Charcot-Marie-Tooth Disease, Type 4b3

A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is caused by homozygous or compound heterozygous mutation in the SBF1 gene (603560) on chromosome 22q.

For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating CMT, see CMT4A (214400).

Clinical Features

Nakhro et al. (2013) reported 3 Korean sisters, born of unrelated parents, with onset of progressive demyelinating CMT in or near the first decade of life (5 to 11 years). All presented with distal leg weakness, 2 with gait ataxia. Examination of the patients as adults showed atrophy and weakness in the proximal and distal muscles of the upper and lower limbs, most prominently in lower leg and intrinsic hand muscles. There was areflexia and distal sensory loss, with vibration and position senses more severely affected than pain and temperature. All had pes planus, 2 had scoliosis, and none had glaucoma. Two patients became wheelchair-bound in their mid-forties. Median and ulnar nerve conduction velocities were less than 38 m/s in all patients, and sural nerve biopsy of 1 patient showed absence of large myelinated fibers, focally folded myelin sheaths, few onion bulbs, and occasional regenerating clusters of axons.

Clinical Variability

Bohlega et al. (2011) reported 3 adult brothers, born of consanguineous Saudi parents, with a syndromic form of sensorimotor polyneuropathy. All had microcephaly and cognitive impairment, each with an IQ around 50. Brain imaging of 2 patients showed brain atrophy. The patients developed progressive distal lower extremity weakness and atrophy between 10 and 20 years of age, resulting in immobility in 2 patients. Two patients also developed significant upper limb involvement, resulting in loss of basic hand function. Distal sensory impairment and loss of reflexes were noted. Electrophysiologic studies showed a sensorimotor axonal polyneuropathy with nerve conduction velocities between 34 and 46 m/s. Sural nerve biopsy of 1 patient showed moderately depleted myelinated axons, no onion bulbs, and some axonal sprouting. Muscle biopsy showed neurogenic angulated fibers and mild fiber-type grouping. Additional features included significant strabismus, ophthalmoplegia, facial weakness, variable syndactyly of the hands and feet, dysarthria, and urinary incontinence.

Inheritance

The transmission pattern of CMT4B3 in the family reported by Nakhro et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of a consanguineous Saudi family with sensorimotor peripheral neuropathy and mental retardation, Bohlega et al. (2011) found linkage to chromosome 22q13.31-q13.33.

Molecular Genetics

In 3 Korean sisters with Charcot-Marie-Tooth disease, Nakhro et al. (2013) identified compound heterozygous missense mutations in the SBF1 gene (603560.0001 and 603560.0002). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. Functional studies were not performed.

In affected members of a consanguineous Saudi family with CMT4B3 and mental retardation, Alazami et al. (2014) identified a homozygous missense mutation in the SBF1 gene (D443N; 603560.0003). The mutation was found by exome sequencing. Functional studies of the variant were not performed.