2025 Volume 14 Issue 4 Pages 249-257
The mitochondrial DNA A3243G variant, located in the MT-TL1 gene encoding tRNALeu(UUR), represents one of the most clinically significant pathogenic mitochondrial mutations. This point mutation accounts for approximately 80% of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) syndrome cases and is the primary cause of Maternally Inherited Diabetes and Deafness (MIDD) syndrome. The clinical spectrum associated with this mutation ranges from asymptomatic carriers to severe multisystem disease with early mortality. The pathophysiology involves impaired mitochondrial protein synthesis leading to respiratory chain dysfunction, with phenotypic expression determined by heteroplasmy levels and tissue-specific energy demands. Understanding the complex inheritance patterns, genetic bottleneck effects during oogenesis, and heteroplasmy variations is crucial for comprehending the variable clinical presentations observed in affected families. Histological examination reveals characteristic features including ragged-red fibers, cytochrome c oxidase-deficient fibers, and abnormal mitochondrial proliferation. Current therapeutic approaches focus on metabolic support, antioxidant therapy, and management of specific complications, with L-arginine showing promise for stroke-like episodes. However, careful attention to drug safety profiles and potential mitochondrial toxicity is essential in treatment planning. Understanding the diverse clinical manifestations and implementing appropriate screening strategies are crucial for early diagnosis and optimal patient management. This review synthesizes current knowledge regarding the A3243G variant's pathophysiology, clinical features, diagnostic approaches, and therapeutic interventions.
