Mitochondrial Complex V (Atp Synthase) Deficiency, Mitochondrial Type 1

A number sign (#) is used with this entry because mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1) is caused by mutation in the MTATP6 gene.

For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see 604273.

Clinical Features

Tatuch et al. (1992) reported a female infant with lactic acidemia, hypotonia, and neurodegenerative disease leading to death at the age of 7 months. Autopsy revealed lesions typical of Leigh disease (see 256000), both in the basal ganglia and in the brainstem. A maternal uncle and aunt died 5 months and 1 year, respectively, after a similar clinical course, while another maternal uncle, 33 years of age, had retinitis pigmentosa, ataxia, and mental retardation. The index patient had more than 95% abnormal mtDNA in her skin fibroblasts, brain, kidney, and liver tissues, as measured by laser densitometry. The maternal aunt who died at 1 year likewise had more than 95% abnormal mtDNA in her lymphoblasts. The uncle with retinitis pigmentosa had 78% and 79% abnormal mtDNA in his skin fibroblasts and lymphoblasts, respectively, while an asymptomatic maternal aunt and her son had no trace of the mutation. The mother of the index case had 71% and 39% abnormal mtDNA in her skin fibroblasts and lymphoblasts, respectively.

Shoffner et al. (1992) reported a family in which 2 daughters died at 2.5 years and 14 months of Leigh syndrome. Pathologic analyses showed classic basal ganglial lesions, vascular proliferation, and glioses. Two brothers manifested psychomotor retardation, ataxia, hypotonia, and retinal degeneration. The mother had retinal degeneration and experienced migraine headaches. The mother's 2 sisters were normal. The 4 affected children had high levels of mutant mtDNA, in excess of 95% by Southern blot. The mother had a 78% level of mutant mtDNA while her 2 sisters had 100% normal mtDNA.

Molecular Genetics

In a female infant with MC5DM1 resulting in Leigh syndrome, Tatuch et al. (1992) identified a heteroplasmic mutation (8993T-G; 516060.0001) in the MTATP6 gene. The patient had more than 95% abnormal mtDNA in fibroblasts, brain, kidney, and liver. In a family with multiple affected members, Shoffner et al. (1992) identified the same mutation.

In the family reported by van Erven et al. (1987) in which the mother and all 4 children were affected with MC5DM1 resulting in Leigh syndrome, de Vries et al. (1993) identified a heteroplasmic mutation in the MTATP6 gene (516060.0002).