Charcot-Marie-Tooth Disease, Type 4k

A number sign (#) is used with this entry because of evidence that autosomal recessive Charcot-Marie-Tooth disease type 4K (CMT4K) is caused by homozygous or compound heterozygous mutation in the SURF1 gene (185620) on chromosome 9q34.

Description

Charcot-Marie-Tooth disease type 4K is an autosomal recessive demyelinating peripheral neuropathy characterized by onset in the first decade of distal muscle weakness and atrophy associated with impaired distal sensation. Both upper and lower limbs are affected. Affected individuals may also have nystagmus and late-onset cerebellar ataxia. Laboratory studies show increased serum lactate and isolated mitochondrial complex IV deficiency (summary by Echaniz-Laguna et al., 2013).

For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).

Clinical Features

Echaniz-Laguna et al. (2013) reported 2 adult sibs, born of consanguineous Algerian parents, with demyelinating CMT. The 42-year-old proband had normal early psychomotor development and presented at age 8 years with easy fatigability, kyphoscoliosis, muscle atrophy of the hands and feet, and distal sensory impairment of the lower limbs with abolished reflexes in all 4 limbs. Electrophysiologic studies showed severely decreased nerve conduction velocities consistent with a demyelinating neuropathy. Peroneal nerve biopsy showed axonal loss and hypomyelinated fibers. At age 42, he was able to walk short distances independently, but he also had nystagmus and mild hearing loss. Ataxia was not observed. Laboratory studies showed lactic acidosis under resting conditions, and brain imaging showed hyperintense lesions in the putamina. Skeletal muscle biopsy showed marked reduction of COX-specific fibers as well as decreased COX activity (18% of control values), consistent with mitochondrial complex IV deficiency; analysis of patient fibroblasts showed an isolated COX deficiency (26% of control values). The patient's older sister presented before age 10 years with the same symptoms. After age 40, she developed marked cerebellar ataxia. Her brain MRI was normal. An unrelated French girl presented at age 3 years with wasting of hand and foot muscles, abolished tendon reflexes in all 4 limbs, and reduced sensation in the lower limbs. Electrophysiologic studies showed severely decreased nerve conduction velocities. She also had increased plasma lactate. Brain imaging showed nonspecific abnormalities in the brainstem periaqueductal region. After age 10, she developed cerebellar ataxia and altered finger-nose and heel-knee tests. Muscle and skin biopsies were refused.

Inheritance

The transmission pattern of CMT4K in the families reported by Echaniz-Laguna et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with CMT4K, Echaniz-Laguna et al. (2013) identified homozygous or compound heterozygous mutations in the SURF1 gene (185620.0016-185620.0018). Western blot analysis of mitochondria-enriched preparations of patient fibroblasts from 1 of the families showed virtual absence of the SURF1 protein. Fully assembled COX was also markedly reduced. In the whole cohort, SURF1 mutations were found in 2 (5%) of 41 families with autosomal recessive demyelinating CMT after exclusion of mutations in known CMT4-related genes.