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J Med Genet 2005;42:358-365 doi:10.1136/jmg.2004.022178
  • Letters to JMG

Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect

  1. R Claramunt1,
  2. L Pedrola1,
  3. T Sevilla2,
  4. A López de Munain3,
  5. J Berciano4,
  6. A Cuesta1,
  7. B Sánchez-Navarro1,
  8. J M Millán5,
  9. G M Saifi6,
  10. J R Lupski6,
  11. J J Vílchez2,
  12. C Espinós1,
  13. F Palau1
  1. 1Laboratory of Genetics and Molecular Medicine, Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain
  2. 2Department of Neurology, Hospital Universitari La Fe, Valencia, Spain
  3. 3Department of Neurology, Hospital Donostia, San Sebastian, Spain
  4. 4Department of Neurology, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain
  5. 5Genetics Unit, Hospital Universitari La Fe, Valencia, Spain
  6. 6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  1. Correspondence to:
 Dr Francesc Palau
 Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, C/Jaume Roig 11, 46010 Valencia, Spain; fpalauibv.csic.es
  • Received 28 April 2004
  • Revised 23 June 2004

Charcot-Marie-Tooth (CMT) disease is a motor and sensory neuropathy with clinical and genetic heterogeneity. Patients usually present in the first or second decade of life with distal muscle atrophy in the legs, areflexia, foot deformity (mainly pes cavus), and steppage gait. In most cases, hands are also involved as the disease progresses. CMT is the most frequent inherited neuropathy, with a prevalence in Spain of 28 in 100 000.1 Based on electrophysiological studies and histopathologic findings in nerve biopsies, CMT has been subcategorised into two main and distinct neuropathies: (i) demyelinating CMT (CMT1, MIM 118200) associated with reduction in a nerve conduction velocities (NCVs) in all nerves and segmental demyelination and remyelination (“onion bulbs”); and (ii) axonal CMT (CMT2, MIM 118220) associated with normal or almost normal NCVs and loss of myelinated axons. Other phenotypes are associated with motor and sensory nerve involvement: Déjérine-Sottas neuropathy (DSN, MIM 145900) is a severe demyelinating neuropathy with onset in infancy, delayed motor milestones, and NCVs less than 10 m/s; congenital hypomyelinating neuropathy (CHN, MIM 605253) is a dysmyelinating neuropathy characterised by infantile hypotonia, distal muscle weakness, and marked reduction of NCVs; hereditary neuropathy with liability to pressure palsies (HNPP, MIM 162500) is a milder sensory and motor neuropathy with periodic episodes of numbness, muscular weakness, and atrophy.2

Genetic heterogeneity is characteristic of the disease not just because of the large number of genes and loci associated with CMT (currently 21 genes),3–5 but also because the disease may segregate with different Mendelian patterns. The most frequent pattern of inheritance is autosomal dominant, but autosomal recessive and X linked segregation are also observed.

The relationship of the type of CMT, demyelinating or axonal, with specific genes is not perfect. For instance, MPZ mutations are usually manifested clinically as an autosomal dominant …

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