Myopathy, Mitochondrial, And Ataxia

A number sign (#) is used with this entry because of evidence that mitochondrial myopathy and ataxia (MMYAT) is caused by compound heterozygous mutation in the MSTO1 gene (617619) on chromosome 1q22. One family with a heterozygous mutation has been reported.

Clinical Features

Nasca et al. (2017) reported 2 sisters and an unrelated boy with mitochondrial myopathy and ataxia. The patients presented in the first year of life with delayed motor development and poor growth. The sisters were never able to walk independently, and had tremor, dysdiadochokinesia, and dysmetria associated with cerebellar hypoplasia on brain imaging. The younger sister had muscle weakness, pes cavus, and hyporeflexia. EMG showed a myopathic pattern, and muscle biopsies showed variability in fiber diameter with some dystrophic features. Serum creatine kinase was increased. Additional features included asymmetry of the chest, with pectus excavatum, enlarged hemithorax, and scoliosis. The patients had thick hair and a high-arched palate. One of the sisters had pigmentary retinopathy with papillary pallor but no abnormality of visual acuity, whereas the other had only papillary pallor without retinopathy. As teenagers, the girls had severely impaired motor function and were unable to walk. The authors stated that the girls had normal cognition, but elsewhere in the article that the girls had mild mental retardation. Analysis of skeletal muscle showed decreased mtDNA content (27% of controls in 1 patient), but normal activity of the mitochondrial respiratory chain, although complex II activity was decreased in 1 of the sisters. The 7-year-old boy showed difficulty walking in the first year of life, with frequent falls and positive Gowers sign, although his motor function improved with time. Muscle weakness was predominantly proximal, but he did have peroneal weakness; reflexes were normal. Other features included fine intention tremor and dysdiadochokinesis associated with cerebellar hypoplasia. He did not have ophthalmologic abnormalities. EMG showed a myopathic process; muscle biopsy showed dystrophic changes with vacuolar degeneration of mitochondria on ultrastructural examination. Serum creatine kinase was increased. He had normal cognition but speech articulation difficulties.

Gal et al. (2017) reported a Hungarian woman and her 3 adult children with a complex neurologic disorder with highly variable manifestations. The mother reportedly had delayed psychomotor development, but did not present until age 38 with myalgia, weakness or the small hand muscles, pes varus, and cognitive dysfunction. She had short stature and mild dysmorphic features, including micrognathia, small close-set eyes, and myopathic face. Neurologic examination showed truncal and limb ataxia, distal muscle weakness with decreased reflexes, distal sensory impairment, anxiety, and depression. Brain imaging showed frontal atrophy and enlarged interhemispheric fissure. EMG showed a myopathic pattern, but serum creatine kinase was normal. Muscle biopsy was abnormal with increased fiber size variation and increased numbers of mitochondria with abnormal shape as well as lipid droplets and glycogen accumulation. Her resting serum lactate level was normal, but the lactate stress test indicated altered aerobic metabolism. Her 3 adult children had either normal or delayed psychomotor development, and variable psychiatric abnormalities, including social anxiety, autistic features, and even schizophrenia. Two had ataxic gait, muscle weakness, and/or poor coordination, whereas the third had no neurologic signs at age 20. Two had learning difficulties and 1 had mild cerebellar ectopia. Endocrine abnormalities were found in the mother and 2 of the children: these included delayed bone age, hyperthyroidism, hyperprolactinemia, and primary amenorrhea. Additional variable features included joint hyperlaxity, hypoacusis, lipomas, micrognathia, pectus excavatum, kyphoscoliosis, poor coordination, and mild dysmorphic features, such as micrognathia or prominent jaw and long face. All had normal serum creatine kinase and decreased vitamin D levels.

Inheritance

The transmission pattern of MMYAT in the families reported by Nasca et al. (2017) was consistent with autosomal recessive inheritance.

The transmission pattern of MMYAT in the family reported by Gal et al. (2017) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with MMYAT, Nasca et al. (2017) identified compound heterozygous mutations in the MSTO1 gene (617619.0001-617619.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Fibroblasts derived from 2 affected sisters sisters showed clear fragmentation of the mitochondrial network compared to controls, and dynamic studies showed a decrease in the activity of mitochondrial network formation, mitochondrial fusion, and mitochondrial movements. Fibroblasts derived from the sisters also showed reduced mtDNA content (39% and 68%, respectively).

In a mother and her 3 adult children with MMYAT, Gal et al. (2017) identified a heterozygous missense mutation in the MSTO1 gene (V8M; 617619.0005). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed increased aggregated mitochondria and fragmented mitochondria, as well as dynamic abnormalities in mitochondrial network formation, fusion, and movements compared to controls. The decrease in fusion activity could be quantified as a 40% decrease compared to controls, and could be rescued by transfection of wildtype MSTO1. However, further studies showed no impairment of calcium signaling, basal respiration, or mitochondrial bioenergetics.