ATAD3 duplications bridge mitochondrial diseases and Aicardi–Goutières syndrome

A recurrent duplication of the ATAD3 locus has been linked to a severe mitochondrial disorder that starts before or shortly after birth. This condition progresses rapidly and is characterized by cardiomyopathy (disease of the heart muscle), high blood lactate levels, cataracts, and encephalopathy (disorder of the brain).

In this study, we analyzed nine new patients with duplication of the ATAD3 locus to better understand their clinical symptoms, brain imaging findings, and molecular mechanisms. Five patients showed signs during pregnancy, such as intrauterine growth restriction and cardiomyopathy, leading to medical termination of pregnancy in one case. All patients born alive had hypotonia (decreased muscle tone), often along with cardiomyopathy, cataract, and elevated blood lactate levels. Two patients with a different type of duplication survived beyond 2 years but developed severe progressive brain atrophy and epilepsy. Brain magnetic resonance imaging revealed white matter abnormalities and cystic brain lesions in most cases. Magnetic resonance spectroscopy detected a lactate peak in all tested patients. Additionally, basal ganglia calcification was observed in some patients.