Kristl G. Claeys

Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.

Charcot‐Marie‐Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive.

Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

BACKGROUND The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. METHODS We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. FINDINGS We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. INTERPRETATION The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

A Higher Order Motion Region in Human Inferior Parietal Lobule: Evidence from fMRI

The proposal that motion is processed by multiple mechanisms in the human brain has received little anatomical support so far. Here, we compared higher- and lower-level motion processing in the human brain using functional magnetic resonance imaging. We observed activation of an inferior parietal lobule (IPL) motion region by isoluminant red-green gratings when saliency of one color was increased and by long-range apparent motion at 7 Hz but not 2 Hz. This higher order motion region represents the entire visual field, while traditional motion regions predominantly process contralateral motion. Our results suggest that there are two motion-processing systems in the human brain: a contralateral lower-level luminance-based system, extending from hMT/V5+ into dorsal IPS and STS, and a bilateral higher-level saliency-based system in IPL.

A novel GABRG2 mutation associated with febrile seizures

Mutations in the gene encoding the γ2 subunit of the γ-aminobutyric acid type A receptor (GABRG2) have been reported to cause childhood absence epilepsy (CAE), febrile seizures (FS), and generalized epilepsy with FS plus (GEFS+). The authors analyzed GABRG2 in 47 unrelated patients with CAE, FS, and GEFS+ and identified a novel mutation that cosegregated with FS. Electrophysiologic studies demonstrated altered current desensitization and reduced benzodiazepine enhancement in mutant receptors.

Charcot-Marie-Tooth disease: a clinico-genetic confrontation.

Charcot‐Marie‐Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients.

The effect of cognitive load on saccadic eye movements

The present study tested the hypothesis that, unlike prosaccades, antisaccades require controlled processing, due to the prepotent response that needs to be inhibited. The effect of the Random time Interval Generation (RIG) task (Vandierendonck, A., De Vooght, G., & Van der Goten, K. (1998). European Journal of Cognitive Psychology, 10, 413-444) on these saccade latencies and errors was studied. This task has the advantage that it loads executive processes, with only minimal interference with verbal or visuo-spatial components. A first experiment compared saccade performance within the prosaccade and the antisaccade task, executed alone and in combination with the RIG task and fixed tapping (added to exclude possible motor component interference explanations). A second experiment investigated the influence of task characteristics on the effects found. Although it was shown that antisaccades are more prone to interference of an executive interference task, it seems that prosaccades are also vulnerable. Interference on prosaccades could originate from a controlled execution of these saccades. A third experiment confirmed that endogenously generated prosaccades are susceptible to dual-task interference and showed that controlled saccade execution, without the need to inhibit a prepotent response, is sufficient to produce interference.

Attention to 3-D Shape, 3-D Motion, and Texture in 3-D Structure from Motion Displays

We used fMRI to directly compare the neural substrates of three-dimensional (3-D) shape and motion processing for realistic textured objects rotating in depth. Subjects made judgments about several different attributes of these objects, including 3-D shape, the 3-D motion, and the scale of surface texture. For all of these tasks, we equated visual input, motor output, and task difficulty, and we controlled for differences in spatial attention. Judgments about 3-D shape from motion involve both parietal and occipito-temporal regions. The processing of 3-D shape is associated with the analysis of 3-D motion in parietal regions and the analysis of surface texture in occipito-temporal regions, which is consistent with the different behavioral roles that are typically attributed to the dorsal and ventral processing streams.

Familial occipitotemporal lobe epilepsy and migraine with visual aura Linkage to chromosome 9q

Objective: To map the disease-causing locus in a large Belgian family with occipitotemporal lobe epilepsy associated with migraine with visual aura and to describe the clinical, electrophysiologic, and imaging characteristics. Methods: DNA samples from 21 family members were obtained and an 8 cM density genome-wide scan was performed. The authors interviewed 21 individuals and performed interictal EEG in 14 and brain MRI in 13 individuals. Results: Nine at risk family members and one deceased individual had epilepsy with occipital and temporal lobe symptomatology, variable age at onset, usually good prognosis, no epileptic EEG features, and normal brain MRI. Five of the 10 patients had a history of migraine with aura (p = 0.0026). Seizures and migraine attacks occurred as separate episodes in all but one patient. Three patients described light flashes both as epileptic and migraine aura. Epilepsy and migraine started at the same age in three patients and remitted simultaneously in two. The epileptic phenotype had a dominant mode of inheritance with a reduced penetrance of 75%. A conclusive two-point lod score of 3.3 was obtained for marker D9S257 at recombination fraction zero. Haplotype analysis defined a candidate region of 9.95 cM (5.96 Mb) between markers GATA152H04 and D9S253 located at chromosome 9q21-q22 based upon recombinations in affected individuals. Conclusions: The clinical association in this family of occipitotemporal lobe epilepsy and migraine with visual aura and the conclusive linkage of the occipitotemporal lobe epilepsy/migraine with aura trait to a single locus suggests a common monogenic gene defect.

Muscle glycogenosis due to phosphoglucomutase 1 deficiency.

To the Editor: Muscle glycogen storage diseases are rare inborn diseases caused by errors of metabolism associated with either dynamic, exercise-related symptoms or permanent muscle weakness. The m...

CORE-ROD MYOPATHY CAUSED BY MUTATIONS IN THE NEBULIN GENE

Nemaline myopathy (NM) and central core disease (CCD), 2 of the most frequent congenital myopathies, are clinically and genetically heterogeneous disorders of skeletal muscle. NM (OMIM 161800) is caused by mutations in at least 6 different genes encoding thin filament proteins of the striated muscle sarcomere: skeletal alpha-actin ( ACTA1 ), nebulin ( NEB ), beta-tropomyosin ( TPM2 ), slow alpha-tropomyosin ( TPM3 ), slow skeletal muscle troponin-T ( TNNT1 ), and cofilin-2 ( CFL2 ). CCD (OMIM 117000) is mainly caused by mutations in the gene encoding the skeletal muscle ryanodine receptor ( RYR1 ), a Ca2+ channel involved in excitation-contraction coupling. Congenital myopathies with the combination of distinct “cores” and “rods” in the same muscle fibers have been described in a small number of cases. In 2 families mutations have been identified in RYR1 1,2 and in others, linkage has been found to a locus on chromosome 15.3 Here we report a patient with recessively inherited core-rod myopathy caused by compound heterozygous mutations in NEB . This observation broadens the spectrum of genes involved in core-rod myopathies. ### Case report. The patient is a 27-year-old white man. He presented at birth with generalized hypotonia and required immediate intubation and resuscitation. Spontaneous movements were very poor and he had seizures from the first week. Restrictive respiratory insufficiency led to continuous mechanical ventilation via tracheotomy at the age of 2 years. The patient did not acquire independent walking but was able to take a few steps with orthosis at the age of 4; diffuse muscle weakness with axial predominance was observed. Electromyography showed myopathic patterns and normal motor and sensory responses. Serum creatine kinase levels were normal. The patient developed …