The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy.
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. The locus responsible for CMT4C was previously assigned to the chromosome 5q23 region by homozygosity mapping and mutations in the SH3TC2 (KIAA1985) gene have been subsequently identified mainly in families around the Mediterranean basin but also frequently in European Gypsies. No English families have been reported to date. To determine the frequency, phenotype and neuropathology of CMT due to SH3TC2 mutations we screened 23 English autosomal recessive (AR) demyelinating CMT families. Five families with AR demyelinating CMT and SH3TC2 mutations were identified, four families were homozygous for the R954X mutation and the fifth family was compound heterozygous for the R954X and E657K mutations. There was significant clinical variation between these families with some cases presenting with a severe childhood onset neuropathy with respiratory and cranial nerve involvement, compared to other families with mild scoliosis and foot deformity. Characteristic sural nerve neuropathology was seen in three families with frequent demyelinating fibres surrounded by excess Schwann cell lamellae forming basal lamina onion bulbs and abnormally long and attenuated Schwann cell processes. One patient homozygous for the R954X mutation had a 20-year history of an inflammatory neuropathy that was superimposed onto the hereditary form, indicating that structural alterations to the SH3TC2 gene could possibly predispose to peripheral nerve inflammation.
Houlden
Henry
H
Department of Molecular Neurosciences and The MRC Centre for Neuromuscular diseases, The National Hospital for Neurology and Neurosurgery, The Institute of Neurology, Queen Square, London, WC1N 3BG, England, UK. h.houlden@ion.ucl.ac.uk
Laura
Matilde
M
Ginsberg
Lionel
L
Jungbluth
Heinz
H
Robb
Stephanie A
SA
Blake
Julian
J
Robinson
Susan
S
King
Rosalind H M
RH
Reilly
Mary M
MM
D000328:Adult; D017668:Age of Onset; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D002648:Child; D025063:Chromosome Disorders / Q000235:genetics; D003389:Cranial Nerve Diseases / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009154:Mutation / Q000235:genetics*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000235:genetics; D012600:Scoliosis / Q000235:genetics; D013497:Sural Nerve / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C488620:SH3TC2 protein, human