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.

Autosomal dominant isolated mitochondrial myopathy (IMMD) 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 (Heiman-Patterson et al., 1997) or develop severe fatal cardiomyopathy (Shammas et al., 2022).

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.

Shammas et al. (2022) reported a family (family UK) in which a mother and her 2 sons had myopathy and fatal cardiomyopathy. The mother had been reported as a child with a mitochondrial myopathy by Salmon et al. (1971). Similar to his mother, one of her sons (the proband) had childhood-onset myopathy with delayed motor milestones, inability to walk or run, positive Gowers sign, frequent falls, and lax ligaments. By 20 years of age, this patient was wheelchair-bound and had received a heart transplant due to progressive cardiomyopathy. He died of lymphoma soon afterwards. The mother died at age 34 years, presumably from cardiomyopathy, and a brother with myopathy and cardiomyopathy had died in childhood. Skeletal muscle biopsy from the proband showed excess lipid droplets in type I fibers, mtDNA deletions, and decreased activities of OXPHOS complexes II-III and IV, suggesting a mitochondrial defect.

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

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.

In a mother and her 2 sons (family UK) with IMMD, Shammas et al. (2022) identified a heterozygous missense mutation in the CHCHD10 gene (G58R; 615903.0005). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation likely occurred de novo in the mother. Expression of the orthologous mutation in mice resulted in clinical and pathologic findings with evidence of mitochondrial stress similar to that observed in the patients. Detailed studies indicated that the mutation resulted in activation of OMA1 (617081)-induced mitochondrial fragmentation and activation of the integrated stress response outside the mitochondria (see ANIMAL MODEL).

Shammas et al. (2022) generated a mouse model with a heterozygous mutation in the Chchd10 gene that was orthologous to the human G58R mutation (615903.0005). Expression of the mutant mouse protein in human cells induced OMA1 activation and caused mitochondrial fragmentation. Heterozygous mutant mice were smaller, had decreased body weight, and died prematurely compared to controls. Mutant mice also showed myopathy with small leg muscles and small muscle fiber size compared to controls, as well as functional motor deficits and decreased cardiac function with atrioventricular heart block. Histologic examination of skeletal muscle showed increased lipid droplets, and both skeletal and cardiac muscle had decreased activities of mitochondrial respiratory complexes I and IV. Cardiac muscle also contained multiple mtDNA deletions and decreased mtDNA copy numbers, suggesting a defect in mtDNA maintenance. The mutant G58R Chchd10 protein formed punctate aggregates within mitochondria in heart and skeletal muscle; mitochondria also contained intracristal inclusions that reflected stress of the inner membrane. There was destabilization of OXPHOS subunits and impaired bioenergetics. These findings were associated with activation of OMA1 (617081) in both mouse tissue and skeletal muscle tissue of the human proband carrying the mutation. The G58R mutation in Oma1-null mice was neonatally lethal, suggesting that activation of Oma1 is critical for early survival. Further studies indicated that in the presence of the G58R mutation, OMA1 activated the integrated stress response (ISR) through cleavage of DELE1 (615741). The findings were consistent with a toxic gain-of-function effect of the G58R mutation. Of note, mutant mice carrying the S59L mutation (615903.0001) had a less severe phenotype, and the mutant S59L protein formed filamentous cellular aggregates that appeared to be outside the mitochondria, suggesting that G58R and S59L have different pathogenetic mechanisms.