Neuronopathy, Distal Hereditary Motor, Type Va

A number sign (#) is used with this entry because distal hereditary motor neuronopathy type VA (dHMN5A or HMN5A), sometimes referred to as distal spinal muscular atrophy type V (DSMAVA), can be caused by heterozygous mutation in the GARS gene (600287) on chromosome 7p14 or by heterozygous mutation in the BSCL2 gene (606158) on chromosome 11q12.

Charcot-Marie-Tooth disease type 2D (CMT2D; 601472), also caused by mutation in the GARS gene, has a similar phenotype.

Silver syndrome (SPG17; 270685), also caused by mutation in the BSCL2 gene, is a similar disorder with an overlapping phenotype characterized by spasticity.

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

Clinical Features

Meadows and Marsden (1969) reported 3 sibs with a form of distal muscular atrophy confined largely to the upper extremities. All had weakness of the hands since early childhood, manifest by difficulty writing. The condition worsened significantly much later in life, in the sixth and seventh decades. Hand weakness and atrophy were apparent in all, and 2 sibs had lower limb weakness with hyporeflexia/areflexia; the remaining sib had hyporeflexia/areflexia without lower limb weakness. EMG and muscle biopsy confirmed a neurogenic disorder. The mode of inheritance was unclear.

Christodoulou et al. (1995) identified a large 5-generation Bulgarian family from Burgass with an autosomal dominant distal spinal muscular atrophy (dSMA) with upper limb predominance. Afflicted members had weakness and wasting which was more prominent in the upper limbs and more selectively involved the thenar muscles and the first dorsal interossei. They had clinical information on 114 family members, of whom 30 were affected. The disease commenced with hand involvement at a mean age of 17 years (median 16 years). In 40% of patients, symptoms subsequently developed in their feet within about 2 years. In 1 branch of the family, mild pyramidal features and, rarely, up-going plantar responses were observed. There were not sensory symptoms or signs except for slightly reduced vibratory sense in the feet in 10% of the patients. Progression of the disease was very slow, with patients still ambulant at the age of 64. Electrophysiologic investigations showed reduced or, in severely wasted muscles, unobtainable compound motor action potentials. Motor conduction velocities and distal latencies were normal, except in severely wasted muscles, where the former were reduced. Christodoulou et al. (1995) concluded that the family fell into the type V category of distal spinal muscular atrophy according to Harding (1993), who proposed a classification into 7 types of distal SMA according to their clinical and genetic features. The family was similar to the one reported by Lander et al. (1976), but differed in that weakness and wasting were more severe in the thenar muscles and first dorsal interossei. The family was considered to be different from the families with Silver syndrome described by Silver (1966) and by van Gent et al. (1985) in that most of their patients also had brisk reflexes and signs of spasticity in addition to hand weakness.

Sambuughin et al. (1998) reported a family in which autosomal dominant CMT2D and distal spinal muscular atrophy type V segregated in the same kindred. All 17 affected members had bilateral weakness and wasting in thenar and first dorsal interossei muscles starting commonly with cold-induced cramps in the hands in their late teens. The mean age at onset was 18 years (range 12 to 36) and progression of illness was very slow. DSMAV was diagnosed in 11 patients based on the presence of hand and peroneal muscle weakness and atrophy without sensory deficits. CMT2D was diagnosed in 6 other patients based on the presence of weakness and atrophy in the same muscle groups, hypoactive knee and ankle reflexes, stocking and glove distribution sensory loss, and reduced sensory nerve action potential amplitudes.

Antonellis et al. (2003) reported an Algerian Sephardic Jewish family with autosomal dominant DSMAV. A father and daughter had bilateral hand amyotrophy and weakness, particularly in the thenar and dorsal interosseus muscles. Motor and sensory nerve conduction velocities were normal.

Van de Warrenburg et al. (2006) reported 2 unrelated Dutch families with overlapping Silver syndrome and distal motor neuropathy caused by the same BSCL2 mutation (N88S; 606158.0013). The first family contained 5 affected individuals spanning 3 generations. All presented with pes cavus and foot of leg muscle weakness and atrophy between 11 and 26 years of age. There was slow progression, with gradually evolving lower limb hypertonia and hyperreflexia with extensor plantar responses without prominent spasticity. Two patients also developed weakness and atrophy of the first dorsal interosseus and abductor pollicis brevis muscles without involvement of the hypothenar muscles. In the second family, there were multiple affected individuals spanning 3 generations. Age at onset was before age 20 years. About half of the patients presented with foot or leg muscle weakness and atrophy, whereas the other half presented with hand muscle weakness and atrophy. Most developed hyperreflexia with extensor plantar responses; spasticity was observed in older patients. Van de Warrenburg et al. (2006) emphasized the phenotypic variability and incomplete penetrance of some symptoms.

