Brain Advance Access originally published online on August 3, 2009
Brain 2009 132(10):2699-2711; doi:10.1093/brain/awp198
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Genes for hereditary sensory and autonomic neuropathies: a genotype–phenotype correlation
1 Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium
2 Neurogenetics Laboratory, Institute Born-Bunge, Antwerpen, Belgium
3 Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium
4 Division of Neurology, University Hospital Antwerp, Antwerpen, Belgium
5 Institute of Human Genetics and Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Graz, Austria
6 AP-HM, Département de Génétique Médicale, Laboratoire de Génétique Moléculaire, Hôpital d’enfants de la Timone, Marseille, France
7 Inserm UMR_S 910: Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine de Marseille, Université de la Méditerranée, Marseille, France
8 Department of Paediatric Immunology, Uluda
University School of Medicine, Bursa, Turkey
9 Institute of Neuropathology, Medical Faculty, RWTH Aachen University, Aachen, Germany
10 Neuromuscular Unit, Sant Joan de Deu Hospital, Barcelona, Spain
11 Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
12 Department of Orthopaedics, University Medical Center, Utrecht, The Netherlands
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}molgen.vib-ua.be
Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype–phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis.
Key Words: HSAN; SPTLC1; RAB7; WNK1/HSN2; NTRK1
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CIPA, congenital insensitivity to pain and anhidrosis; CMT, Charcot-Marie-Tooth disease; HMSN, hereditary motor and sensory neuropathy; HSAN, hereditary sensory and autonomic neuropathy; NCV, nerve conduction velocity; STRs, short tandem repeats; TM, transmembrane domain; SF, Rab subfamily domain; PG/M, conserved domain implicated in binding of phosphate/Mg2+ and guanine binding; F, Ras family domain; PK, protein kinase domain; AI, autoinhibitory domain; CC, coiled coil domain; SP, signal peptide; Cys, cysteine cluster; LRM, leucine rich motif; Ig, immunoglobulin-like domain
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Received April 10, 2009. Revised May 29, 2009. Accepted June 21, 2009.
* These authors contributed equally to this work.