Leigh syndrome represents a heterogeneous class of inherited mitochondrial cytopathies. Individuals with >90% heteroplasmy in MT-ATP6, a gene which encodes ATP synthase protein complex, are reported in the literature to have Leigh Syndrome. Here we report two cases of maternally-inherited pathogenic variants in patients with mild clinical presentations, broadening the known phenotype.

Chart review and literature review of PubMed using the search terms “Leigh Syndrome” or “MT-ATP6” or "Mitochondrial case report"

A 19-month-old female patient with hypertrophic cardiomyopathy, motor delay and one-time seizure in setting of fever was found to be 95% heteroplasmic for the mitochondrial variant m.9176T>C in the MT-ATP6 gene. Her mother is homoplasmic for this pathogenic variant and asymptomatic at 39 years of age. While there are no reports of asymptomatic homoplasmic individuals, the m.9176T>C variant has been reported in multiple families presenting with fully-penetrant Leigh Syndrome.

A 2-year-old female patient with hypotonia and motor delay was found to be homoplasmic for the known pathogenic variant m.8993T>G in the MT-ATP6 gene. Her mother has the same homoplasmic pathogenic variant characterized by mild intellectual disability at 19 years of age. The m.8993T>G pathogenic variant is similarly described in Leigh Syndrome.

Recently, there are extraordinary advancements in understanding and detecting mitochondrial diseases. Our cases series challenges current literature regarding MT-ATP6 pathogenic variants causing Leigh syndrome, requiring additional genetic work-up in affected individuals and a more nuanced clinical prognostication.  The children have neurological deficits however not typical for Leigh syndrome. Future studies to investigate the degree of heteroplasmy in different tissues is underway. The role of genetic modifiers may also critically regulate MT-ATP6 function. Only by understanding how genotype variants lead to phenotype will novel treatments for mitochondrial diseases emerge.