Charcot-Marie-Tooth Disease, Demyelinating, Type 1g

A number sign (#) is used with this entry because of evidence that demyelinating Charcot-Marie-Tooth disease type 1G (CMT1G) is caused by heterozygous mutation in the PMP2 gene (170715) on chromosome 8q21.

Description

Charcot-Marie-Tooth disease type 1G is an autosomal dominant progressive peripheral sensorimotor neuropathy characterized by distal muscle weakness and atrophy with onset in the first or second decade. Affected individuals have difficulty walking, distal sensory impairment with decreased or absent reflexes, and often have foot deformities. Median motor nerve conduction velocities (NCV) are decreased (less than 38 m/s) and sural nerve biopsy shows myelin defects and onion bulb formation (summary by Hong et al., 2016 and Motley et al., 2016).

For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

Clinical Features

Gonzaga-Jauregui et al. (2015) reported a 3-generation family (BAB1468) in which multiple members were diagnosed with autosomal dominant demyelinating Charcot-Marie-Tooth disease. The proband had onset at age 6 years. He had foot deformities, including pes cavus and hammertoes, distal muscle weakness and atrophy, distal sensory impairment, and decreased median motor NCVs. Sural nerve biopsy showed a demyelinating neuropathy and onion bulb formation.

Hong et al. (2016) reported a Korean family (family FC183) in which a mother and her 2 sons had onset of distal muscle weakness and atrophy affecting both the lower and upper limbs. The age at onset was 18 years in the mother and 6 to 8 years in her sons, who were adults at the time of the report. Initial features included frequent falling due to lower limb weakness, with later onset of hand muscle weakness and atrophy causing difficulties in writing, cooking, and fine finger control. The patients also had distal sensory impairment affecting vibration more than pain. Physical examination showed pes cavus, hypo- or areflexia in the lower limbs, and hand tremor (in 2 patients). None had scoliosis, cognition was normal, and all were able to walk. Electrophysiologic studies showed reduced median motor and sensory NCVs, suggestive of a demyelinating process, and sural nerve biopsy from the mother showed a demyelinating neuropathy with myelin abnormalities and onion bulb formation. MRI showed fatty replacement of muscle tissue in the lower limbs that was more severe in the calf.

Motley et al. (2016) reported 8 patients from 2 unrelated families with CMT1G. The patients presented in the first or second decades with distal muscle weakness and atrophy mainly affecting the lower limbs and resulting in foot drop and difficulty walking. Older patients had hand involvement. Physical examination showed hypo- or areflexia of the lower limbs, decreased distal sensation, arched feet, and decreased distal muscle bulk. Electrophysiologic studies showed decreased or absent motor and sensory responses, and EMG was consistent with chronic denervation. Sural nerve biopsy, when performed, showed a decrease in myelinated fibers, thin myelination, and onion bulb formation. There was no evidence of central nervous system involvement.

Punetha et al. (2018) reported a large 4-generation family with CMT1G. The proband was a 30-year-old woman who presented at age 5 years with gradually progressive muscle weakness of the lower limbs. She also had pes cavus that progressed to pes planus in the second decade. She had abnormal steppage gait, areflexia of the lower limbs, and NCV consistent with a demyelinating neuropathy.

Inheritance

The transmission pattern of CMT1G in the families reported by Motley et al. (2016) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a father and son (family BAB1468) with CMT1G, Gonzaga-Jauregui et al. (2015) identified a heterozygous missense mutation in the PMP2 gene (I43N; 170715.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but studies in zebrafish suggested that it was pathogenic (see ANIMAL MODEL). These authors suggested a dominant-negative effect. The proband was part of a cohort of 37 unrelated families with a similar phenotype who underwent whole-exome sequencing.

In 3 affected members of a Korean family (family FC183) with CMT1G, Hong et al. (2016) identified a heterozygous I43N substitution in the PMP2 gene. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Studies of patient cells were not performed, but transgenic mice with the I43N mutation developed a peripheral neuropathy similar to that found in the patients (see ANIMAL MODEL).

In affected members of 2 unrelated families with CMT1G, Motley et al. (2016) identified missense mutations in the PMP2 gene (I52T, 170715.0002 and T51P, 170715.0003). Functional studies of the variant and studies of patient cells were not performed, but Motley et al. (2016) suggested that the mutations may result in aberrant transport of fatty acids and possibly result in a toxic gain of function.

In 4 affected members of a family with CMT1G, Punetha et al. (2018) identified a heterozygous I52T mutation in the PMP2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Punetha et al. (2018) suggested that the PMP2 gene should be included in CMT gene panels.

Animal Model

Gonzaga-Jauregui et al. (2015) found that morpholino knockdown of either of the 2 zebrafish pmp2 orthologs caused a motor neuron phenotype including failure of the motor neuron axons to extend from the notochord, as well as pathfinding errors where the axons failed to innervate the myotomes appropriately. Overexpression of human wildtype PMP2 induced a similar phenotype, suggesting dosage sensitivity.

Hong et al. (2016) found that transgenic mice with the I43N mutation or overexpression of wildtype Pmp2 developed a peripheral neuropathy with impaired motor performance and reduced motor NCVs compared to controls. Nerve biopsy from mutant mice showed a reduced number of large myelinated fibers, aberrant myelination, and shorter internodal length compared to controls, suggesting defects in Schwann cell function.