title: Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I).
abstract: 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.
authors.affiliation: Department of Molecular Neurosciences, The National Hospital for Neurology and Neurosurgery and The Institute of Neurology, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Rosalind
authors.initials: R
authors.lastname: King
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.forename: Mike
authors.initials: M
authors.lastname: Groves
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: Cathy
authors.initials: C
authors.lastname: Woodward
authors.forename: Simon
authors.initials: S
authors.lastname: Hammans
authors.forename: James
authors.initials: J
authors.lastname: Nicoll
authors.forename: Graham
authors.initials: G
authors.lastname: Lennox
authors.forename: Dominic G
authors.initials: DG
authors.lastname: O'Donovan
authors.forename: Carolyn
authors.initials: C
authors.lastname: Gabriel
authors.forename: P K
authors.initials: PK
authors.lastname: Thomas
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D000217:Acyltransferases / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001369:Axons / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D005260:Female; D006239:Haplotypes; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction; D009475:Neurons, Afferent; D010375:Pedigree; D019683:Penetrance; D051102:Serine C-Palmitoyltransferase; D012737:Sex Factors; D013497:Sural Nerve / Q000473:pathology
chemical_list: D000217:Acyltransferases; C487784:SPTLC1 protein, human; D051102:Serine C-Palmitoyltransferase