Charcot-Marie-Tooth Disease, Recessive Intermediate D

A number sign (#) is used with this entry because autosomal recessive intermediate Charcot-Marie-Tooth disease D (CMTRID) is caused by homozygous mutation in the COX6A1 gene (602072) on chromosome 12q24.

For a discussion of genetic heterogeneity of recessive intermediate Charcot-Marie-Tooth disease, see CMTRIA (608340).

Clinical Features

Tamiya et al. (2014) reported 3 patients from 2 unrelated consanguineous Japanese families with early-onset peripheral neuropathy. The male proband in the first family presented with foot drop at age 4 years after normal early development. At age 8 years, motor nerve conduction velocities (NCV) were 43.4 m/s and 45 m/s, but sensory nerve action potentials were undetectable. One year later, sural nerve biopsy showed decreased density of myelinated fibers, decreased myelinated axon caliber, and onion bulb formations. Brain MRI showed mild cerebral atrophy. The disorder was slowly progressive over the next 2 decades, and the patient had distal muscle weakness affecting the upper and lower limbs; he was wheelchair-bound at age 16 years. Examination at age 25 showed distal muscle weakness and atrophy, pes cavus, clawing of the toes, distal sensory impairment, and areflexia of the lower limbs. Electrophysiologic studies at this time showed motor NCV of 35.7 m/s, indicative of a demyelinating neuropathy. Cognition was not affected. The patient's first cousin was similarly affected, with decreased motor NCV. The female proband in the second family showed an unsteady gait in early childhood. At age 5 years, she had steppage gait, pes cavus, hyporeflexia, and distal muscle weakness of the upper and lower limbs. At age 39, she could walk a few steps with support and had distal sensory impairment. Electrophysiologic studies showed mildly delayed NCV (45.3 and 49.6 m/s), consistent with an axonal neuropathy. Sural nerve biopsy was not performed.

Lassuthova et al. (2015) reported a 37-year-old woman, born of unrelated Czech parents, with onset of severe axonal CMT at age 5 years. She had frequent falls and gait instability associated with foot deformities. The disorder was progressive, and she had distal muscle atrophy and weakness affecting the upper and lower limbs, resulting in loss of ambulation. Additional features included distal sensory impairment, neuropathic pain, and finger contractures. She also had hearing loss since age 35.

In a review of intermediate CMT, Berciano et al. (2017) suggested that CMTRID should be reclassified as CMT2 (see, e.g., 118210), because the electrophysiologic studies were more consistent with axonal CMT.

Inheritance

The transmission pattern of CMTRID in the families reported by Tamiya et al. (2014) was consistent with autosomal recessive inheritance.

Mapping

By a parametric linkage analysis in 2 consanguineous families with an autosomal recessive intermediate form of CMT, Tamiya et al. (2014) found linkage of the disorder to a 4.3-Mb region on chromosome 12q24 with a maximum multipoint lod score of 4.23.

Molecular Genetics

In 3 Japanese patients from 2 unrelated consanguineous families with autosomal recessive intermediate Charcot-Marie-Tooth disease D, Tamiya et al. (2014) identified a homozygous 5-bp deletion in the COX6A1 gene (602072.0001). The mutation, which was found by a combination of linkage analysis and whole-genome sequencing, segregated with the disorder in both families, but haplotype analysis did not suggest a founder effect. Patient cells showed significantly decreased levels of COX6A1 mRNA and protein, consistent with potential nonsense-mediated mRNA decay. Mitochondrial COX activity and ATP content were also decreased in patient cells.

In a 37-year-old woman of Czech origin with severe diffuse axonal neuropathy, Lassuthova et al. (2015) identified the same homozygous 5-bp deletion in the COX6A1 gene that was found by Tamiya et al. (2014). Haplotype analysis showed a different haplotypes than those found in the Japanese cases reported by Tamiya et al. (2014), suggesting that this is a mutational hotspot.

Animal Model

Tamiya et al. (2014) found that Cox6a1-null mice had walking difficulties. Histologic examination showed thinned sciatic nerves and neurogenic muscular changes, including small angular fibers and small group atrophy. Electrophysiologic studies showed delayed motor nerve conduction velocities compared to controls. COX activity and ATP contents in liver cells were decreased.