Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.Peer reviewe

Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not

12 páginasNeurons of the peripheral nervous system have long been known to require survival factors to prevent their death during development. But why they selectively become dependent on secretory molecules has remained a mystery, as is the observation that in the central nervous system, most neurons do not show this dependency. Using engineered embryonic stem cells, we show here that the neurotrophin receptors TrkA and TrkC (tropomyosin receptor kinase A and C, also known as Ntrk1 and Ntrk3, respectively) instruct developing neurons to die, both in vitro and in vivo. By contrast, TrkB (also known as Ntrk2), a closely related receptor primarily expressed in the central nervous system, does not. These results indicate that TrkA and TrkC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic-factor-dependent for survival. We suggest that the expansion of the Trk gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number controlH.L. is supported by an Emmy-Nother fellowship of the DFG.Peer reviewe

EEG/fMRI study of ictal and interictal epileptic activity: Methodological issues and future perspectives in clinical practice

Purpose: Electroencephalography/functional magnetic resonance imaging (EEG/fMRI) has been proposed recently as a tool to study electrophysiological activity and, consequently, detect brain regions activated during epileptiform EEG abnormalities. The purpose of the study was to review our two-year experience with studying ictal and interictal activities in patients with epilepsy. Methods: Using EEG/fMRI, we studied hemodynamic changes associated with ictal and interictal EEG abnormalities in 43 patients with partial (31 cases) or generalized (12 cases) epilepsy. Using two different paradigms (block design and event-related design), we studied several forms of EEG activity consisting of (i) interictal abnormalities constantly elicitable by specific stimulation (8 cases); (ii) focal and generalized interictal activity, such as focal spikes or typical and atypical generalized spike-and-wave discharges (18 cases); and (iii) focal and generalized ictal electro-clinical activity, such as tonic seizures or pseudo-absences in frontal lobe epilepsy, typical absences in idiopathic generalized epilepsy, complex partial seizures in temporal lobe epilepsy, and perisylvian seizures in special syndromes (17 patients). Results: EEG/fMRI revealed clear hemodynamic changes related to EEG abnormalities in 21 patients. In 18 of these patients, the changes were highly concordant with electro-clinical findings. In the remaining 22 patients, fMRI analysis data failed to show activation or deactivation clusters, probably owing either to lack or inadequate amount of temporal distribution of abnormal EEG activity, or to intrinsic methodological problems. Conclusions: By defining the electro-clinical and hemodynamic correlates of EEG activity, fMRI may shed light on the neurophysiological mechanisms underlying epileptic phenomena. However, as several methodological issues have yet to be addressed, further studies are warranted to assess the reliability and usefulness of EEG/fMRI in clinical practice. © 2006 International League Against Epilepsy

Diffusion-weighted magnetic resonance imaging in patients with partial status epilepticus

Diffusion-weighted magnetic resonance imaging (DWI) is used to detect changes in the distribution of water molecules in regions affected by various pathologies. Like other conditions, ictal epileptic activity, such as status epilepticus (SE), can cause regional vasogenic/cytotoxic edema that reflects hemodynamic and metabolic changes. This study describes the electroclinical and neuroimaging findings in 10 patients with partial SE whose DWI evaluation disclosed periictal changes related to sustained epileptic activity. In this retrospective study we selected 10 patients with partial SE of different etiologies (six acute symptomatic SE; four with previous epilepsy and concomitant precipitating factors) who underwent video-EEG (electroencephalography) monitoring and a DWI study during the periictal phase. We analyzed ictal electroclinical features and DWI changes in the acute phase and during the follow-up period. DWI images revealed significant signal alterations in different brain regions depending on the location of ictal activity. DWI changes were highly concordant with the electroclinical findings in all 10 patients. As the SE resolved and the clinical conditions improved, DWI follow-up showed that the signal alterations gradually disappeared, thereby documenting their close relationship with ictal activity. This study confirms the usefulness of DWI imaging in clinical practice for a more accurate definition of the hemodynamic/metabolic changes occurring during sustained epileptic activity

Metabolic alterations transients during paroxysmal activity in an epileptic patient with fixation-off sensitivity (FOS): a case study

The purpose of this study was to investigate short-time metabolic variations related to continuous epileptic activity elicited by fixation-off sensitivity (FOS). Time-resolved magnetic resonance spectroscopy was performed on a patient on whom previous clinical findings clearly indicated presence of FOS. The epileptic focus was localized with a simultaneous electroencephalographic and functional magnetic resonance imaging study. The results showed a linear increase of the sum of glutamate and glutamine with time of paroxysmal activity in epileptic focus and much greater concentration of choline-containing compounds in focus than in the contralateral side. D 2006 Elsevier Inc. All rights reserved