Autosomal recessive Charcot-Marie-Tooth (CMT) disease (CMT4) is a complex group of severe childhood motor and sensory neuropathies, characterized by an early age of onset with rapidly progressive distal limb weakness and atrophy. One subgroup designated CMT4 type A (CMT4A) was selected from a series of Tunisian CMT4 families according to the following electrophysiological and pathological criteria: slow motor nerve conduction velocity (MCV), severe hypomyelination upon nerve biopsy with basal lamina onion bulbs and no myelin outfolding. In an attempt to localize the CMT4A locus, we studied four inbred families with 13 affected patients. Significant evidence for linkage was found for several markers from chromosome 8q13-21.1 (D8S279, D8S164, D8S286, D8S84, D8S275 and D8S167). An overall two point peak lod score of z(theta) = 9.19 at theta = 0.00 (95% confidence limit 0.00-0.08) was obtained for D8S164. No evidence of genetic heterogeneity was found. The chromosomal localization of one form of CMT4 will have important implications in clarifying the nosology of this complex group of disorders.
Methods
SUBJECTSAfter obtaining informed consent, each participant (38 members of the family, fig 1) was interviewed and examined by the same physician (KAP). Physical examinations were performed and family histories were taken. Affected status was assigned on the basis of one or more venous malformations. Other vascular anomalies, such as lateral telangiectatic naevi (port wine stains), were occasionally noted but not included as part of the affected phenotype. Blood was drawn from appropriate subjects and DNA was extracted using established methods.3
GENOTYPES AND LINKAGE ANALYSISAnalyses of simple repeat markers were performed as previously described.3 The venous malformation phenotype was analysed as an autosomal dominant disorder with age dependent penetrance. For estimating the age dependent penetrance, four liability classes were created with age ranges 0-12 (penetrance 0 5), 12-21 (penetrance 0-75) 21-45 (0 90), and >45 (0-95), based on observations from more than 10 years of clinical contact with the entire extended family. Disease frequency was set at 0-0001. Two point linkage analysis was performed on a Sun Sparc station 10 using the MLINK subprogram of the LINKAGE computer package (version 4-9).4 The analysis was repeated using the phenotypic information on only the affected subjects to ensure that information was coming only from those with a definitive disease status. Allele frequency was estimated for the markers using the pedigree maximum likelihood estimation from the family data by the method of Boehnke' and did not differ appreciably from the allele frequencies listed in GDB.
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