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

Dierick, I. and Baets, J. and Irobi, J. and Jacobs, A. and De Vriendt, E. and Deconinck, T. and Merlini, L. and Van den Bergh, P. and Rasic, V. M. and Robberecht, W. and Fischer, D. and Morales, R. J. and Mitrovic, Z. and Seeman, P. and Mazanec, R. and Kochanski, A. and Jordanova, A. and Auer-Grumbach, M. and Helderman-van den Enden, A. T. and Wokke, J. H. and Nelis, E. and De Jonghe, P. and Timmerman, V.. (2008) Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies : a genotype-phenotype correlation study. Brain, Vol. 131, H. 5. pp. 1217-1227.

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Official URL: http://edoc.unibas.ch/dok/A6005756

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Abstract

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.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Neuro- und Entwicklungspädiatrie (Weber)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Neuro- und Entwicklungspädiatrie (Weber)
UniBasel Contributors:Fischer, Dirk
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Oxford University Press
ISSN:0006-8950
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:25 Apr 2014 08:00
Deposited On:25 Apr 2014 08:00

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