Neuronopathy, Distal Hereditary Motor, Type Vb

A number sign (#) is used with this entry because of evidence that distal hereditary motor neuronopathy type VB (HMN5B) is caused by heterozygous mutation in the REEP1 gene (609139) on chromosome 2p11. One such family has been reported.

Mutation in the REEP1 gene can also cause spastic paraplegia-31 (SPG31; 610250). Some patients with REEP1 mutations can show overlapping signs of HMN5B and SPG31, indicating that there is a phenotypic spectrum of manifestations associated with REEP1 mutations.

Description

Distal hereditary motor neuronopathy type VB is an autosomal dominant neurologic disorder characterized by onset in the first or second decade of distal muscle weakness and atrophy, primarily affecting the intrinsic hand muscles, but also affecting the lower legs, resulting in abnormal gait and pes cavus (summary by Beetz et al., 2012).

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

Clinical Features

Beetz et al. (2012) reported an Austrian family in which 4 adult individuals spanning 3 generations developed a predominant peripheral motor neuronopathy in the first or second decades of life. Three presented with hand muscle weakness and atrophy confined to the thenar and dorsalis interosseus I muscles, and the fourth patient presented with an unstable gait, but also had hand involvement. Three had mild or moderate peroneal atrophy and weakness. All had pes cavus, which ranged from mild to severe. Patellar tendon reflexes were decreased and Achilles tendon reflexes were absent in all patients. None had increased muscle tone or spasticity. Electrophysiologic studies were performed in 3 patients and showed variable results, but mostly decreased amplitude and conduction velocities in the hand and lower legs. Three of the patients were diagnosed with dHMN type V, and 1 with dHMN.

Inheritance

The transmission pattern of dHMN type VB in the family reported by Beetz et al. (2012) was consistent with autosomal dominant inheritance.

Molecular Genetics

By genomewide linkage analysis followed by exome sequencing of a family with dHMN type V, Beetz et al. (2012) identified a heterozygous splice site mutation in the REEP1 gene (609139.0006), resulting in skipping of exon 5 and a mutant protein lacking residues 102-139. The mutant REEP1 protein showed some localization similar to wildtype, but also accumulated in cytoplasmic compact structures of varying sizes, with the largest structures in the perinuclear regions. REEP1 lacking exon 5 showed colocalization with atlastin-1 (ATL1; 606439), including in the abnormal cytoplasmic structures. In contrast, the A20E mutant protein (609139.0004) associated with SPG31 showed severely altered localization to numerous punctate small structures throughout the cytoplasm and no localization to the endoplasmic reticulum. Moreover, A20E did not colocalize with atlastin. These findings suggested a different pathomechanism of these 2 mutations, which may explain the different associated phenotypes. Beetz et al. (2012) postulated that loss-of-function REEP1 mutations (i.e., A20E) may cause upper motor neuron disease, whereas possible gain-of-function mutations (102_139del) may cause lower motor neuron disease. The findings expanded the phenotypic spectrum associated with REEP1 mutations, similar to that observed with BSCL2 (606158).