Leigh Syndrome: typical phenotype but atypical mitochondrial mutation – a case report

Introduction: Leigh syndrome caused by dysfunction of the mitochondrial metabolism is an inherited, heterogeneous and progressive, neurodegenerative disorder of infancy and early childhood, typically presenting with developmental regression, ataxia and muscular hypotonia.

Case report:: We report on a 2½ year old boy presenting with developmental delay, behavioural disorder, weakness and ataxia. Cerebral MRI showed hyperdensity in the basal ganglia. Laboratory investigations revealed elevated lactate in cerebrospinal fluid, urine and blood (lactate/pyruvate in blood >20µmol/l). Biopsy of the muscle did not reveal any structural or biochemical abnormalities, respiratory chain analysis of complex I-IV was normal. Fibroblast examination detected heteroplasmy compared to wild type of nearly 100% of the mitochondrially encoded ATP Synthase 8 (MT-ATP8), a subunit of the ATP-Synthase-Complex V. Western Blot of the blue native electrophoresis showed an atypical elevation of the F1 subunit as previously described in patients with pathogenic ATP6 mutation. Molecular genetic analysis of the mitochondrial DNA revealed a T>C-mutation at nt. 8430 in the MT-ATP8 leading to a base replacement of leucine to proline and an A>G-mutation at nt. 8623. MT-ATP6 leading to a base replacement of threonine to alanine. The patient showed nearly 100% heteroplasmy for both mutations, compared to 50% heteroplasmy of MT-ATP8 mutation and an 80% heteroplasmy of MT-ATP6 mutation in the healthy mother. Thus, based on the high heteroplasmy and validated according to Polyphen, the MT-ATP8 mutation is considered to be pathogenic, whereas the MT-ATP6 mutation is classified benign. Whether the MT-ATP8 mutation alone or the combination of both mutations is responsible for the phenotype of our patient is to be seen.

Conclusions: Our findings show that dysfunctional MT-ATP8 can cause Leigh Syndrome as already shown for MT-ATP6-mutation. The phenotypic characteristic of the MT-ATP8 mutation has to be further delineated. It is worthwhile to pursue extensive mitochondrial examination even when respiratory chain analysis does not reveal any quantitative defect.