Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort
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The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.
KeywordsHereditary sensory and autonomic neuropathies Genetics
We are grateful to the patients and families who support our research. We would like to thanks the following for essential grant support; The Medical Research Council (MRC) MMR and HH (MRC fellowship, G108/638 and G0802760), The Brain Research Trust (BRT) (HH), Ataxia UK (HH), The BMA Vera Down Award (HH) and the Muscular Dystrophy Campaign UK and association USA (HH and MMR). SMM and MMR are grateful to the NINDS/ORD (1U54NS065712-01) for their support. MAS was supported by the College of Medicine Research Center (CMRC, Project No. 05-495), College of Medicine, King Saud University, Riyadh, Saudi Arabia. This work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. This study was funded by a UCLH/UCL Comprehensive Biomedical Research Centre (CBRC) Grant. We would like to thank the following for essential grant support; The Medical Research Council (MRC) MMR and HH (MRC fellowship, G108/638 and G0802760), The Brain Research Trust (BRT) (HH), Ataxia UK (HH), The BMA Vera Down Award (HH) and the Muscular Dystrophy Campaign UK and association USA (HH and MMR). SMM and MMR are grateful to the NINDS/ORD (1U54NS065712-01) for their support. MAS was supported by the College of Medicine Research Center (CMRC, Project No. 05-495), College of Medicine, King Saud University, Riyadh, Saudi Arabia. FM is supported by the Great Ormond Street Hospital Children’s charity. This work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme.
Conflicts of interest
GL Davidson, JM Polke, M Laura, MAM Salih, J Blake, S Brandner, N Davies, R Horvath, S Price, M Donaghy, M Roberts, N Foulds, G Ramdharry, D Soler, MP Lunn, H Manji, MB Davis have no disclosures. SM Murphy is the recipient of a Post Doctoral training fellowship from the Inherited Neuropathy Consortium Rare Disease Clinical Research Consortium supported by the NINDS/ORD (1U54NS065712-01). F Muntoni serves on a scientific advisory board for AVI BioPharma, Inc.; serves on the editorial boards of Neuromuscular Disorders and Neuropaediatrics; is listed as an author on a pending patent re: Tailed antisense nucleotides to redirect splicing; receives publishing royalties for Duchenne Muscular Dystrophy (Oxford University Press, 2003); and receives research support from AVI BioPharma, Inc., PTC Therapeutics, Inc., GlaxoSmithKline, Wellcome Trust, the European Union, Medical Research Council UK, Muscular Dystrophy Campaign, Muscular Dystrophy Association USA, Spinal Muscular Atrophy Foundation, the NIH, the Association Francaise contre les myopathies (AFM), the NIHR, and the Great Ormond Street Hospital Children’s Charity. H Houlden receives research support from The Medical Research Council (MRC fellowship, G108/638 and G0802760), The Brain Research Trust, Ataxia UK, The BMA Vera Down Award and the Muscular Dystrophy Campaign UK and association USA. MM Reilly receives research support from The Medical Research Council, the Muscular Dystrophy Campaign and NINDS/ORD (1U54NS065712-01). This work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme.
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