Atypical and mild clinical manifestation in a boy with mitochondrial ATP6 mutation

Case Report: Mitochondrial DNA mutations of ATP6 affect a subunit of ATP synthase (complex V of the oxidative phosphorylation) and present mostly as severe neurologic diseases with neuropathy, ataxia, retinitis pigmentosa [NARP] or as maternal inherited Leigh syndrome (MILS). Only recently, patients with hypertrophic CMP and ATP6 mutations have been described.

We report on a 4.5-year-old boy with mild global psychomotor retardation and a distinctive disturbance of speech development. MRI revealed only slightly asymmetric enlargements of the ventricles; in MR spectroscopy, small lactate peaks were detected on both sides. During an intercurrent infection severe muscular hypotonia was noticed. Lactate levels in blood were elevated once (4.5 mmol/L) and normal on repeated measurements. In the muscle biopsy, a slightly diminished ATP synthesis was measured. The oligomycin sensitive ATP synthase was moderately diminished. Sequencing of both mitochondrial encoded subunits ATP6 and ATP8 showed the known pathogenic 8993T>G mutation in the ATP6 gene with a mutation load of more than 90%.

Conclusion: Children with global psychomotoric retardation and disturbances in speech development are not highly suspicious for a mitochondrial disease. In our patient muscular hypotonia during an infection and a singular moderate lactate elevation led to further investigations. Only mutation analysis proved the defect since biochemical investigations of ATP synthesis were not unequivocally conclusive. Our patient clearly demonstrates an enlarged clinical spectrum of ATP6 defects, which were so far restricted to NARP, MILS, and CMP.