Fabry disease (FD) is an X-linked inherited lysosomal storage disorder caused by mutations in the GLA gene, encoding for the enzyme α-galactosidase A. Although hundreds of mutations in the GLA gene ...have been described, many of them are variants of unknown significance. Here we report a novel GLA mutation, p.Ile239Met, identified in a large Hungarian three-generation family with FD. A 69 year-old female index patient with a clinical history of renal failure, hypertrophic cardiomyopathy, and 2nd degree AV block was screened for mutation in the GLA gene. Genetic screening identified a previously unreported heterozygous mutation in exon 5 of the GLA gene (c.717A>G; p.Ile239Met). Family screening indicated that altogether 6 family members carried the mutation (5 females, 1 male, average age: 55 ± 16 years). Three family members, including the index patient, manifested the cardiac phenotype of hypertrophic cardiomyopathy, while two other family members were diagnosed with left ventricular hypertrophy. Taking affection status as the presence of hypertrophic cardiomyopathy, left ventricular hypertrophy or elevated lyso-Gb3 levels, all affected family members carried the mutation. Linkage analysis of the family gave a two-point LOD score of 2.01 between the affection status and the p.Ile239Met GLA mutation. Lyso-Gb3 levels were elevated in all carrier family members (range: 2.4-13.8 ng/mL; upper limit of normal +2STD: ≤ 1.8 ng/mL). The GLA enzyme level was markedly reduced in the affected male family member (< 0.2 µmol/L/hour; upper limit of normal ± 2STD: ≥ 2.6 µmol/L/hour). We conclude that the p. Ile239Met GLA mutation is a pathogenic mutation for FD associated with predominant cardiac phenotype.
Summary Cathodal transcranial direct current stimulation (tDCS) decreases cortical excitability. The purpose of the study was to investigate whether cathodal tDCS could interrupt the continuous ...epileptiform activity. Five patients with focal, refractory continuous spikes and waves during slow sleep were recruited. Cathodal tDCS and sham stimulation were applied to the epileptic focus, before sleep (1 mA; 20 min). Cathodal tDCS did not reduce the spike-index in any of the patients.
The transcriptional regulator DntR, which previously has been isolated from bacterial strains capable of degrading 2,4-dinitrotoluene (DNT), was engineered in order to improve the ability to detect ...DNT. A directed evolution strategy was employed, where sequence diversity first was created by random mutagenesis in three subsequent rounds, followed by recombination of previously selected mutants. A gfp gene was used as a reporter for transcriptional activity mediated by DntR and cells with higher GFP expression after addition of DNT were sorted out using fluorescence-activated cell sorting (FACS). A DntR mutant, which displayed 10 times higher induction levels than wild-type DntR in response to DNT was isolated. This mutant still maintained low levels of gfp expression in the absence of DNT. The detection limit was ∼10 µM, a 25-fold improvement compared to wild-type DntR. The functional role of some substitutions found in this clone is discussed in the framework of the structural changes observed when comparing the recently determined structures of DntR with and without bound inducer ligand.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hsp27 belongs to the small heat shock protein family, which are ATP-independent chaperones. The most important function of Hsp27 is based on its ability to bind non-native proteins and inhibit the ...aggregation of incorrectly folded proteins maintaining them in a refolding-competent state. Additionally, it has anti-apoptotic and antioxidant activities. To study the effect of Hsp27 on memory and synaptic functions, amyloid-β (Aβ) accumulation, and neurodegeneration, we generated transgenic mice overexpressing human Hsp27 protein and crossed with APPswe/PS 1 dE9 mouse strain, a mouse model of Alzheimer's disease (AD). Using different behavioral tests, we found that spatial learning was impaired in AD model mice and was rescued by Hsp27 overexpression. Electrophysiological recordings have revealed that excitability of neurons was significantly increased, and long-term potentiation (LTP) was impaired in AD model mice, whereas they were normalized in Hsp27 overexpressing AD model mice. Using anti-amyloid antibody, we counted significantly less amyloid plaques in the brain of APPswe/PS 1 dE9/Hsp27 animals compared to AD model mice. These results suggest that overexpression of Hsp27 protein might ameliorate certain symptoms of AD.
