Study on the gene and phenotypic characterisation of autosomal recessive demyelinating motor and sensory neuropathy (Charcot-Marie-Tooth disease) with a gene locus on chromosome 5q23-q33
- Anneke Gabreëls-Festena,
- Sylvia van Beersumb,
- Lilian Eshuisa,
- Eric LeGuernc,
- Fons Gabreëlsa,
- Baziel van Engelena,
- Edwin Marimanb
- aInstitute of Neurology , bDepartment of Human Genetics, University Hospital Nijmegen, The Netherlands , cINSERM U289, Hôpital de la Salpêtrière, Paris, France
- Dr A Gabreëls-Festen, Institute of Neurology, University Hospital Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Telephone 0031 24 3615291; fax 0031 24 3541122; emaila.gabreels-festen{at}czzorlnm.azn.nl
- Received 20 February 1998
- Revised 2 October 1998
- Accepted 16 October 1998
Abstract
OBJECTIVES To report the occurrence of the autosomal recessive form of demyelinating Charcot-Marie-Tooth disease (CMT) with a locus on chromosome 5q23–33 in six non-related European families, to refine gene mapping, and to define the disease phenotype.
METHODS In an Algerian patient with autosomal recessive demyelinating CMT mapped to chromosome 5q23-q33 the same unique nerve pathology was established as previously described in families with a special form of autosomal recessive demyelinating CMT. Subsequently, the DNA of patients with this phenotype was tested from five Dutch families and one Turkish family for the 5q23-q33 locus.
RESULTS These patients and the Algerian families showed a similar and highly typical combination of clinical and morphological features, suggesting a common genetic defect. A complete cosegregation for markers D5S413, D5S434, D5S636, and D5S410 was found in the families. Haplotype construction located the gene to a 7 cM region between D5S643 and D5S670. In the present Dutch families linkage disequilibrium could be shown for various risk alleles and haplotypes indicating that most of these families may have inherited the underlying genetic defect form a common distant ancestor.
CONCLUSIONS This study refines the gene localisation of autosomal recessive demyelinating CMT, mapping to chromosome 5q23–33 and defines the phenotype characterised by a precocious and rapidly progressive scoliosis in combination with a relatively mild neuropathy and a unique pathology. Morphological alterations in Schwann cells of the myelinated and unmyelinated type suggest the involvement of a protein present in both Schwann cell types or an extracellular matrix protein rather than a myelin protein. The combination of pathological features possibly discerns autosomal recessive demyelinating CMT with a gene locus on chromosome 5q23–33 from other demyelinating forms of CMT disease.
- Charcot-Marie-Tooth disease
- hereditary demyelinating neuropathy
- autosomal recessive inheritance
- chromosome 5
