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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.
Address correspondence and reprint requests to Dr. Henry Houlden, Department of Molecular Neurosciences, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, England h.houlden{at}ion.ucl.ac.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 
-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.
Abbreviations: CMAP = compound muscle action potential; CMT = Charcot-Marie-Tooth disease; dHMN = distal hereditary motor neuropathy; HSP = heat shock protein; NCS = nerve conduction studies.
e-Pub ahead of print on October 1, 2008, at www.neurology.org.
The authors acknowledge the Medical Research Council (MRC) for the clinician scientist fellowship to H.H. and the Muscular Dystrophy Campaign and Brain Research Trust (BRT) for funding support. This work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centers funding scheme.
Disclosure: The authors report no disclosures.
Received October 24, 2007. Accepted in final form April 24, 2008.
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Neurology 2008 71: 1656-1657.
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  C. Gooch and M. Shy Hereditary motor neuropathy and heat shock proteins: A shocking transformation Neurology, November 18, 2008; 71(21): 1656 - 1657. [Full Text] [PDF]
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