Weckhuysen S.,Neurogenetics Group |
Weckhuysen S.,University of Antwerp |
Korff C.M.,University of Geneva
Current Neurology and Neuroscience Reports | Year: 2014
Next-generation sequencing technologies have tremendously increased the speed of gene discovery in monogenic epilepsies, enabling us to identify a genetic cause in an increasing proportion of patients, and to better understand the underlying pathophysiology of their disease. The rapid speed with which new genes are being described lately, confronts clinicians with the difficult task of keeping up to date with the continuous supply of new publications. This article aims to discuss some of the genes that were recently discovered in monogenic familial epilepsy syndromes or epileptic encephalopathies for which an underlying cause remained unknown for a long time. © 2014 Springer Science+Business Media.
Raducu M.,Autonomous University of Madrid |
Baets J.,Neurogenetics Group |
Baets J.,University of Antwerp |
Fano O.,Autonomous University of Madrid |
And 2 more authors.
European Journal of Human Genetics | Year: 2012
Limb-girdle muscular dystrophy type 2O (LGMD2O) belongs to a group of rare muscular dystrophies named dystroglycanopathies, which are characterized molecularly by hypoglycosylation of α-dystroglycan (α-DG). Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose β-1,2-N- acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202). By functional analysis of various luciferase constructs, we localized a proximal POMGNT1 promoter and we found a 75% decrease in luciferase activity in the mutant construct when compared with the wild type. Electrophoretic mobility shift assay (EMSA) revealed binding sites for the Sp1, Ets1 and GATA transcription factors. Surprisingly, the mutation generated an additional ZNF202 binding site and this transcriptional repressor bound strongly to the mutant promoter while failing to recognize the wild-type promoter. Although the genetic causes of dystroglycanopathies are highly variable, they account for only 50% of the cases described. Our results emphasize the importance of extending the mutational screening outside the gene-coding region in dystroglycanopathy patients of unknown aetiology, because mutations in noncoding regions may be the cause of disease. Our findings also underline the requirement to perform functional studies that may assist the interpretation of the pathogenic potential of promoter alterations. © 2012 Macmillan Publishers Limited All rights reserved.
Bandopadhyay R.,University College London |
de Belleroche J.,Neurogenetics Group
Trends in Molecular Medicine | Year: 2010
Several neurodegenerative diseases, including Parkinson's disease (PD) are associated with protein misfolding and the formation of distinct aggregates, resulting in a putative pathological protein load on the nervous system. A variety of factors cause proteins to aggregate, including aggregation-prone sequences, specific mutations, protein modifications and also dysregulation of the protein degradation machinery. Molecular chaperones are responsible for maintaining normal protein homeostasis within the cell by assisting protein folding and modulating protein-degrading pathways. Here, we review the fundamental mechanisms of neurodegeneration occurring in PD involving α-synuclein fibrillisation and aggregation, endoplasmic reticulum stress, ubiquitin proteasome systems, autophagy and lysosomal degradation. Molecular chaperones serve a neuroprotective role in many of these pathways, and we discuss recent evidence indicating that these proteins might provide the basis for new therapeutic approaches. © 2009 Elsevier Ltd. All rights reserved.
Mullen S.A.,University of Melbourne |
Suls A.,Neurogenetics Group |
Suls A.,Bunge |
Suls A.,University of Antwerp |
And 6 more authors.
Neurology | Year: 2010
Background: Familial glucose transporter type 1 (GLUT1) deficiency due to autosomal dominant inheritance of SLC2A1 mutations is associated with paroxysmal exertional dyskinesia; epilepsy and intellectual disability occur in some family members. We recently demonstrated that GLUT1 deficiency occurs in over 10% of patients with early-onset absence epilepsy. Methods: This family study analyses the phenotypes in 2 kindreds segregating SLC2A1 mutations identified through probands with early-onset absence epilepsy. One comprised 9 individuals with mutations over 3 generations; the other had 6 individuals over 2 generations. Results: Of 15 subjects with SLC2A1 mutations, epilepsy occurred in 12. Absence seizures were the most prevalent seizure type (10/12), with onset from 3 to 34 years of age. Epilepsy phenotypes varied widely, including idiopathic generalized epilepsies (IGE) with absence (8/12), myoclonic-astatic epilepsy (2/12), and focal epilepsy (2/12). Paroxysmal exertional dyskinesia occurred in 7, and was subtle and universally undiagnosed prior to molecular diagnosis. There were 2 unaffected mutation carriers. Conclusions: GLUT1 deficiency is an important monogenic cause of absence epilepsies with onset from early childhood to adult life. Individual cases may be phenotypically indistinguishable from common forms of IGE. Although subtle paroxysmal exertional dyskinesia is a helpful diagnostic clue, it is far from universal. The phenotypic spectrum of GLUT1 deficiency is considerably greater than previously recognized. Diagnosis of GLUT1 deficiency has important treatment and genetic counseling implications. © 2010 by AAN Enterprises, Inc.
Kim Y.O.,University of Melbourne |
Kim Y.O.,Chonnam National University |
Korff C.M.,University of Geneva |
Villaluz M.M.G.,University of Melbourne |
And 8 more authors.
Developmental Medicine and Child Neurology | Year: 2013
STXBP1 encephalopathy is associated with a range of movement disorders. We observed head stereotypies in three patients. These comprised a slow (<1Hz), high-amplitude, horizontal, 'figure-of-eight' pattern, beginning at age 4-6 years and resulting in neck muscle hypertrophy, in two males; a faster (2-3Hz), side-to-side, 'no' movement, starting at the age of 9 years 6 months was observed in one female. Upper limb and truncal stereotypies and vocalization occurred intermittently with the head movements. The stereotypies increased with excitement but settled with concentration and sleep. Head and upper limb stereotypies are valuable clinical clues to the diagnosis of STXBP1 encephalopathy in patients with profound impairments. © 2013 Mac Keith Press.