Charcot-Marie-Tooth Disease, Axonal, Type 2w

A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2W (CMT2W) is caused by heterozygous mutation in the HARS gene (HARS1; 142810) on chromosome 5q31.

Description

Charcot-Marie-Tooth disease type 2W is an autosomal dominant neurologic disorder characterized by a peripheral neuropathy mainly affecting the lower limbs and resulting in gait difficulties and distal sensory impairment, although most patients also have upper limb involvement. The age at onset is highly variable, ranging from childhood to late adulthood (summary by Safka Brozkova et al., 2015).

For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Clinical Features

Safka Brozkova et al. (2015) reported 23 patients from 4 unrelated families with axonal Charcot-Marie-Tooth disease. The age at onset was highly variable, even within the same family, ranging from childhood to late adulthood (age 62 years). Most patients presented with gait difficulties, steppage gait, or foot deformities; a few presented with pain or hand weakness. Other features included pes cavus, hammer toes, and distal sensory impairment. Upper limbs were rarely affected. Electrophysiologic studies showed normal or mildly decreased nerve conduction velocities.

Inheritance

The transmission pattern of CMT2W in the families reported by Safka Brozkova et al. (2015) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a 64-year-old man with a 15-year history of impaired sensation in the lower extremities and electrophysiologic studies consistent with axonal Charcot-Marie-Tooth disease, Vester et al. (2013) identified a heterozygous missense mutation in the HARS gene (R137Q; 142810.0002). The patient was ascertained from a larger cohort of 363 individuals with peripheral neuropathy. Generation of a yeast strain with deletion of the Hst1 gene (the ortholog of HARS) showed that the R137Q variant could not complement the Hst1 deletion, suggesting that it is a loss-of-function allele. Expression of the R137Q variant specifically in GABA motor nerves of C. elegans caused gross morphologic defects in commissural axons, with failure to reach the dorsal nerve cord, axonal beading, defasciculation, and breaks in the nerve cord. The animals with the variant also showed locomotor defects.

In affected members of 4 unrelated families with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W), Safka Brozkova et al. (2015) identified 4 different heterozygous missense mutations in the HARS gene (142810.0003-142810.0006). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. All mutations caused a loss of function in yeast complementation assays, and 1 of the mutations was dominantly neurotoxic in a C. elegans model.