Myopathy, Scapulohumeroperoneal

A number sign (#) is used with this entry because of evidence that scapulohumeroperoneal myopathy (SHPM) is caused by heterozygous mutation in the ACTA1 gene (102610) on chromosome 1q42. One such family has been reported.

Description

Scapulohumeroperoneal myopathy is an autosomal dominant muscle disorder characterized by slowly progressive muscle weakness and atrophy affecting both proximal and distal muscles of the upper and lower limbs. Onset is usually in the first decade and can be as early as infancy, although some patients do not notice symptoms until young adulthood. There is marked variability in severity (summary by Zukosky et al., 2015).

Clinical Features

Armstrong et al. (1966) reported an black family in which 19 individuals had slowly progressive muscle weakness affecting the upper and lower limbs. The patients reported onset of proximal weakness in late childhood or early adolescence, with difficulty arising from sitting, climbing stairs, and raising the arms above the head. The disorder was slowly progressive, and later involved distal muscle weakness and atrophy of all affected muscles. Affected individuals had a waddling gait and wasting of the muscles of the shoulder girdle. Deep tendon reflexes were decreased or absent. Muscle biopsy showed some mild dystrophic changes, such as fiber-type grouping and increased internal nuclei. Electrophysiologic studies of 2 patients showed normal nerve conduction velocities with slightly increased motor unit potentials, which Armstrong et al. (1966) interpreted as suggestive of a neurogenic origin.

Zukosky et al. (2015) reported follow-up of the family reported by Armstrong et al. (1966). There were 33 affected individuals spanning 6 generations; 12 patients were reported in detail. The disorder was slowly progressive, but showed highly variable severity, and both upper and lower extremities were affected. The lower extremities had an initial pattern of distal more than proximal involvement with early foot drop, but proximal involvement became more pronounced with age. The overall distribution was scapulohumeroperoneal with hand involvement. The most severely affected individuals presented in infancy with hypotonia, foot eversion, and dorsiflexion weakness. Running in childhood was awkward, followed by progressive weakness resulting in loss of independent ambulation and development of scoliosis in the fifth or sixth decade. However, other affected individuals did not notice weakness until early adulthood. Most patients had mild facial weakness and weakness of the neck flexor muscles. In the upper limb, there was proximal weakness of the biceps and triceps, some scapular winging, and definite weakness of the distal muscles, including wrist, finger, and thumb muscles. In the lower extremities, affected individuals had weakness of the hip flexors, knee flexors and extensors, and milder involvement of the leg abductors and adductors. Distal weakness of the lower extremities was also prominent, including dorsi- and plantar flexion and foot eversion and inversion; all patients had impaired gait. There was no cardiac or respiratory involvement. Muscle imaging showed atrophy and fatty replacement of affected muscles. Muscle biopsy showed degenerative changes, including variability in fiber size, increased internal nuclei, and fatty infiltration. The were groups of type 1 fiber atrophy, consistent with fiber-type disproportion. Nemaline rods and actin aggregates were not observed. Electrophysiologic studies showed some apparent denervation, with decreased values of motor unit number estimation, but this could be attributed to nonfunctional neuromuscular junctions resulting from muscle fiber atrophy. The overall findings were consistent with a myopathic process rather than a neurogenic process.

Inheritance

The transmission pattern of SHPM in the family reported by Zukosky et al. (2015) was consistent with autosomal dominant inheritance.

Mapping

By linkage analysis of a large family with SHPM originally reported by Armstrong et al. (1966), Zukosky et al. (2015) found linkage to a 4.8-Mb region on chromosome 1q42.12-q42.13 (lod score of 3.651).

Molecular Genetics

In affected members of a large family with SHPM originally reported by Armstrong et al. (1966), Zukosky et al. (2015) identified a heterozygous missense mutation in the ACTA1 gene (E197D; 102610.0018). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transfection of the mutation into COS7 cells showed that the mutant protein had normal actin localization and did not form nemaline rods. Injection of the mutation into zebrafish embryos did not result in any morphologic abnormalities or abnormal muscle histology up to 6 days after fertilization. Zukosky et al. (2015) postulated that a pathogenic process fundamentally different from changes in actin cytoarchitecture or rod formation was responsible for the phenotype, such as changes in interaction or force generation, actin filament stability, or differences in the directionality of actin filament growth.