ATAD3 duplications bridge mitochondrial diseases and Aicardi-Goutières syndrome

A recurrent 68-kb heterozygous duplication of the ATAD3 locus has been implicated in a mitochondrial disorder characterized by prenatal or neonatal onset and rapidly fatal course with cardiomyopathy, hyperlactataemia, cataract, and encephalopathy. We analysed the clinical, neuroimaging, and molecular spectrum associated with duplication of the ATAD3 gene cluster in nine patients (four males, five females; age range: 3 days-3 years, median: 11 days, mean: 7.8 months, SD: 1 year 1 month). Five patients presented with prenatal signs (intrauterine growth restriction in four of nine and cardiac abnormalities in three of nine) leading to medical termination of pregnancy in one case. All live-born children presented with neonatal hypotonia, frequently associated with cardiomyopathy (five of eight), cataract or corneal opacities (five of eight), and hyperlactataemia (six of eight). Two patients carrying distinct duplications exhibited a long survival (>2 years) and presented with major progressive brain atrophy with epileptic encephalopathy. We documented elevated cerebrospinal fluid neopterin in one and increased cerebrospinal fluid alpha-interferon activity in the other. Brain magnetic resonance imaging showed white matter T2 hyperintensity (seven of seven) and temporal cystic leukoencephalopathy (five of seven). Nuclear magnetic resonance spectroscopy showed a lactate peak in five of five patients; brain computed tomography showed basal ganglia calcifications in two of three patients. In this study, we expand the clinical spectrum of ATAD3 duplications, including prolonged survival and severe neurological involvement with neuroimaging similarities to Aicardi-Goutières syndrome and more broadly interferonopathy. We suggest a putative common mechanism that involves mitochondrial nucleic acid leakage and interferon response.