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Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)

Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)
Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)
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.
phenotype, peripheral nervous system, neuropathology, mutation, hereditary neuropathy
0006-8950
411-425
Houlden, Henry
b4cd8392-164c-4d35-8933-690a804ebb18
King, Rosalind
1a9dce73-7e81-4ea9-b38f-d58033186c27
Blake, Julian
e052b218-ef85-49fd-9eac-1660e6562da2
Groves, Mike
3ad25bba-dcf3-4fbd-9342-ee2b3a31d24e
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Woodward, Cathy
6e1f7e7d-3004-4f50-bff0-2d8e82ade515
Hammans, Simon
6553eac5-9322-4f2b-b677-d4ba698fc10b
Nicoll, James A.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Lennox, Graham
41779b72-9b1a-4a9d-82c5-07336f69b808
O'Donovan, Dominic G.
909ea188-26f0-4cdb-8e50-4a2d7c2f1d66
Gabriel, Carolyn
b17ae0ba-fdfc-4897-b379-12b77ec39456
Thomas, P.K.
63cf7b7f-8bbd-4853-ab0e-3c7908d6358b
Reilly, Mary M.
b94e936d-c0cd-40b0-8c8a-9eb0b7a3144c
Houlden, Henry
b4cd8392-164c-4d35-8933-690a804ebb18
King, Rosalind
1a9dce73-7e81-4ea9-b38f-d58033186c27
Blake, Julian
e052b218-ef85-49fd-9eac-1660e6562da2
Groves, Mike
3ad25bba-dcf3-4fbd-9342-ee2b3a31d24e
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Woodward, Cathy
6e1f7e7d-3004-4f50-bff0-2d8e82ade515
Hammans, Simon
6553eac5-9322-4f2b-b677-d4ba698fc10b
Nicoll, James A.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Lennox, Graham
41779b72-9b1a-4a9d-82c5-07336f69b808
O'Donovan, Dominic G.
909ea188-26f0-4cdb-8e50-4a2d7c2f1d66
Gabriel, Carolyn
b17ae0ba-fdfc-4897-b379-12b77ec39456
Thomas, P.K.
63cf7b7f-8bbd-4853-ab0e-3c7908d6358b
Reilly, Mary M.
b94e936d-c0cd-40b0-8c8a-9eb0b7a3144c

Houlden, Henry, King, Rosalind, Blake, Julian, Groves, Mike, Love, Seth, Woodward, Cathy, Hammans, Simon, Nicoll, James A., Lennox, Graham, O'Donovan, Dominic G., Gabriel, Carolyn, Thomas, P.K. and Reilly, Mary M. (2006) Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). Brain, 129 (2), 411-425. (doi:10.1093/brain/awh712).

Record type: Article

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.

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Published date: 2006
Keywords: phenotype, peripheral nervous system, neuropathology, mutation, hereditary neuropathy

Identifiers

Local EPrints ID: 27604
URI: http://eprints.soton.ac.uk/id/eprint/27604
ISSN: 0006-8950
PURE UUID: 74383d00-1247-4246-92b7-910679aa679a
ORCID for James A. Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

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Date deposited: 25 Apr 2006
Last modified: 16 Mar 2024 03:26

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Contributors

Author: Henry Houlden
Author: Rosalind King
Author: Julian Blake
Author: Mike Groves
Author: Seth Love
Author: Cathy Woodward
Author: Simon Hammans
Author: James A. Nicoll ORCID iD
Author: Graham Lennox
Author: Dominic G. O'Donovan
Author: Carolyn Gabriel
Author: P.K. Thomas
Author: Mary M. Reilly

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