CMT 2: Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporad

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Neurology. 2008 Oct 1.

Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and

sporadic distal HMN/CMT type 2.

Houlden H, M, Wavrant-De Vrièze F, Blake J, Wood N, Reilly MM.

From the Department of Molecular Neurosciences (H.H., M.L., N.W.,

M.M.R.), and Center for Neuromuscular Disease (H.H., M.L., J.B.,

N.W., M.M.R.), Institute of Neurology and The National Hospital for

Neurology and Neurosurgery, Queen Square, London, UK; Laboratory of

Neurogenetics (F.W.-D.V.), National Institute on Aging, National

Institutes of Health, Bethesda, MD; and Department of Clinical

Neurophysiology (J.B.), Norfolk and Norwich University Hospital,

Norwich, Norfolk, UK.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common

inherited neuromuscular disorder and is characterized by significant

clinical and genetic heterogeneity. Recently, mutations in both the

small heat shock protein 27 (HSP27 or HSPB1) and 22 (HSP22 or HSPB8)

genes have been reported to cause autosomal dominant CMT with minimal

sensory involvement (CMT 2F/CMT2L) and autosomal dominant distal

hereditary motor neuropathy type II (dHMN II).

METHODS: We analyzed the HSPB1 and HSPB8 genes in a large clinically

well-characterized series of dHMN and CMT type 2 (CMT2) cases and

families using linkage analysis and direct sequencing of these genes.

RESULTS: We identified a novel homozygous mutation in the alpha-

crystallin domain of HSPB1 segregating in an autosomal recessive

fashion in a family with distal HMN/CMT2. A further four heterozygous

HSPB1 mutations were identified in four autosomal dominant families

dHMN/CMT2, and two sporadic cases were identified with probable de

novo mutations. In the autosomal dominant and autosomal recessive

families, there were no clinical sensory findings, but reduced sural

nerve action potential amplitudes were found in some affected

individuals, indicating that long sensory axons are mildly affected

in this predominantly motor disorder.

CONCLUSIONS: This extends the clinical and electrophysiologic

spectrum of HSPB1 mutations and identifies four unreported dominant

HSPB1 mutations and the first family where the HSPB1 mutation acts in

a recessive way to cause distal HMN.