Neuronopathy, Distal Hereditary Motor, Type Iib

A number sign (#) is used with this entry because distal hereditary motor neuronopathy type 2B (dHMN2B or HMN2B) is caused by heterozygous mutation in the gene encoding heat-shock 27-kD protein-1 (HSPB1; 602195) on chromosome 7q11. Axonal Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) is an allelic disorder with a similar phenotype.

For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN (dHMN), see HMN type I (HMN1; 182960).

Clinical Features

Houlden et al. (2008) reported 5 families with HMN2B. All patients had a remarkably similar slowly progressive disease course with a mean age at onset ranging from 21 to 54 years. Muscle weakness and atrophy started and predominated in the distal lower limb muscles. Muscle weakness and wasting progressed to the upper limbs approximately 5 to 10 years later along with proximal lower limb problems. Sensory disturbances were absent in all patients except 1 proband with a long history of diabetes mellitus. Tendon reflexes were depressed or absent in all cases. One of the families was consanguineous, consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 4 different families with dHMN, Evgrafov et al. (2004) identified 4 different mutations in the HSPB1 gene (602195.0001-602195.0004).

Houlden et al. (2008) identified 4 different heterozygous mutations in the HSPB1 gene (see, e.g., 602195.0001; 602195.0007) in affected members of 4 of 25 families with HMN2B. Two of 30 patients with sporadic dHMN also had mutations. An additional patient with autosomal recessive inheritance was found to have a homozygous mutation (602195.0008). All patients had a predominant motor neuropathy without clinical sensory abnormalities. No HSPB1 mutations were found in 90 families with CMT2.

Animal Model

D'Ydewalle et al. (2011) demonstrated that transgenic mice expressing the P182L (602195.0004) Hspb1 mutation developed clinical and pathologic features of distal HMN. Mutant mice developed progressive motor impairment, decreased muscle strength, and clawed hindpaws, but no sensory abnormalities. There was distal axonal loss on nerve biopsy, as well as a decrease in acetylated alpha-tubulin (TUBA1A; 602529) in peripheral nerves.