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

A number sign (#) is used with this entry because this form of axonal Charcot-Marie-Tooth disease type 2, here designated CMT2N, is caused by heterozygous mutation in the AARS gene (AARS1; 601065) on chromosome 16q22.

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

Clinical Features

Latour et al. (2010) reported a large 5-generation French family in which at least 17 individuals had an axonal form of Charcot-Marie-Tooth disease with a mean age at onset of 28 years (range, 6-54). One patient was described in detail. She first noted symptoms at age 25 during her first pregnancy. She had mild to moderate motor disability of the lower right limb and occasional motor disability of the right hand. Physical examination at age 30 showed normal gait, but difficulty standing on the heels. She had bilateral distal motor weakness in the lower limbs without amyotrophy or foot deformities, and weak reflexes. Examination of the upper limbs was normal. All affected family members were ambulatory, although 1 occasionally used a wheelchair. None had pyramidal or cerebellar signs. Electromyographic studies showed a motor and sensory axonal neuropathy with a mean motor nerve conduction velocity of 41 m/s.

Lin et al. (2011) reported a Taiwanese family with autosomal dominant CMT2N confirmed by genetic analysis (N71Y; 601065.0002). There was marked variability in the age of onset (range, 11 to 45 years) and severity. The proband presented at age 51 years with slowly progressive weakness and atrophy of the legs that began at age 30 years after normal development. Physical examination showed marked atrophy and mild weakness of the muscles in the legs and feet, and milder atrophy and weakness of the intrinsic hand muscles. He had absent ankle reflexes, hyporeflexia, and mildly decreased distal sensation. His mother, brother, and son had a similar disorder. His 2 younger sisters and niece, who also carried the mutation, denied neurologic symptoms, but neurologic examination showed distal muscle mild atrophy, weakness in the intrinsic foot muscles, and generalized hyporeflexia in all of them.

McLaughlin et al. (2012) reported a large unrelated Australian family with CMT2N confirmed by genetic analysis. Nine individuals showed early-onset axonal neuropathy with variable sensorineural deafness. Clinical features included progressive gait difficulty, foot drop, pes cavus, and hammer toes. Nerve conduction velocities were within the intermediate range, and audiology showed mild to moderate high frequency sensorineural loss.

Mapping

By genomewide scan of a large French family with an axonal form of CMT, Latour et al. (2010) defined a new locus within a 7.1-cM (10.2-Mb) region between markers D16S503 and D16S3018 (maximum 2-point parametric lod score of 4.77 at D16S3050).

Molecular Genetics

In affected members of a large French family with axonal CMT, Latour et al. (2010) identified a heterozygous mutation in the AARS gene (R329H; 601065.0001). Affected members of an unrelated affected French family were found to carry the same mutation. Haplotype analysis excluded a founder effect in these families.

McLaughlin et al. (2012) identified heterozygosity for the AARS R329H mutation in affected members of an Australian family with CMT2N.

In affected members of a Taiwanese family with CMT2N, Lin et al. (2011) identified a heterozygous mutation in the AARS gene (N71Y; 601065.0002).