Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8

The mitochondrial DNA (mtDNA) genes MT-ATP6 and MT-ATP8 encode for subunits α and 8 (A6L) of the adenosine triphosphate synthase complex. Pathogenetic variants in MT-ATP6/8 cause incurable mitochondrial syndromes encompassing a wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI. Typically, higher levels of mtDNA variants lead to more severe symptomatology although even individuals with similar mtDNA mutational loads exhibit high clinical variability. Hence, the establishment of potential therapeutics is currently challenging. In this article, we present an international multicenter study designed to provide a retrospective natural history of patients with MT-ATP6/8 deficiency and to identify primary and secondary end points for future clinical trials.

Clinical, biochemical, and molecular genetics data of patients with genetically confirmed MT-ATP6/8 defects were collected and analyzed from Italian, German, US, and Spain national reference centers through ethical committee-approved mitochondrial patients' national registries or local programs.

A cohort of 111 patients, 98 unreported, were analyzed (55 male, 56 female). Patients had infantile-onset disease (<1 year) in 44% of cases, pediatric-onset (≥1 year and ≤12 years) in 36%, and late-onset (>12 years) in 20%. Kaplan-Meier analysis showed a significant difference (p value = 0.0349) in the survival of infantile and pediatric patients compared with adult patients, although only 8% of patients were not alive at the last follow-up. The CNS was the most frequently affected tissue (93%), followed by the muscle (75%), eye (46%), and heart (18%). Brain MRI showed isolated Leigh-like lesions (58%), Leigh-like lesions and cortical and/or cerebellar atrophy (15%), isolated cerebellar atrophy (10%), and other lesions (21%). At the last follow-up, 11% of patients were wheelchair-bound. Metabolic acidosis or acute deterioration complicated the clinical course in ≅55% of early-onset patients. Molecular genetics studies identified 26 pathogenic variants (6 of them novel). Reduced citrulline levels and increased alanine and lactate levels were reported in 56%, 49%, and 71% of patients, respectively, suggesting their role as potential biomarkers.

Our results define a more accurate classification based on the age at onset for MT-ATPase deficiency and provide fundamental clinical and biochemical data for disease management.