CMTDIF is an autosomal dominant neurologic disorder characterized by onset around adolescence of slowly progressive distal muscle atrophy and weakness affecting the upper and lower limbs and resulting in steppage gait. There is distal sensory impairment with decreased ... CMTDIF is an autosomal dominant neurologic disorder characterized by onset around adolescence of slowly progressive distal muscle atrophy and weakness affecting the upper and lower limbs and resulting in steppage gait. There is distal sensory impairment with decreased reflexes. Nerve conduction velocities are variable, ranging from the demyelinating to the axonal range (summary by Soong et al., 2013). For a discussion of genetic heterogeneity of CMTDI, see 606482.
Lee et al. (2010) reported a 3-generation Han Chinese family in which 7 patients had Charcot-Marie-Tooth disease. The proband was a 49-year-old man who had been wheelchair-bound for 3 years. He had normal motor development as a child, ... Lee et al. (2010) reported a 3-generation Han Chinese family in which 7 patients had Charcot-Marie-Tooth disease. The proband was a 49-year-old man who had been wheelchair-bound for 3 years. He had normal motor development as a child, but reported slowly progressive weakness and atrophy of the legs since adolescence. Physical examination showed marked atrophy and weakness of the muscles in the legs, feet, and intrinsic hand muscles, with generalized areflexia, pes cavus, and hammer toes. He had diminished sensation of all modalities in the distal parts of the 4 extremities. All 3 of his children were affected. His 2 sons showed a similar disorder with onset around adolescence. His 17-year-old daughter denied neurologic symptoms, but examination revealed mild atrophy and weakness of intrinsic foot muscles, generalized areflexia, mild pes cavus, and hammer toes. The proband's sister had a less severe phenotype, and her daughter also denied any neurologic signs, but examination showed mild features. The proband's deceased father was reportedly affected. Nerve conduction velocities (NCV) of the 6 patients studied varied widely, ranging from 16.5 to 45.7 m/s. The male patients had definitive demyelinating sensorimotor polyneuropathy with axonal loss, whereas the female patients had a milder phenotype with mild or intermediate slowing of motor nerve conduction velocities. Sural nerve biopsy of the proband showed severe loss of myelinated fibers and many onion bulb formations with clusters of regenerating fibers. Soong et al. (2013) reported a 9-year-old Han Chinese girl who presented with slowly progressive weakness of the distal lower limbs since age 5 years. She had high-arched feet, hammer toes, atrophy, and weakness of the intrinsic muscles of the feet, impaired dorsiflexion of the feet, and generalized areflexia. Examination showed mildly diminished sensation for all modalities in regions distal to the ankles despite a lack of sensory complaints. Nerve conduction studies showed a demyelinating sensorimotor polyneuropathy with axonal loss with decreased median NCV of 20 m/s.
In affected members of a Chinese family with dominant intermediate CMT (Lee et al., 2010), Soong et al. (2013) identified a heterozygous mutation in the GNB4 gene (G53D; 610863.0001). The mutation was identified by exome sequencing. An unrelated ... In affected members of a Chinese family with dominant intermediate CMT (Lee et al., 2010), Soong et al. (2013) identified a heterozygous mutation in the GNB4 gene (G53D; 610863.0001). The mutation was identified by exome sequencing. An unrelated Chinese girl with demyelinating CMT carried a different heterozygous mutation that occurred de novo (K89E; 610863.0002). The frequency of GNB4 mutations in the CMT cohort was 0.8% (2 of 251 families). Immunofluorescence studies of patient sural nerves showed GNB4 staining of onion bulb formations in a rosette pattern. However, immunohistochemical studies showed weaker GNB4 expression in patient sural nerve biopsies compared to controls. Expression of both mutations in COS-7 cells showed that the mutant proteins had impaired bradykinin-induced G protein-coupled receptor intracellular signaling compared to the wildtype protein. The mutant proteins were stable in transfected cells, and Soong et al. (2013) postulated a dominant-negative effect. The findings indicated that GNB4-related G protein-coupled receptor signaling is important for proper function of peripheral nerves.