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Brain Advance Access published online on March 5, 2008
Brain, doi:10.1093/brain/awn029
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Ines Dierick1,2,*, Jonathan Baets2,3,*, Joy Irobi1,2, An Jacobs1,2, Els De Vriendt1,2, Tine Deconinck2,3, Luciano Merlini4, Peter Van den Bergh5, Vedrana Milic Rasic6, Wim Robberecht7, Dirk Fischer8,9, Raul Juntas Morales10, Zoran Mitrovic11, Pavel Seeman12, Radim Mazanec13, Andrzej Kochanski14, Albena Jordanova1,2,15, Michaela Auer-Grumbach16, A. T. J. M. Helderman-van den Enden17, John H. J. Wokke18, Eva Nelis2,3, Peter De Jonghe2,3,19 and Vincent Timmerman1,2

1Peripheral Neuropathy Group, VIB Department of Molecular Genetics, 2Neurogenetics laboratory, Institute Born-Bunge, 3Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium, 4Muscle Unit, Division of Medical Genetics, Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy, 5Service de Neurologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium, 6Clinic of Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia, 7Department of Neurology, University Hospital Gasthuisberg, Leuven, Belgium, 8Muskelzentrum St Gallen, Kantonsspital St Gallen, St Gallen, 9Department of Neurology, University Hospital of Basel, Basel, Switzerland, 10Neurology Department, University Hospital of Montpellier, Montpellier, France, 11National Center for Neuromuscular Diseases, Department of Neurology, University Hospital Center Zagreb, Zagreb, Croatia, 12Department of Child Neurology, Charles University, 2nd School of Medicine Prague, 13Department of Neurology, Charles University, 2nd School of Medicine and University Hospital Motol, Prague, Czech Republic, 14Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland, 15Laboratory of Molecular Pathology, Sofia Medical University, Sofia, Bulgaria, 16Institute of Medical Biology and Department of Internal Medicine, Diabetes and Metabolism, Medical University Graz, Austria, 17Department of Clinical Genetics, Leiden University Medical Center, Leiden, 18Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands and 19Division of Neurology, University Hospital Antwerpen, Antwerpen, Belgium

Correspondence to: Prof. Dr Vincent Timmerman, PhD, Peripheral Neuropathy Group, VIB - Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium E-mail: vincent.timmerman{at}ua.ac.be

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.

Key Words: distal HMN; BSCL2; HSPB1; HSPB8; SETX

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CMAP, compound muscle action potential; CMT, Charcot–Marie–Tooth disease; EMG, electromyography; HMN, hereditary motor neuropathy; HMSN, hereditary motor and sensory neuropathy; NCV, nerve conduction velocity; SMA, spinal muscular atrophy; SNAP, sensory nerve action potentials; STRs, short tandem repeats

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Received October 12, 2007. Revised January 25, 2008. Accepted February 8, 2008.

*These authors contributed equally to this work.


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