochondrial encephalopathy due to 13042G>A de novo mutation--a 5 year follow up.

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.

Muscle pathology in myotonic dystrophy: light and electron microscopic investigation in eighteen patients.

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.

Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

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.

Erythropoietin concentration in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

Erythropoietin (EPO) acts as a neuroprotective factor and is upregulated after neuronal injury. It has been reported that in cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients, the EPO concentration is decreased. In this study, EPO levels in serum and CSF of 30 patients with ALS and in 15 controls, using an ELISA technique, were estimated. EPO level in serum was decreased, especially in patients with bulbar onset ALS. A trend toward a progressive EPO decline with the duration of the disease in the mild + moderate ALS cases was observed. In severe cases, a tendency towards a positive correlation of EPO and duration of the disease was present. Serum EPO values were age related only in mild + moderate ALS in patients below 40 years of age. In CSF, the EPO levels were significantly decreased. Lower EPO values in the bulbar onset ALS when compared with the spinal onset ALS were present. The EPO decrease did not correlate with the severity and duration of the disease. Age relation of the EPO level only in the mild + moderate ALS cases more than 40 years was present. Lack of differences in EPO levels between patients with ALS of rapid and slow progression indicates that EPO concentration cannot be used as a prognostic factor. Nevertheless, the decreased serum and CSF EPO concentration and the known EPO neuroprotective action may indicate that EPO administration can be a new promising therapeutic approach in ALS.

Evaluation of matrix metalloproteinases in serum of patients with amyotrophic lateral sclerosis with pattern recognition methods.

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.

MuSK-positive myasthenia gravis is rare in the Polish population.

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.

Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

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-, alpha-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.

Elevated levels of anti-Chlamydia pneumoniae IgA and IgG antibodies in young adults with ischemic stroke.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia.

BACKGROUND: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by episodic hyperkinetic movement attacks. We have recently identified mutations in the MR-1 gene causing familial PNKD. METHODS: 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 MR-1 mutations and 6 did not. RESULTS: Patients with PNKD with MR-1 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 MR-1 mutations were more variable in their age at onset, precipitants, clinical features, and response to medications. Several were induced by persistent exercise. CONCLUSIONS: 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 (MR-1) gene mutations. Other "PNKD-like" families exist, but atypical features suggests that these subjects are clinically distinct from PNKD and do not have MR-1 mutations. Some may represent paroxysmal exertional dyskinesia.

APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers.

BACKGROUND: Previous studies have examined the role of APOE 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 APOE epsilon polymorphism. METHODS: Studies of MS and APOE 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 APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. RESULTS: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of epsilon2 or epsilon4 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 APOE genotypes in 1,279 MS families were also negative (p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE 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. CONCLUSION: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

A single-fibre EMG study of neuromuscular transmission in migraine patients.

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.

Correlating phenotype and genotype in the periodic paralyses.

BACKGROUND: 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. OBJECTIVE: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy.

The authors analyzed the CLCN2 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 CLCN2 mutations may be a rare cause of familial epilepsy. Further studies are needed to test if polymorphisms in this gene are associated with epilepsy.

Improvement of motor function in early Parkinson disease by safinamide.

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 > or =30% from baseline (responders) after 3 months from 21.4% (placebo) to 37.5% (p < 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; p > or = 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.

Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis.

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. Genotypes 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 epsilon4 allele was not related to the disease course or the ApoE epsilon2 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 (P < 0.05) and by a higher value of EDSS. According 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.

Serum IgM anti-GM1 ganglioside antibodies in lower motor neuron syndromes.

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.

CADASIL: new cases and new questions.

We described the first two unrelated Polish families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In the morphological examination with light microscopy, two kinds of changes were observed: (1). panarteritis nodosa-like changes with eosinophilic fibrinoid necrosis of the vessel wall and perivascular inflammatory infiltrates and (2). basophilic granular material in the tunica media characteristic of CADASIL. At electron microscopy, we found deposits of granular osmophilic material (GOM) within the wall of arteries, veins and capillary vessels. Our findings imply two questions requiring further investigation: Why in the genetically determined vascular disorder are the features of systemic inflammatory vascular disease present? Why in capillary walls deprived of smooth muscle cells are deposits of GOM present?

Effect of Riluzole on serum amino acids in patients with amyotrophic lateral sclerosis.

OBJECTIVES: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[The effect of selegiline and vitamin E in the treatment of ALS: an open randomized clinical trials]. / Ocena skutecznosci selegiliny i witaminy E w leczeniu SLA: otwarta randomizowana próba kliniczna.

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.

[Kennedy's disease: expansion of the CAG trinucleotide]. / Choroba Kennedy'ego: ekspansja trójki nukleotydowej CAG.

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.