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

A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2T (CMT2T) is caused by homozygous or compound heterozygous mutation in the MME gene (120520) on chromosome 3q25. Some patients may carry heterozygous MME mutations.

Description

Charcot-Marie-Tooth disease type 2T (CMT2T) is a slowly progressive autosomal recessive sensorimotor peripheral neuropathy with onset in middle age (Higuchi et al., 2016).

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

Clinical Features

Higuchi et al. (2016) reported 10 unrelated Japanese patients with adult-onset Charcot-Marie-Tooth disease. Most of the patients had one or more similarly affected family members, and 6 of the families were consanguineous. The mean age at disease onset was 47.2 years (range, 36-56 years), and all patients had slowly progressive weakness and atrophy of the distal lower limb muscles, resulting in gait disturbance, although none were wheelchair-bound. All also had distal sensory impairment and hyporeflexia. Electrophysiologic studies were consistent with an axonal neuropathy, with an intermediate phenotype in 1 patient. Sural nerve biopsy from 2 patients showed a decrease in the density of large myelinated fibers with thick myelin sheaths and clusters of myelinated fibers. None of the patients had additional neurologic signs, including pyramidal signs, cerebellar ataxia, cognitive impairment, or signs of Alzheimer disease. Brain imaging of 5 patients did not show cerebral atrophy.

Inheritance

The transmission pattern of CMT2T in the families reported by Higuchi et al. (2016) was consistent with autosomal recessive inheritance.

Auer-Grumbach et al. (2016) reported families with autosomal dominant transmission of susceptibility to late-onset CMT2T.

Molecular Genetics

In 10 Japanese probands with CMT2T, Higuchi et al. (2016) identified homozygous or compound heterozygous mutations in the MME gene (see, e.g., 120520.0001-120520.0005). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families in which segregation was analyzed. All but 1 of the mutations resulted in a splice site defect or a truncated protein, consistent with a loss-of-function mechanism. Sural nerve biopsy from 2 unrelated patients showed absent immunostaining for MME in a patient with a truncating mutation and decreased immunostaining for MME in a patient with a missense mutation. MME mutations accounted for 13% of patients with a diagnosis of autosomal recessive CMT who underwent whole-exome sequencing, and Higuchi et al. (2016) concluded that mutations in the MME gene are the most frequent cause of autosomal recessive axonal CMT in the Japanese population.

Susceptibility to Late-Onset Charcot-Marie-Tooth Disease Type 2T

In 19 probands of European descent with late-onset axonal CMT, Auer-Grumbach et al. (2016) identified 11 different heterozygous variants in the MME gene (see, e.g., 120520.0007-120520.0009), including 7 loss-of-function alleles and 4 missense alleles. The variants in the first 3 families were found by whole-exome sequencing; subsequent MME variants were found in 6 of 45 additional probands with a similar disorder who underwent direct sequencing of the MME gene. Select patient samples and in vitro cellular studies were consistent with decreased tissue availability of neprilysin and impaired enzymatic activity. Examination of repositories of whole-exome data from more than 10,000 individuals with neurologic and other disorders found 12 more individuals with heterozygous truncating variants, 10 of whom had polyneuropathy, motor neuron disorder, or sensory ataxia. Statistical analysis showed that MME loss-of-function variants were overrepresented among cases with late-onset CMT2T compared to controls in several large databases; however, some of the variants were also present in controls and sometimes showed incomplete penetrance in family studies, suggesting that heterozygous variants may confer susceptibility to the late-onset axonal CMT.