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.

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.

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.

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.

Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita.

Myotonia, defined as delayed relaxation of muscle after contraction, is seen in a group of genetic disorders that includes autosomal dominant myotonia congenita (Thomsen's disease) and autosomal recessive myotonia congenita (Becker's 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 Becker's, but not Thomsen's disease. Becker's and Thomsen's 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 Gln-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.

Treatment of myotonic dystrophy with acetazolamide.

This report describes a patient with myotonic dystrophy who had severe action and percussion myotonia. The patient was unresponsive to diphenylhydantoin therapy. Treatment with acetazolamide, 250 mg daily, decreased the myotonia markedly. A possible mechanism of the favorable effect of acetazolamide in myotonia is discussed.

Myotonia induced with clofibrate in rats.

Myotonia was induced in rats with clofibrate given in daily subcutaneous injections of 0.4 g/kg. The first myotonic discharges were recorded electromyographically from the extensor digitorum longus, tibialis anterior, and gastrocnemius muscles after 4 days on clofibrate, but from the soleus not until after 11 days. Clofibrate induced myotonic activity in chronically denervated muscle also. During repetitive nerve stimulation the electrical response of the muscle was declining in all myotonic rats. It did so also when repetitive stimulation was applied directly to the muscle, which would seem to suggest a myotonic defect as the cause. Several drugs were tested and diphenylhydantoin proved to inhibit myotonia most effectively. Animals on an extended clofibrate schedule (12 weeks) had ECG abnormalities resembling those seen in patients with myotonic dystrophy.

Progressive supranuclear palsy with lower motor neuron involvement. A case report.

The clinical picture of progressive supranuclear palsy is relatively constant, including supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia in extension, parkinsonian signs, postural instability and dementia. A case is reported, which is unusual in having flexor dystonia of the neck and marked signs of lower motor neuron involvement.

Plasma membranes of muscle in experimental myotonia in rats.

Determinations of protein and phospholipid composition, as well as enzymatic activity, were carried out in plasma membranes isolated from the muscle of rats, after different periods of 20,25-diazacholesterol administration. A decrease in the level of phospholipids, and in the total amount of plasma membrane proteins, connected with a relative reduction in the amount of protein of a molecular weight of 100000 daltons, was found. The activity of (Na+ + K+)-ATP-ase gradually decreased while a reverse tendency was observed in the case of 5'-nucleotidase. Changes in ATP-ase and phospholipids appeared even prior to electrophysiologically recorded signs of the myotonia. The mechanism of these changes and their possible role in myotonia are discussed.

Sarcoplasmic reticulum in experimental myotonia in rats.

Determinations of enzymatic activity, protein structure and phospholipid composition of sarcoplasmic reticulum isolated from the soleus muscle (S), extensor digitorum longus muscle (EDL) and gastrocnemius muscle (G) in rats were carried out after various periods of 20,25-diazacholesterol administration. The sarcoplasmic reticulum from G and EDL of myotonic rats exhibited a rise in basal ATP-ase activity and a fall of total phospholipids. The protein of molecular weight of 100000 daltons in G and EDL was slightly more pronounced.

Dissections after childbirth.

The occurrence of spontaneous internal carotid or vertebral artery dissection after childbirth remains rare. To our knowledge, seven cases of arterial dissection in the postpartum period have been described in the literature as single case reports. We report four additional cases of internal carotid and vertebral artery dissection in the puerperal period, documented by angiography. Physicians should consider the possibility of arterial dissection in any young patient presenting with acute ischemic stroke, including women in the postpartum period. The availability of modern noninvasive ultrasound and imaging techniques may result in earlier diagnosis and facilitate identification of this condition.

Myofibrillar protein pattern in experimental myotonia in rats.

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 alpha-actinin was demonstrated in m. gastrocnemius. A change of the same character, not statistically significant, was observed in the m. extensor digitorum longus.

Factor V Leiden, prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase C677T genotype in young adults with ischemic stroke.

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.

ApoE polymorphism in Polish patients with Alzheimer's disease.

Alzheimer's disease is a genetically heterogeneous disorder of CNS. The presence of APOE-epsilon 4 allele is known to increase the risk of early and late onset sporadic and late onset familial forms of AD. In various Western European countries, USA, Canada, Japan and Australia the allelic frequency ranges between 0.1-0.18 in controls, and between 0.24-0.52 in AD patients. In the present study on Polish population, we analyzed the frequency of APOE-epsilon 4 allele in persons with Alzheimer's disease (AD). APOE genotypes were determined in 30 mild to moderate AD (83%) and mixed dementia (MIX, 17%), as well as in 11 nondemented first-degree relatives of AD (NDR), recruited from AD patient registry in Warsaw. Among the AD and MIX patients the APOE-epsilon 4, epsilon 3, epsilon 2 allele frequency was 0.333, 0.65 and 0.017 respectively.

[Disorders of neuromuscular transmission]. / Zaburzenia transmisji nerwowo-miesniowej.

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.

[Symptomatic treatment and palliative care of ALS]. / Leczenie objawowe i opieka paliatywna w SLA.

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).

[Neurogenic pulmonary edema: case report and analysis of pathogenesis]. / Neurogenny obrzek pluc: opis przypadku i omówienie patogenezy.

We describe a young female with subarachnoid haemorrhage (SAH) who developed neurogenic pulmonary edema (NPE). The symptoms of NPE were associated with severe mitral regurgitation. Both NPE and mitral insufficiency were completely reversible. The pathogenesis of NPE and cardiac injury is discussed.

[The role of mitochondrial respiratory chain in the pathogenesis of ALS]. / Rola mitochondrialnego lancucha oddechowego w patogenezie SLA.

Mitochondrial dysfunction and abnormal electron chain transport (ECT) may be involved in the pathogenesis of ALS. The aim of this study was to investigate the effect of cerebrospinal fluid (CSF) from ALS patients on the activity of ECT enzymes in mitochondrial cerebral crude preparations in the rats. We found that CSF inhibited the activity of complex I-III in 20%, complex II-III in 12% and complex IV in 33% of the ALS patients. CSF from the controls did not affect the activity of complex I-III and II-III. The effect of the CSF ultrafiltrates with cut off below 5000 daltons on the activity of ECT enzymes was also investigated. The CSF ultrafiltrates inhibited the activity of complex I-III, complex II-III and complex IV in 38%, 44% and 53% of the ALS patients, and in 80%, 53% and 43% of the controls, respectively. The results of this study and our previously reported experiments on the sera of ALS patients may indicate that neurotoxic effects of body fluids from ALS patients could be mediated by inhibition of the respiratory chain enzymes. This confirms an important role of mitochondrial dysfunction in the pathogenesis of ALS.

[Isaacs-Mertens syndrome: continuous activity of motor units]. / Zespól Isaacsa-Mertensa: ciagla czynnosc jednostki ruchowej.

The syndrome of Isaacs-Mertens is a rare neuromuscular disease in which the motor unit is continuously active. The diagnosis is based on electrophysiological methods and pharmacological tests. The involvement of laryngeal muscles observed in the reported female patient has been as yet rarely described in this syndrome. In the treatment long-term administration of carbamazepine 600 mg daily gave a considerable clinical improvement. The pathological mechanism of the syndrome is discussed in the light of the performed examinations and a review of the pertinent literature.