Charcot-Marie-Tooth Disease, Dominant Intermediate G

A number sign (#) is used with this entry because of evidence that dominant intermediate Charcot-Marie-Tooth disease G (CMTDIG) is caused by heterozygous mutation in the NEFL gene (162280) on chromosome 8p21.

Description

CMTDIG is an autosomal dominant neurologic disorder with a highly variable phenotype. Most affected individuals have onset in the first or second decades of slowly progressive distal motor weakness and atrophy, resulting in gait instability and distal upper limb impairment, as well as distal sensory impairment. More severely affected individuals may have pes cavus and claw hands and become wheelchair-bound, whereas other affected individuals have later onset with a milder disease course. Electrophysiologic studies tend to show median motor nerve conduction velocities (NCV) in the 'intermediate' range, between 25 and 45 m/s (summary by Berciano et al., 2017).

In a review of intermediate CMT, Berciano et al. (2017) noted that advanced axonal degeneration may induce secondary demyelinating changes resulting in decreased NCV and attenuated compound muscle action potential (CMAP) in median nerve conduction studies. They thus suggested that testing the upper arm, axilla to elbow, may provide more accurate assessment of NCV and CMAP and reveal an intermediate phenotype (review by Berciano et al., 2017).

For a discussion of genetic heterogeneity of CMTDI, see 606482.

Clinical Features

Zuchner et al. (2004) reported a 3-generation German family with heterogeneous manifestations of CMT. Two patients reported onset of lower extremity weakness at ages 15 and 34 years, 1 patient had foot deformities at age 4 years, and the oldest patient presented with deafness at age 46. They had slowly progressive gait disturbances and lower limb weakness and atrophy associated with distal sensory impairment and decreased or absent reflexes. Three patients had pes cavus, and 3 had decreased reflexes in the upper limbs, but there was minimal clinical hand involvement. A set of 21-year-old twins, sons of one of the affected individuals, were asymptomatic even though they carried the mutation. It was unclear whether the deafness observed in the oldest patient was related to CMT. Electrophysiologic studies showed normal motor nerve conduction velocities (NCV) and compound action muscle potentials (CMAP) in the median and ulnar nerves. NCV in peroneal and tibial nerves were mildly decreased. Sural nerve biopsies from 2 patients showed a reduction of large myelinated axons and clusters of regenerated myelinated nerve fibers, reflecting axonal atrophy, degeneration, and regeneration. Zuchner et al. (2004) concluded that demyelination and remyelination were secondary to primary axonal dysfunction, and suggested that the phenotype in this family was 'intermediate' CMT.

Fabrizi et al. (2007) reported 2 Italian sibs (family E) with CMTDIG. In the first or second decades, the patients had onset of muscle weakness and atrophy affecting the upper and lower limbs and associated with distal loss of vibration sense and areflexia. One patient had hearing loss. Brain imaging of 1 patient was normal. Electrophysiologic studies of the median nerve showed decreased NCV (29 and 30 m/s) with decreased CMAP, suggesting a mixed axonal and demyelinating neuropathy. Sural nerve biopsy showed no neurofilaments and contained only microtubules, indicating structural alterations of the cytoskeleton. There were also defects in the myelin sheath, which Fabrizi et al. (2007) suggested were secondary changes. The sibs' father was reportedly similarly affected.

Elbracht et al. (2014) reported 8 members of a multigenerational family with onset of CMTDIG in infancy or early childhood. One patient had delayed motor development and walked on tiptoes, but others had slowly progressive gait abnormalities beginning in childhood and worsening in adolescence, usually accompanied by distal sensory impairment. Older family members showed proximal muscle weakness, and several used walking aids. The patients had foot deformities, hypo- or areflexia, and variable involvement of the upper limbs. Median motor NCVs ranged from 38 to 43 m/s, and CMAPs were reduced. EMG suggested some myopathic changes in 1 of the patients. Sural nerve biopsy showed a chronic mixed axonal/demyelinating polyneuropathy with a marked reduction in myelinated nerve fiber density. Many myelinated fibers showed axonal atrophy, but there were also regenerating fibers as well as myelin abnormalities. Focal axonal accumulation of organelles and vesicular material was also observed. An unrelated patient (patient 9) had normal motor and sensory function until age 50, when he developed distal muscle weakness and sensory impairment of the upper and lower limbs. His laboratory studies indicated an intermediate form of CMT. Serum creatine kinase was mildly increased in most patients.

