Genetic linkage evidence for heterogeneity in Charcot‐Marie‐Tooth neuropathy (HMSN type I)

Abstract

A genetic linkage study performed on a large family with autosomal dominant Charcot-Marie-Tooth neuropathy (HMSN type I) showed affected family members to have slow motor nerve conduction velocities, hypoactive tendon reflexes, and distal muscle weakness and atrophy. Results excluded close linkage of the neuropathy in this family to the Duffy blood group locus on chromosome 1. Previous studies in other families have shown positive linkage of HMSN type I to the Duffy locus. The present results provide support for the concept of genetic heterogeneity in HMSN type I. Comparison of this new family with the previous families showing linkage to Duffy reveals that the hereditary neuropathy not linked to the Duffy locus may have less severe slowing of motor nerve conduction velocities and less prominent onion bulb change evident on sural nerve biopsy.

Myelin protein zero (MPZ) gene mutations in nonduplication type 1 Charcot-Marie-Tooth disease

“…myelinating peripheral neuropathies characterized by slowly progressive atrophy and weakness of the distal muscles, secondary to a myelin deficit resulting in uniform reductions in motor nerve conduction velocity (Lupski et al, 1991aDyck et al, 1993;Kaku et al, 1993). CMTlB is the chromosome 1-linked subtype of this genetically heterogeneous disorder (Bird et al, 1982(Bird et al, , 1983. Mutations in MPZ have also been identified in rare patients with Dejerine-Sottas syndrome (DSS) (Hayasaka et al, 1993b) who present with similar clinical features, but which are more severe and of earlier onset than CMTl (Dyck and Gomez, 1968;Dyck et al, 1971Dyck et al, , 1993.…”

Charcot-Marie-Tooth Disease

“…However, it was soon evident that CMT1 in most families did not map to this locus. 19 This disorder was therefore referred to as CMT1b. Vance et al 20 in 1989 and Raeymaekers et al 21 in 1991 mapped CMT1a to chromosome 17p11.2, and in 1991 Lupski et al 16 described a DNA duplication within the region.…”

A bootstrap approach to estimating power for linkage heterogeneity

“…Genetic heterogeneity involving two or more loci has been demonstrated in a number of genetic diseases including Charcot-Marie-Tooth disease [Bird et al, 1983;Vance et al, 19891 and tuberous sclerosis [Fryer et al, 1987;Kandt et al, 19921. To assess the power of detecting locus heterogeneity and the significance level for a given likelihood ratio, we developed a computer program that uses a resampling strategy described by Tenvilliger and O t t [1992], which is modelled after the multisample bootstrap of Efron [1982].…”