Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (also known as SUCLA2-related mitochondrial DNA depletion syndrome) is a rare inherited metabolic disorder caused by mutations in the SUCLA2 gene, which encodes the beta subunit of succinyl-CoA ligase (succinate-CoA ligase, ADP-forming). This enzyme plays a critical role in the citric acid cycle and in maintaining mitochondrial DNA (mtDNA) copy number. Deficiency leads to progressive depletion of mtDNA in affected tissues, impairing mitochondrial energy production. The condition primarily affects the brain and skeletal muscles (encephalomyopathy), and is characteristically associated with elevated methylmalonic acid in the urine (methylmalonic aciduria), which serves as a biochemical hallmark distinguishing it from other mtDNA depletion syndromes. Clinical features typically present in infancy and include hypotonia (low muscle tone), progressive muscle weakness, psychomotor delay or regression, failure to thrive, feeding difficulties, and sensorineural hearing loss. Many patients develop dystonia, seizures, and progressive encephalopathy. Lactic acidosis is commonly observed in blood and cerebrospinal fluid. Additional features may include mild hepatic involvement and growth retardation. The disease follows a progressive course, and affected individuals often experience significant neurological deterioration over time. There is currently no cure for this condition. Treatment is supportive and symptomatic, focusing on nutritional support, management of seizures with anticonvulsant medications, physical therapy, and hearing aids or cochlear implants for hearing loss. Avoidance of valproic acid is generally recommended due to its potential to worsen mitochondrial dysfunction. Supplementation with cofactors such as coenzyme Q10 and riboflavin has been tried in some patients, though evidence of efficacy remains limited. Genetic counseling is recommended for affected families.

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