A number sign (#) is used with this entry because of evidence that axonal Charcot-Marie-Tooth disease type 2Y (CMT2Y) is caused by heterozygous mutation in the VCP gene (601023) on chromosome 9p13.

Charcot-Marie-Tooth disease type 2Y is an autosomal dominant peripheral neuropathy characterized by distal muscle weakness and atrophy associated with length-dependent sensory loss. Most patients have involvement of both the lower and upper limbs. The age at onset and the severity of the disorder are highly variable (summary by Gonzalez et al., 2014).

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

Gonzalez et al. (2014) reported a family in which 5 living individuals had axonal Charcot-Marie-Tooth disease with highly variable severity. The patients were first cousins and ranged in age from 48 to 66 years. The most severely affected individual developed gait and running difficulties due to muscle weakness and distal sensory impairment in early childhood. She also had foot deformities requiring arthrodesis, and later needed forearm crutches for mobility. She had long-standing dysarthria, dyspnea, and mood and behavioral abnormalities. A first cousin developed walking difficulties requiring orthotics in her early twenties. The 3 remaining patients had onset of balance problems, difficulties with fine movements of the hands, and distal sensory impairment after age 50. All patients had absent Achilles reflexes and distal muscle atrophy, and most had foot abnormalities, including pes cavus and high arches. Four of the 5 had distal weakness affecting the upper limb associated with atrophy of the hand muscles. One patient had proximal weakness of the lower limbs; none had proximal weakness of the upper limbs. Electrophysiologic studies showed intermediate slowing of nerve conduction velocities, consistent with an axonal neuropathy. Sural nerve biopsy was not reported. The overall disability was considered mild in 2 patients, moderate in 2 patients, and severe in 1. The deceased mothers of the patients were identical twins who reportedly had high arches and hammertoes and developed weakness and sensory loss in their fourth and fifth decades of life.

Jerath et al. (2015) reported a 60-year-old man of Dutch and Italian descent with CMT2Y. He had a long-standing history of toe-walking and high arches since childhood, but had normal developmental milestones and played ice hockey into his fifties. He then noticed progressive paresthesias in the distal lower limbs, followed by weakness and cramping of the distal upper and lower limbs, frequent falls, and unsteady gait. He also complained of memory and word-finding difficulties. Neurologic examination showed scapular winging and proximal upper limb weakness, lordosis, pes cavus, hammertoes, tight heel cords, and proximal and distal lower limb weakness. He had a wide-based gait and was unable to walk long distances. Reflexes were decreased or absent. Electrophysiologic studies were consistent with an axonal sensorimotor neuropathy with variably decreased amplitudes and prolonged latencies. Serum creatine kinase was increased, and muscle biopsy showed chronic active neurogenic atrophy. Family history revealed a deceased father with amyotrophic lateral sclerosis, dementia, and Paget disease of bone, a sister with flat, narrow feet, and a daughter with high arches and toe-walking. There was no family history of inclusion body myositis. The phenotype in the proband was complex and seemed to represent an entity along the spectrum of a lower motor neuron syndrome and axonal neuropathy. Jerath et al. (2015) commented on the phenotypic variability associated with VCP mutations.

The transmission pattern of CMT2Y in the family reported by Gonzalez et al. (2014) was consistent with autosomal dominant inheritance.

In 5 affected members of a family with CMT2Y, Gonzalez et al. (2014) identified a heterozygous missense mutation in the VCP gene (E185K; 601023.0010). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the variant impaired autophagic function of VCP, leading to the accumulation of immature autophagosomes. ATPase function of the variant was normal.

In a 60-year-old man of Dutch and Italian descent with CMT2Y, Jerath et al. (2015) identified a heterozygous missense mutation in the VCP gene (G97E; 601023.0011). In vitro functional expression studies showed that the mutant protein had increased ATPase activity compared to wildtype. The mutation was found by exome sequencing.