Myopathy, Isolated Mitochondrial, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that autosomal dominant isolated mitochondrial myopathy (IMMD) is caused by heterozygous mutation in the CHCHD10 gene (615903) on chromosome 22q11. One such family has been reported.

Description

Autosomal dominant isolated mitochondrial myopathy is characterized by onset of proximal lower limb weakness and exercise intolerance in the first decade of life. The disorder is slowly progressive, with later involvement of facial muscles, muscles of the upper limbs, and distal muscles. Patients may also have respiratory compromise (summary by Heiman-Patterson et al., 1997).

Clinical Features

Heiman-Patterson et al. (1997) reported a 5-generation family of Puerto Rican descent in which 15 members had childhood onset of slowly progressive exercise intolerance and proximal lower limb muscle weakness. Neck flexor, shoulder girdle, and distal leg muscles became affected in the second decade, and mild facial weakness appeared in the third to fourth decades. All patients had moderate to severe restrictive lung function, but no cardiac involvement. Short stature was also present. Cognitive, sensory, and cerebellar function were normal. Laboratory studies showed lactic acidemia and increased serum creatine kinase. EMG showed a myopathic pattern. Muscle biopsy of 3 patients showed ragged-red fibers and increased numbers of mitochondria with abnormal cristae and globular mitochondrial inclusions. Two patients studied showed variable decreases in activity of mitochondrial complexes II, III, and IV. Six patients treated with steroids reported clinical improvement. In 1 patient, Southern blot analysis excluded large scale rearrangements of mitochondrial DNA, and sequencing of several candidate mitochondrial genes did not reveal any mutations. In a follow-up of the patients reported by Heiman-Patterson et al. (1997), Ajroud-Driss et al. (2015) noted that skeletal muscle biopsies also showed glycogen and lipid accumulation.

Inheritance

The transmission pattern of isolated mitochondrial myopathy in the family reported by Heiman-Patterson et al. (1997) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of the family with isolated mitochondrial myopathy reported by Heiman-Patterson et al. (1997), Ajroud-Driss et al. (2015) identified a heterozygous missense mutation in the CHCHD10 gene (R15S/G58R; 615903.0004). The mutation, which was found by linkage analysis and candidate gene sequencing, segregated completely with the disorder in the family. Cells transfected with the G58R mutation or the R15S/G58R mutants showed fragmentation of the mitochondria compared to wildtype or cells transfected only with R15S. The findings suggested that the R15S variant may not be pathogenic.