Berciano et al. (2015) reported a Spanish woman and her 3 sons with a dominant intermediate form of CMT. The proband, one of the sons, had pes cavus and nonprogressive clumsy walking since infancy. Physical examination at age 17 years showed distal sensory impairment, areflexia, generalized hypotonia, and mild spasticity of the lower limbs with extensor plantar responses. He did not have peroneal amyotrophy or calf paresis at that time. The disorder became progressive during his twenties, and by age 39, he had severe gait impairment manifest as a steppage waddling gait with spasticity, inability to walk on the heels or tiptoes, and positive Gowers sign, suggesting proximal involvement. He also showed amyotrophy of the lower legs, forearms, and hands, as well as sensory impairment up to the thighs. Other family members had onset of walking difficulties in the first or second decades, with variable progression of the disorder similar to the proband. Both upper and lower limbs were affected. Laboratory studies showed increased serum creatine kinase, and electrophysiologic studies showed intermediate NCV in the median nerve (34 to 43 m/s). CMAPs were relatively preserved. Distal motor latencies were prolonged, and sensory nerve action potentials (SNAPs) were unobtainable or severely reduced. EMG showed chronic de-reinnervation. Examination of more proximal upper-limb nerve segments showed intermediate NCV slowing with normal CMAP amplitudes, consistent with the family being classified as having 'dominant intermediate CMT.' The patients also showed prolongation of blink reflexes, suggesting dysfunction of central sensory pathways in the brain. Berciano et al. (2015) noted that patients with intermediate CMT may have secondarily reduced CMAP amplitude in distal nerve segments, resulting from primary axonal degeneration.

Berciano et al. (2016) reported a Spanish mother and son, aged 38 and 5 years, with early-onset CMT. The mother had a severe, complex neurologic disorder combining progressive cerebellar ataxia and peripheral neuropathy. She had delayed walking at age 3, and in her teens she developed progressive clumsiness, weakness in the lower limbs and hands, and dysarthria. She was wheelchair-bound in her thirties. Physical examination showed steppage gait and marked postural instability, as well as distal muscle weakness and atrophy, claw hands, and pes cavus. She also had nystagmus, possibly abnormal smooth pursuit, and reduced or absent blink reflexes. Brain imaging showed cerebellar atrophy. Her upper arm NCV was 47.5 m/s, consistent with intermediate results; median motor NCVs were reduced to within the demyelinating range. Her son had delayed motor milestones, was starting to show areflexia clinically, and had NCVs of the upper arm in the intermediate range, but he did not have significant clinical disease. Molecular analysis of common spinocerebellar ataxia (SCA) genes excluded pathogenic mutations.

Inheritance

The transmission pattern of CMTDIG in the family reported by Berciano et al. (2015) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 4 affected members of a 3-generation German family with CMTDIG, Zuchner et al. (2004) identified a heterozygous missense mutation in the NEFL gene (E396K; 162280.0010). The mutation, which was found by direct sequencing of the NEFL gene, segregated with the disorder in the family. Two asymptomatic family members also carried the mutation: they were 21 years of age, possibly suggesting age-related incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed.

In 2 Italian sibs (family E) with CMTDIG, Fabrizi et al. (2007) identified heterozygosity for the E396K mutation in the NEFL gene.

Elbracht et al. (2014) identified heterozygosity for the E396K mutation in the NEFL gene in 8 members of a multigenerational family with onset of CMTDIG in infancy or early childhood as well as in an unrelated patient (patient 9) with CMTDIG who had onset at age 50; he had no family history of CMT. The discrepancy in the phenotype among patients with the same mutation suggested additional genetic modifiers and broadened the phenotypic spectrum associated with this mutation. Functional studies of the variant were not performed.

Berciano et al. (2015) identified heterozygosity for the E396K mutation in the NEFL gene in 4 affected members of a Spanish family with CMTDIG. The variant, which was found by exome sequencing of candidate disease genes, was confirmed by Sanger sequencing and segregated with the disorder. Functional studies of the variant and studies of patient cells were not performed.

In a Spanish woman and her son with CMTDIG, Berciano et al. (2016) identified a heterozygous missense mutation in the NEFL gene (N98S; 162280.0011). The mutation was found by exome sequencing. Functional studies of the variant were not performed.