Brain Advance Access published online on December 19, 2005
Brain, doi:10.1093/brain/awh712
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1 Department of Molecular Neurosciences, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK; Centre for Neuromuscular Disease, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK; Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK
* To whom correspondence should be addressed. 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.
Received June 7, 2005
Revised September 25, 2005
Accepted November 1, 2005
Article
Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)
Henry Houlden 1,
Rosalind King 2,
Julian Blake 3,
Mike Groves 4,
Seth Love 5,
Cathy Woodward 6,
Simon Hammans 7,
James Nicoll 7,
Graham Lennox 8,
Dominic G. O'Donovan 8,
Carolyn Gabriel 9,
P. K. Thomas 6,
and
Mary M. Reilly 10 *
2 Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK
3 Department of Clinical Neurophysiology, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK; Centre for Neuromuscular Disease, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK; Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK
4 Department of Molecular Neurosciences, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK; Division of Neuropathology, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK
5 Department of Neuropathology, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK
6 Department of Molecular Neurosciences, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK
7 Wessex Neurological Centre, Southampton General Hospital, Southampton, UK
8 Departments of Neurology and Neuropathology, Addenbrooke's Hospital, Cambridge, UK
9 Department of Neurology, St Mary's Hospital, Praed Street, London
10 Department of Molecular Neurosciences, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK; Centre for Neuromuscular Disease, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK
Mary M. Reilly, E-mail: mreilly{at}ion.ucl.ac.uk
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