Scapuloperoneal Spinal Muscular Atrophy

A number sign (#) is used with this entry because of evidence that scapuloperoneal spinal muscular atrophy (SPSMA) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.

Congenital distal spinal muscular atrophy (600175) and hereditary motor and sensory neuropathy IIC (HMSN2C; 606071) are allelic disorders with overlapping phenotypes.

Clinical Features

DeLong and Siddique (1992) reported an extensive New England kindred of French Canadian extraction, in which 20 persons in 5 generations had a neurogenic scapuloperoneal amyotrophy that most nearly resembled the Stark-Kaeser form of chronic scapuloperoneal amyotrophy (181400) but had features which forced them to consider it unique. The features of the variable clinical disorder included congenital absence of muscles, progressive scapuloperoneal atrophy, laryngeal palsy, and progressive distal weakness and amyotrophy. One patient was born with torticollis and congenital hip dysplasia. There was delayed motor development and normal intellect. He showed weakness and atrophy of the proximal upper and lower muscles, facial muscle paresis, abducens weakness, and neck flexor weakness. His shoulders were rounded with laterally displaced scapulae. One leg was shorter than the other. He had a wide-based gait, hyperlordosis, and Gowers sign. At age 22, he had significant distal muscle weakness and atrophy. Other affected family members had similar features, with variable laryngeal palsy resulting in hoarse voice and respiratory stridor, and variable weakness and atrophy of the proximal and distal muscles of the upper and lower limbs. There was little or no progression. Muscle biopsies showed grouped fiber atrophy, consistent with a neurogenic process. DeLong and Siddique (1992) observed that the expression of the disease was more severe and progressive in succeeding (third and fourth) generations (suggesting genetic anticipation) and in different branches of the family. Linkage to markers in the Charcot-Marie-Tooth region of chromosome 17 (118220) was excluded.

Clinical Variability

Berciano et al. (2011) reported a family in which 2 of 5 individuals carrying the same heterozygous mutation in the TRPV4 gene (R269C; 605427.0011) had different phenotypes: a 44-year-old woman had scapuloperoneal spinal muscular atrophy and her 7-year-old daughter had congenital distal spinal muscular atrophy (600175). The 3 other individuals with the mutation were clinically and electrophysiologically asymptomatic 9, 40, and 70 years of age, respectively, consistent with incomplete penetrance. The mother had sloped shoulders since childhood and later developed progressive lower leg muscle weakness and atrophy. She also had transient dysphonia. Muscle biopsy showed evidence of chronic denervation and renervation, and electrophysiologic studies showed reduced compound muscle action potentials with normal nerve conduction velocities, consistent with a motor axonal neuropathy. The daughter was born with congenital arthrogryposis and showed delayed motor development and laryngomalacia with stridor and vocal cord paresis necessitating intermittent tracheostomy placement. She was wheelchair-bound at age 7 due to limited joint mobility and lower limb muscle weakness, and also had weakness and atrophy of the shoulder girdle muscles.

Mapping

In the New England kindred of French Canadian origin described by DeLong and Siddique (1992), Isozumi et al. (1996) demonstrated linkage of this neurologic disorder to 7 microsatellite markers that map to 12q24.1-q24.31. The highest lod score with 2-point linkage analysis was 6.67 at theta = 0.00 with marker D12S353. Multipoint analysis gave maximum lod scores of 7.38 between D12S354 and D12S79, and also 7.38 between D12S369 and the gene for neuronal nitric oxide synthase (163731). Thus the gene for the disorder in this family, which they symbolized SPSMA (for 'scapuloperoneal spinal muscular atrophy'), lies within the 19-cM interval between D12S338 and D12S366.

Molecular Genetics

In the family reported by DeLong and Siddique (1992), Deng et al. (2010) identified a heterozygous mutation in the TRPV4 gene (R316C; 605427.0010). Deng et al. (2010) noted that some of the affected individuals had skeletal abnormalities, including congenital hip dysplasia, scoliosis, small hands, and 1 arm or leg shorter than the other.

History

In a large Italian American family with scapuloperoneal muscular dystrophy, Wilhelmsen et al. (1996) found evidence suggestive of linkage to chromosome 12q (lod score of 2.95 at marker D12S82; multipoint lod score of 3.0). However, 10 individuals classified as 'not affected' shared the chromosome 12q haplotype with affected individuals, suggesting incomplete penetrance, double recombination in these 'not affected' individuals, or false-positive linkage. Therefore, Quinzii et al. (2008) performed a new genomewide scan on this family with microsatellite markers in leukocyte DNA from 27 family members (14 affected and 13 unaffected), which established linkage to chromosome Xq26. Genetic analysis identified a pathogenic mutation in the FHL1 gene (300163.0001) that segregated with the disorder.