OBJECTIVE:To assess the general interest in and motivation for cross-border mobility among residents and junior neurologists from member states of the European Union and neighboring countries.
...METHODS:Questionnaire-based paper survey among 118 participants of a neurology course.
RESULTS:Ninety-seven (82%) participants returned the survey. Most of them had at one point considered relocating within or to the European Union for postgraduate education (87%) or employment (71%). Common motivations were superior prospects for clinical training (85%), resources at work and academic environment (both 80%), and remuneration (70%). Barely half of the surveyed intended to return to their home country. The attractiveness of Europe as a destination for migration was ranked over other continents. The most common reasons that reduce enthusiasm for relocation were the loss of family connection (55%) and uncertain future prospects (41%), whereas language barriers were less relevant (21%).
CONCLUSION:There is keen interest of the upcoming generation of neurologists to relocate within and to the European Union. The motives include regional differences in training and career opportunities as well as economic welfare. Appropriate steps toward the harmonization of educational and career prospects are urgently required to ensure adequate provision of neurology service and patient care throughout Europe.
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, M-protein agglutination, disialosyl antibodies) syndrome is a rare polyneuropathy. IgM paraproteins react with ganglioside-containing disialylated ...epitopes resulting in dorsal root ganglionopathy and B-lymphocyte infiltration of cranial and peripheral nerves. Clinical features include ataxia, slight muscle weakness, areflexia, sensory- and cranial nerve symptoms. Case studies have reported the efficacy of rituximab and intravenous immunoglobulin (IVIg) treatments. We present the case of a 57-year-old man, who had difficulty walking, with numbness and clumsiness in all limbs. He had areflexia, vibratory sensation loss and ataxia. Laboratory tests showed IgM monoclonal components and disialosyl antibodies in the serum. Nerve conduction studies indicated severe sensorimotor demyelinating polyneuroradiculopathy. Despite IVIg and rituximab treatments, the patient's disease course gradually worsened and he died of respiratory failure. Neuropathological examination revealed dorsal column- and dorsal root atrophy with mixed mononuclear cell infiltration. This article aims to draw attention to this syndrome, and the use of early potent immunosuppressive treatment to improve patients' quality of life.
Phospholipase A2-associated Neurodegeneration (PLAN) is a group of neurodegenerative diseases associated with the alterations of PLA2G6. Some phenotype-genotype association are well known but there ...is no clear explanation why some cases can be classified into distinct subgroups, while others follow a continuous clinical spectrum.
Long-term neurological, and psychiatric follow-up, neuropathological, radiological, and genetic examinations, were performed in three affected girls and their family.
Two 24-years old twins and their 22-years old sister harbored the p.P622S, and p.R600W mutation in PLA2G6. The age of onset and the most prominent presenting symptoms (gaze palsy, ataxia, dystonia, psychomotor regression indicated atypical neuroaxonal dystrophy (ANAD), however, optic atrophy, severe tetraparesis would fit into infantile neuroaxonal dystrophy (INAD). All siblings had hyperintensity in the globi pallidi and substantiae nigrae which is reported in ANAD, whereas it is considered a later neuroradiological marker in INAD. The slow progression, rigidity, bradykinesis, and the prominent psychiatric symptoms indicate PLA2G6-related dystonia-parkinsonism. Abnormal mitochondria, lipid accumulation and axonal spheroids were observed in the muscle and nerve tissue. Brain deposition appeared 6 years following the initial cerebellar atrophy. Mild MRI alterations were detected in the asymptomatic carrier parents.
