Myopathy, Distal, With Rimmed Vacuoles

A number sign (#) is used with this entry because of evidence that distal myopathy with rimmed vacuoles (DMRV) is caused by heterozygous mutation in the SQSTM1 gene (601530) on chromosome 5q35.

Description

Distal myopathy with rimmed vacuoles is an autosomal dominant myopathic disorder characterized by adult onset of muscle weakness affecting the distal upper and lower limbs, which may result in walking difficulties, as well as proximal weakness of the shoulder girdle muscles. Muscle biopsy shows rimmed vacuoles (summary by Bucelli et al., 2015).

Clinical Features

Bucelli et al. (2015) reported 2 brothers with onset of muscle weakness at ages 52 and 42 years, respectively. Both developed ankle dorsiflexion weakness and had difficulties raising the arms above the head. Absent ankle reflexes and steppage gait were present in one. Physical examination showed weakness of the wrists, ankles, fingers, and toes. Their deceased mother developed foot drop in her mid-sixties, and a deceased maternal uncle had a similar phenotype. An unrelated man had onset of a similar disorder at age 50. He had foot drop with weakness of the ankle muscles, finger extensor weakness, and shoulder muscle weakness with mild scapular winging. Laboratory studies of all patients showed variably increased serum creatine kinase, and muscle biopsy showed marked variation in fiber size, internal nuclei, scattered pyknotic nuclei, rimmed vacuoles, and myofibrillar disorganization with Z-band streaming. Immunostaining showed SQSTM1- and TDP43 (605078)-positive inclusions in scattered myofibers. None of the patients had features of Paget disease (see 167250) or dementia.

Inheritance

The transmission pattern of the distal myopathy with rimmed vacuoles in the family reported by Bucelli et al. (2015) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 2 brothers and an unrelated man with a late-onset distal myopathy, Bucelli et al. (2015) identified a heterozygous splice site mutation in the SQSTM1 gene (601530.0003). The mutation in the family was found by whole-exome sequencing; the mutation in the patient with sporadic disease was found by targeted exome sequencing. Analysis of patient cells and muscle tissue showed that the variant resulted in the expression of 2 different cryptically spliced abnormal isoforms, a deletion variant lacking the PEST2 domain and a truncating variant lacking the UBA domain. In vitro studies showed that the deletion and truncating SQSTM1 mutant proteins were translated and had distinct patterns of expression: 1 was excluded from the nucleus and did not colocalize with ubiquitin, whereas the other accumulated as large perinuclear inclusions that contained ubiquitin. Expression in murine myofibers showed that 1 of these variants was present throughout the sarcoplasm and associated with myofibrillar structures, whereas the other was found only as large subsarcolemmal and sarcoplasmic inclusions.

Nomenclature

Because mutation in the SQSTM1 gene can result in frontotemporal dementia/amyotrophic lateral sclerosis (FTDALS3; 616437), Paget disease of bone (PDB3; 167250), and myopathy (DMRV), Boutoleau-Bretonniere et al. (2015) and Bucelli et al. (2015) proposed that these SQSTM1-related disorders be integrated into the multisystem proteinopathies, a group of genetic disorders clinically characterized by variable penetrance of FTD, ALS, PDB, and myopathy, as multisystem proteinopathy-4 (MSP4). These disorders, unified by the pathologic accumulation of ubiquitin and TDP43 (605078), have also been designated 'inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia' (IBMPFD), with mutations in VCP causing IBMPFD1/MSP1 (167320), mutations in HNRNPA2B1 causing IBMPFD2/MSP2 (615422), and mutations in HNRNPA1 causing IBMPFD3/MSP3 (615424). Another disorder, childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), is also caused by mutations in SQSTM1.