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

Objectives-To report the occurrence of the autosomal recessive form of demy elinating Charcot-Marie-Tooth disease (CMT) with a locus on chromosome 5q23 -33 in six non-related European families, to refine gene mapping, and to de fine the disease phenotype. Methods-In an Algerian patient with autosomal recessive demyelinating CMT m apped to chromosome 5q23-q33 the same unique nerve pathology was establishe d as previously described in families with a special form of autosomal rece ssive demyelinating CMT. Subsequently, the DNA of patients with this phenot ype 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 highl y typical combination of clinical and morphological features, suggesting a common genetic defect. A complete cosegregation for markers D5S413, D5S534, D5S636, and D5S410 was found in the families. Haplotype construction locat ed the gene to a 7 cM region between D5S643 and D5S670. In the present Dutc h families linkage disequilibrium could be shown for various risk alleles a nd 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 combina tion with a relatively mild neuropathy and a unique pathology. Morphologica l. alterations in Schwann cells of the myelinated and unmyelinated type sug gest 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 demyelinatin g CMT with a gene locus on chromosome 5q23-33 from other demyelinating form s of CMT disease.