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

A number sign (#) is used with this entry because of evidence that axonal Charcot-Marie-Tooth disease type 2Z (CMT2Z) is caused by heterozygous mutation in the MORC2 gene (616661) on chromosome 22q12.

Description

Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an autosomal dominant peripheral neuropathy characterized by onset, usually in the first decade, of distal lower limb muscle weakness and sensory impairment. The disorder is progressive, and affected individuals tend to develop upper limb and proximal muscle involvement in an asymmetric pattern, resulting in severe disability late in adulthood (summary by Sevilla et al., 2016).

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

Clinical Features

Frith et al. (1994) described 21 cases in a large Australian family (CMT105) with autosomal dominant peroneal muscular atrophy associated with extensor plantar responses in some cases. The onset of the disease was typically within the first 2 decades. Spasticity was not a feature. Peripheral nerve conduction velocity showed normal or only mildly slowed motor nerve conductions with reduced amplitudes of sensory action potentials. Sural nerve biopsies demonstrated absence of significant myelination and no onion bulb formation. The electrical, physiologic, and biopsy results were similar to those found in axonal HMSN II (CMT2). Vucic et al. (2003) also studied the large family previously reported by Frith et al. (1994). The mean age of onset was 12.8 years (range 4 to 47) with difficulty walking and running. Patients had marked distal weakness and wasting of the lower limbs with sensory loss. Many patients had pes cavus and hammertoes. There were mild pyramidal signs in many, but not all, patients, including mild increases in tone, brisk reflexes, and extensor plantar responses, but no clonus or spastic gait. Four patients had spastic dysphonia. In this family, Zhu et al. (2005) excluded mutations in the MFN2 gene (608507).

Albulym et al. (2016) reported follow-up of family CMT105. Sixteen affected family members were examined. Patients had early onset of a length-dependent axonal motor and sensory neuropathy. Initially the distal lower and upper limbs were primarily affected, but over decades, the weakness spread proximally. Many required a wheelchair later in life. Pyramidal features included increased muscle tone and extensor plantar reflexes without over spasticity. Learning difficulties were present in many affected individuals. Three individuals had a distinctive high-pitched speech, and 2 had mild pigmentary retinal changes. Nerve biopsy showed a reduction of myelinated axons.

Sevilla et al. (2016) reported a 4-generation family in which 7 individuals had sensorimotor peripheral neuropathy. Five patients, ranging in age from 17 to 75 years, were still living at the time of report. The first symptoms appeared in the first or second decade, and most presented with cramping in the lower limbs associated with distal lower limb weakness and sensory loss. Hand weakness appeared after distal lower limb paresis in most patients. Asymmetric proximal muscle weakness, including neck flexion weakness, frequently appeared later in the disease course. The oldest family member was wheelchair-bound; he had significant disability of the upper limbs as well as urinary incontinence associated with absent detrusor contractility. Two of the patients had hearing loss. Sevilla et al. (2016) also reported 2 unrelated patients with sporadic disease. These patients presented after birth or in infancy with hypotonia, muscle weakness, and delayed motor development. One patient was lost to follow-up at age 19 months, whereas the other showed a progressive disease course with severe proximal and distal muscle weakness affecting the upper and lower limbs at age 45 years; she was wheelchair-bound. Electrophysiologic studies of all patients showed normal or near-normal motor nerve conduction velocities with decreased amplitudes of compound muscle and sensory nerve action potentials. Electromyography showed chronic neurogenic changes and spontaneous activity at rest, including fasciculations and myokymia. MRI, performed on 2 unrelated patients, showed fatty replacement of muscle in the legs. Sural nerve biopsy, also performed on 2 unrelated patients, showed predominant loss of large myelinated fibers with occasional small onion bulbs and regenerative clusters and thin myelin sheaths. There was a multifocal pattern of myelinated fiber loss, which was consistent with the observed asymmetric and random-like pattern of muscle weakness.

Albulym et al. (2016) reported 4 unrelated patients with CMT2Z. All had onset of progressive walking difficulties due to distal and later proximal muscle weakness and atrophy as well as distal sensory impairment. Three patients became wheelchair-bound between 25 and 40 years of age. Nerve conduction studies were consistent with a motor and sensory axonal neuropathy. None had upper motor neuron signs. Two patients were noted to have hand weakness, including one with finger contractures. One patient had developmental delay and another had mild learning difficulties.

Inheritance

The transmission pattern of CMT2Z in the family reported by Sevilla et al. (2016) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a family with CMT2Z, Sevilla et al. (2016) identified a heterozygous missense mutation in the MORC2 gene (R190W; 616661.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Direct sequencing of the MORC2 gene in 52 unrelated probands with CMT2 identified 2 patients with de novo heterozygous missense mutations: 1 patient had the R190W mutation, and the other had a S25L mutation (616661.0002). Functional studies of the variants were not performed.

In affected members of a large Australian family (CMT105), originally reported by Frith et al. (1994), Albulym et al. (2016) identified a heterozygous missense mutation in the MORC2 gene (R252W; 616661.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Analysis of 45 unrelated probands with CMT2 identified 4 additional families with heterozygous MORC2 missense mutations: 2 families carried R252W and 2 carried a different missense mutation (E236G; 616661.0003). Functional studies of the variants and studies of patient cells were not performed.