ClinVar

In a patient with mitochondrial complex V (ATP synthase) deficiency mitochondrial type 1 (MC5DM1; 500015), resulting in Leigh syndrome (see 256000), Castagna et al. (2007) identified a heteroplasmic 9185T-C transition in the MTATP6 gene, resulting in a leu220-to-pro (L220P) substitution in the fifth transmembrane helix at the inner surface of the outer mitochondrial membrane. After a normal development, the boy presented at age 8.5 years with a 3-month history of frequent falls, ataxia, slowed speech, poor concentration, bilateral pes cavus, and absent ankle reflexes. Three months later, he developed saccadic paresis and nystagmus and rapidly deteriorated into a comatose state, followed by death. Brain MRI showed symmetric hyperintense signals in the basal ganglia with prominent cerebellar involvement, consistent with Leigh syndrome. The proband had a similarly affected brother, and both boys had greater than 90% mutant DNA levels. The mother and a maternal uncle had isolated peripheral neuropathy and ataxia with 86% and 85% heteroplasmy for the mutation, respectively. Family history revealed 4 additional maternal relatives with the mutation: 2 had Leigh syndrome, and 2 had isolated ataxia. Percentage of heteroplasmy correlated with the severity of the phenotype. Studies of the proband's mitochondria showed a 30% decrease in ATPase activity, although the overall process of ATP synthesis was not affected.