Mitochondrial DNA-associated Leigh syndrome

Mitochondrial DNA-associated Leigh syndrome (also known as maternally inherited Leigh syndrome or mtDNA-associated Leigh syndrome) is a severe progressive neurological disorder caused by pathogenic variants in mitochondrial DNA (mtDNA). It is a subtype of Leigh syndrome, a genetically heterogeneous condition characterized by bilateral symmetric necrotizing lesions in the brainstem and basal ganglia, visible on brain MRI. Because the genetic defects reside in mitochondrial DNA, the condition is transmitted through maternal (mitochondrial) inheritance, meaning an affected mother passes the mutation to all of her children, though clinical severity can vary due to heteroplasmy (the proportion of mutant versus normal mitochondria in cells). The disease primarily affects the central nervous system but can also involve multiple organ systems that have high energy demands, including the heart, skeletal muscles, liver, and kidneys. Key clinical features include psychomotor regression or developmental delay, hypotonia, dystonia, ataxia, respiratory abnormalities (including episodic hyperventilation or apnea), feeding difficulties, failure to thrive, and lactic acidosis. Optic atrophy, nystagmus, and seizures are also commonly observed. Symptoms typically present in infancy or early childhood, often triggered or worsened by intercurrent illness or metabolic stress. The most commonly implicated mtDNA genes include MT-ATP6 (particularly the m.8993T>G and m.8993T>C variants), MT-ND3, MT-ND5, MT-ND6, and MT-CO3, all encoding subunits of the mitochondrial respiratory chain complexes. Currently, there is no cure for mitochondrial DNA-associated Leigh syndrome. Treatment is primarily supportive and symptomatic, focusing on nutritional support, management of lactic acidosis, seizure control, and physical and occupational therapy. Some patients may receive supplementation with cofactors such as coenzyme Q10, thiamine, riboflavin, or L-carnitine, although evidence for their efficacy remains limited. Avoidance of metabolic stressors such as prolonged fasting and illness is important. The prognosis is generally poor, with many affected individuals experiencing progressive neurological decline, though the course can be variable depending on the specific mutation and degree of heteroplasmy.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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