The colorful clinical symptoms, the slightly discordant phenotype, and the neuroimaging data in the family supports the view that despite the distinct definition of age-related phenotypes in PLAN, these are not strict disease categories, but rather a continuous phenotypic spectrum. The mild MRI alterations of the parents and the family history suggest that even heterozygous pathogenic variants might be associated with clinical symptoms, although systematic study is needed to prove this.
While there is strong evidence for the central role of the human MT+/V5 in motion processing, its involvement in motion adaptation is still the subject of debate. We used transcranial direct current ...stimulation (tDCS) to test whether MT+/V5 is part of the neural network involved in the long-term adaptation-induced motion after-effect in humans. It was found that both cathodal and anodal stimulation over MT+/V5 resulted in a significant reduction of the perceived motion after-effect duration, but had no effect on performance in a luminance-change-detection task used to determine attentional load during adaptation. Our control experiment excluded the possibility that the observed MT+/V5 stimulation effects were due to a diffused modulation of the early cortical areas, i.e. by the stimulation applied over MT+/V5. These results provide evidence that external modulation of neural excitability in human MT+/V5 affects the strength of perceived motion after-effect and support the involvement of MT+/V5 in motion adaptation processes.
•First comprehensive epidemiology study in Hungarian Charcot-Marie-Tooth patients.•59.9% of our CMT patients received a genetic diagnosis.•Associated features co-occurred in more than one fifth of ...the cases.
Charcot-Marie-Tooth neuropathy (CMT) is a genetically and clinically heterogeneous group of neuromuscular disorders with an overall prevalence of 1 per 2500. Here we report the first comprehensive genetic epidemiology study of Hungarian CMT patients. 409 CMT1 and 122 CMT2 patients were enrolled and genetic testing of PMP22, GJB1, MPZ, EGR2 and MFN2 genes were performed routinely. NDRG1 and CTDP1 genes were screened only for founder mutations in Roma patients. Causative genetic mutations were identified in 67.2% of the CMT1 and in 33.6% of the CMT2 cases, which indicates an overall success rate of 59.9% in the study population. Considering all affected individuals, alterations were most frequently found in PMP22 (40.5%), followed by GJB1 (9.2%), MPZ (4.5%), MFN2 (2.5%), NDRG1 (1.5%), EGR2 (0.8%) and CTDP1 (0.8%). The phenotypic spectrum and the disease severity of the studied patients also varied broadly. Deafness and autoimmune disorders were more often associated with PMP22 duplication, while MFN2 and GJB1 mutations were frequently present with central nervous system abnormalities. Our study may be helpful in determining the strategy of genetic diagnostics in Hungarian CMT patients.
Neuronal hyperexcitability is a phenomenon associated with early Alzheimer’s disease. The underlying mechanism is considered to involve excessive activation of glutamate receptors; however, the exact ...molecular pathway remains to be determined. Extracellular recording from the CA1 of hippocampal slices is a long-standing standard for a range of studies both in basic research and in neuropharmacology. Evoked field potentials (fEPSPs) are regarded as the input, while spiking rate is regarded as the output of the neuronal network; however, the relationship between these two phenomena is not fully clear. We investigated the relationship between spontaneous spiking and evoked fEPSPs using mouse hippocampal slices. Blocking AMPA receptors (AMPARs) with CNQX abolished fEPSPs, but left firing rate unchanged. NMDA receptor (NMDAR) blockade with MK801 decreased neuronal spiking dose dependently without altering fEPSPs. Activating NMDARs by small concentration of NMDA induced a trend of increased firing. These results suggest that fEPSPs are mediated by synaptic activation of AMPARs, while spontaneous firing is regulated by the activation of extrasynaptic NMDARs. Synaptotoxic Abeta(1-42) increased firing activity without modifying evoked fEPSPs. This hyperexcitation was prevented by ifenprodil, an antagonist of the NR2B NMDARs. Overall, these results suggest that Abeta(1-42) induced neuronal overactivity is not dependent on AMPARs but requires NR2B.
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