Brain Advance Access originally published online on December 19, 2005
Brain 2006 129(2):411-425; doi:10.1093/brain/awh712
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Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)
1 Departments of Molecular Neurosciences, 2 Clinical Neurophysiology, 3 Division of Neuropathology and 4 Centre for Neuromuscular Disease, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, 5 Department of Clinical Neurosciences, Royal Free and University College Medical School, London, 6 Department of Neuropathology, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, 7 Wessex Neurological Centre, Southampton General Hospital, Southampton, 8 Departments of Neurology and Neuropathology, Addenbrooke's Hospital, Cambridge, 9 Department of Neurology, St Mary's Hospital, Praed Street, London and 10 Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK
Correspondence to: Dr Mary Reilly, Centre for Neuromuscular Disease, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, Queen Square, London, WC1N 3BG, UK E-mail: mreilly{at}ion.ucl.ac.uk
Hereditary sensory and autonomic neuropathy type I (HSAN I) is the most frequent type of hereditary neuropathy that primarily affects sensory neurons. The genetic locus for HSAN I has been mapped to chromosome 9q22.1–22.3 and recently the gene was identified as SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1. Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. We analysed the SPTLC1 gene for mutations in 8 families with HSAN I, 60 individuals with sporadic sensory neuropathy, 6 HSAN II families, 20 Charcot-Marie-Tooth type I families and 20 families with Charcot-Marie-Tooth type II. Six HSAN I families and a single sporadic neuropathy case had an identical SPTLC1 mutation. No mutations were found in the other groups. Genetic haplotyping across the HSAN I critical region in 5 families and the sporadic case suggested a common founder. Several characteristics, previously not widely recognized were identified, including lack of penetrance of the SPTLC1 mutation in some individuals, variability in age of onset along with an earlier age of onset in younger generations, in some patients surprisingly early and often severe motor involvement and an earlier onset characterized by motor involvement with demyelinating features in males compared to females in 4 families. The sensory findings were often disassociated with prominent pain and temperature loss. Neurophysiology mainly showed a sensory axonal neuropathy but in many individuals there was electrical evidence of demyelination. Sural nerve biopsies from six affected individuals and the post-mortem findings in 1 case showed mainly axonal loss. This in depth study on the phenotype of HSAN I in 6 families and a single sporadic case with a common founder identifies a number of poorly recognized features in this disorder and highlights the clinical heterogeneity both within and between families suggesting the influence of other genetic and acquired factors.
Key Words: phenotype; peripheral nervous system; neuropathology; mutation; hereditary neuropathy
Abbreviations: AD = autosomal dominant; CMT = Charcot-Marie-Tooth; HSAN I = hereditary sensory and automatic neuropathy type 1
Received June 7, 2005. Revised September 25, 2005. Accepted November 1, 2005.
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