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Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

I Dierick, J Baets, J Irobi, A Jacobs, Vriendt E De, T Deconinck, L Merlini, den Bergh P Van, VM Rasic, W Robberecht, D Fischer, RJ Morales, Z Mitrovic, P Seeman, R Mazanec, A Kochanski, A Jordanova, M Auer-Grumbach, den Enden AT Helderman-van,...

. 2008 ; 131 (Pt 5) : 1217-1227.

Language English Country Great Britain

Document type Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc14055606

Grant support
NR9517 MZ0 CEP Register

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.

Clinic of Child Neurology and Psychiatry University of Belgrade Belgrade Serbia

Department of Child Neurology Charles University 2nd School of Medicine Prague

Department of Clinical Genetics Leiden University Medical Center Leiden

Department of Neurology Charles University 2nd School of Medicine and University Hospital Motol Prague Czech Republic

Department of Neurology University Hospital Gasthuisberg Leuven Belgium

Department of Neurology University Hospital of Basel Basel Switzerland

Department of Neurology University Medical Center Utrecht Utrecht The Netherlands

Division of Neurology University Hospital Antwerpen Antwerpen Belgium

Institute of Medical Biology and Department of Internal Medicine Diabetes and Metabolism Medical University Graz Austria

Laboratory of Molecular Patholog y Sofia Medical University Sofia Bulgaria

Muscle Unit Division of Medical Genetics Department of Experimental and Diagnostic Medicine University of Ferrara Ferrara Italy

Muskelzentrum St Gallen Kantonsspital St Gallen St Gallen

National Center for Neuromuscular Diseases Department of Neurology University Hospital Center Zagreb Zagreb Croatia

Neurogenetics Group VIB Department of Molecular Genetics University of Antwerp Antwerpen Belgium

Neurogenetics laboratory Institute Born Bunge

Neurology Department University Hospital of Montpellier Montpellier France

Neuromuscular Unit Mossakowski Medical Research Centre Polish Academy of Sciences Warsaw Poland

Peripheral Neuropathy Group VIB Department of Molecular Genetics University of Antwerp Antwerpen Belgium

Service of Neurologíe Cliniques Universitaires Saint Luc Université Catholique de Louvain Brussels Belgium

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Literatura

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$a Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.
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