Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy.
Three families presenting with X-linked recessive Charcot-Marie-Tooth neuropathies (CMT) were studied both clinically and genetically. The disease phenotype in family 1 was typical of CMT type 1, except for an infantile onset; two of five affected individuals were mentally retarded, and obligate-carrier females were unaffected. Families 2 and 3 showed distal atrophy with weakness, juvenile onset, and normal intelligence. Motor-nerve conduction velocities were significantly slowed, and electromyography data were consistent with denervation in affected CMT males in all three families. Thirty X-linked RFLPs were tested for linkage studies against the CMT disease loci. Family 1 showed tight linkage (recombination fraction [theta] = 0) to Xp22.2 markers DXS16, DXS143, and DXS43, with peak lod scores of 1.75, 1.78, and 2.04, respectively. A maximum lod score of 3.48 at DXS16 (theta = 0) was obtained by multipoint linkage analysis of the map DXS143-DXS16-DXS43. In families 2 and 3 there was suggestion of tight linkage (theta = 0) to Xq26 markers DXS86, DXS144, and DXS105, with peak lod scores of 2.29, 1.33, and 2.32, respectively. The combined maximum multipoint lod score of 1.81 at DXS144 (theta = 0) for these two families occurred in the map DXS10-DXS144-DXS51-DXS105-DXS15-DXS52++ +. A joint homogeneity analysis including both regions (Xp22.2 and Xq26-28) provided evidence against homogeneity (chi 2 = 9.12, P less than .005). No linkage to Xp11.12-q22 markers was observed, as was reported for X-linked dominant CMT and the Cowchock CMT variant. Also, the chromosomes 1 and 17 CMT loci were excluded by pairwise linkage analysis in all three families.
Department of Pediatrics, Pediatrics Genetics Muscle Laboratory, University of Iowa Hospitals, Iowa City 52242.
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Ionasescu
J
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Trofatter
J L
JL
Haines
A M
AM
Summers
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R
Ionasescu
C
C
Searby
D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1; D002886:Chromosomes, Human, Pair 17; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006579:Heterozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D014960:X Chromosome