Brusse et al. (2009) reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMN5 who carried a heterozygous N88S mutation in the BSCL2 gene. The phenotype was variable, and the distribution of muscle weakness and atrophy included predominantly the feet (in 4), the hands (in 1), or both upper and lower extremities (in 4). Three individuals showed evidence of pyramidal features, including spasticity, hyperrflexia, and extensor plantar responses. Severity of the disease ranged from adolescent patients with disabling muscle weakness to an elderly patient with only mild weakness of the ankle dorsiflexors and bilateral pes cavus. Brusse et al. (2009) noted the extreme phenotypic variability associated with the N88S mutation in their family and in those reported by Auer-Grumbach et al. (2005) and van de Warrenburg et al. (2006), who also carried the N88S mutation, and suggested the presence of other genetic or environmental factors. In their family, Brusse et al. (2009) used genomewide linkage analysis to identify a candidate disease modifier on chromosome 16p13.3-p13.12 that was shared by all 12 affected individuals (maximum lod score of 3.28). One family member without the N88S mutation but with the chromosome 16p haplotype showed mild electrophysiologic abnormalities. Brusse et al. (2009) postulated that a locus on chromosome 16p may contain a disease modifier in their family.

Mapping

Linkage studies in the Bulgarian family reported by Christodoulou et al. (1995) excluded the SMA locus (253300) on chromosome 5. Using more than 140 microsatellite polymorphic markers for a genome screen, Christodoulou et al. (1995) found a maximum lod score of 5.99 at theta = 0.007 for locus D7S795 located on 7p. Sambuughin et al. (1998) mapped the disorder in their family to a region on 7p15 between markers D7S2496 and D7S1514.

Ellsworth et al. (1999) performed a more detailed linkage analysis of the region on 7p and found overlap between the areas defined by Christodoulou et al. (1995) and Sambuughin et al. (1998) and the area defined by Ionasescu et al. (1996) in a CMT2D family. Ellsworth et al. (1999) determined that the most likely location of the CMT2D gene is between markers D7S2496 and D7S632. They suggested that defects in a single gene account for the disease in all of the families.

Genetic Heterogeneity

In a large 4-generation Austrian family with autosomal dominant DSMAV, Auer-Grumbach et al. (2000) excluded linkage to the DSMAV locus on 7p, indicating genetic heterogeneity of the disorder. Linkage was also excluded from the adult spinal muscular atrophy locus on chromosome 12q (158590) and the juvenile ALS locus on 9q (ALS4; 602433). Twenty-one family members were affected with a highly variable phenotype. Most affected members had onset before age 20 years of a progressive asymmetric wasting of the thenar and the first dorsal interosseus muscles. Twenty patients had foot deformity, ranging from mild to severe, and about half had peroneal muscular atrophy. A subset of patients also had brisk tendon reflexes. Sensory abnormalities were virtually absent.

Molecular Genetics

Irobi et al. (2004) reviewed the molecular genetics of the distal motor neuropathies.

Mutations in the GARS Gene

In the families with DSMAV reported by Christodoulou et al. (1995) and Antonellis et al. (2003) and the family with both DSMAV and CMT2D reported by Sambuughin et al. (1998), Antonellis et al. (2003) identified mutations in the GARS gene (600287.0002-600287.0004).

Dubourg et al. (2006) identified a mutation in the GARS gene (G526R; 600287.0004) in 12 affected members from 3 French families of Sephardic Jewish origin with HMN type V. Four mutation carriers were clinically asymptomatic, suggesting incomplete penetrance. Most presented with distal upper limb involvement between the second and fourth decades; none had sensory involvement. Haplotype analysis suggested a founder effect.

Mutations in the BSCL2 Gene

In affected members of 1 Italian, 1 English, and 8 Austrian families with DSMAV, including the one reported by Auer-Grumbach et al. (2000), Windpassinger et al. (2004) identified a heterozygous asn88-to-ser mutation in the BSCL2 gene (N88S; 606158.0013). In the same study, Windpassinger et al. (2004) also identified mutations in the BSCL2 gene in patients with Silver syndrome, indicating that the 2 disorders are extreme phenotypes with the same genetic etiology. The large affected Austrian kindred comprised 4 family branches with Silver syndrome and 8 family branches with DSMAV; all affected Austrian patients had the N88S mutation in the BSCL2 gene.

By in vitro functional expression analysis, Ito and Suzuki (2007) demonstrated that the N88S and S90L mutations in the BSCL2 gene disrupt glycosylation of the seipin protein. Overexpressed mutant seipin was highly ubiquitinated and degraded by the proteasome, and improper glycosylation exacerbated endoplasmic reticulum (ER) retention. Mutant proteins activated the unfolded protein response (UPR), resulting in apoptotic cell death through ER stress. Ito and Suzuki (2007) concluded that the N88S and S90L mutations, which result in motor neuron disease, have a gain-of-function effect, resulting in conformational protein changes, activation of the UPR, cell death, and neurodegeneration. Ito and Suzuki (2009) provided a review.