Identification of a Novel GLA Gene Mutation, p.Ile239Met, in Fabry Disease With a Predominant Cardiac Phenotype.

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.

International Issues: Cross-border mobility of junior neurologists within and to the European Union.

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.

Transcranial direct current stimulation in refractory continuous spikes and waves during slow sleep: a controlled study.

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.

Simple autonomic seizures and ictal enuresis.

Human micturition is physiologically controlled via a complex and finely tuned network of cortical and subcortical regions, hitherto not fully understood. We report the case of a 42-year-old man with juvenile myoclonic epilepsy (JME) and post-traumatic epilepsy. Ictal enuresis was the only manifestation of the de novo post-traumatic simple autonomic seizures. Source analysis of the ictal epileptiform discharges showed activation of the cortical areas surrounding the right inferior frontal sulcus, adjacent to the lesional zone. The case depicted here further endorses recent neuroimaging studies which strongly implicate this cortical region in the regulation and the initiation of the micturition.

Task-related temporal and topographical changes of cortical activity during ultra-rapid visual categorization.

The aim of our study was to provide electrophysiological evidence about the modulation of the categorization process by task requirements in the human brain. Event-related potentials (ERP) were recorded during three different categorization tasks using matched stimulus sets. In all cases, the subjects were required to differentiate between "animal" and "non-animal" stimuli. In the first task (two-choice task), they were asked to press corresponding buttons to each stimulus types. The second task was a go/no-go paradigm, only animal stimuli required motor response. The third task was a counting task; participants had to count the animal stimuli without any motor response. The reaction times in the go/no-go paradigm were significantly shorter. ERP differences between animal and non-animal pictures in the go/no-go task also appeared earlier and were localized at more posterior scalp positions compared to the two-choice task. Comparing animal responses in the two-choice task and in the go/no-go paradigm, we found a significant difference in the 130- to 170-ms time window over the fronto-central, centro-parietal regions. Similar differences were found between the responses to animal pictures in the two-choice task and in the counting paradigm. We used brain electric source analysis (BESA) algorithm on difference waves to localize the best fitting dipoles and determine the localization of brain areas contributing to scalp potential differences. The results show that different task requirements evoke different activity in the medial part of the temporal pole. The data we provided here draw attention to the careful handling of results obtained from categorization experiments, because different task requirements can affect the early categorization process itself.

Direct current stimulation over MT+/V5 modulates motion aftereffect in humans.

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.

Oscillatory brain activity and transcranial direct current stimulation in humans.

The aim of this study was to induce changes of the oscillatory activity in the visual cortex of healthy human subjects by modulation of neuronal excitability using weak transcranial direct current stimulation (tDCS). tDCS is a non-invasive stimulation method which induces prolonged, polarity-dependent increases or reductions in cortical excitability. An increase in high frequency oscillatory activity in the beta and gamma frequency ranges is closely related in time to the N70 peak of the primary visual evoked potential (VEP), which is an early sensory component of visual activation. Therefore this potential can be used to observe tDCS-induced changes related to oscillatory activity. VEPs were recorded using sinusoidal luminance gratings in an on/off mode before, immediately after and 10, 20, 30 min after the end of 10 min anodal or cathodal stimulation. Cathodal stimulation significantly decreased while anodal stimulation slightly increased the normalized beta and gamma frequency powers. We have shown here that tDCS transiently and reversibly changed the organized cortical activity elicited by visual stimulation. Since gamma activity is also related to a higher level of information processing, tDCS might be a suitable method to affect higher order cognitive processes.