Leigh syndrome arises from impaired mitochondrial energy metabolism, which deprives developing brain cells of sufficient energy to function and survive. Variants in the LRPPRC gene have been identified in some individuals with this condition. LRPPRC encodes a protein involved in the regulation of mitochondrial gene expression, and disruption of this protein interferes with the assembly and function of the mitochondrial respiratory chain. Two inheritance patterns have been reported for Leigh syndrome: mitochondrial inheritance and autosomal recessive inheritance. When inherited in an autosomal recessive pattern, an individual must inherit two altered copies of the relevant gene, one from each parent. Parents who each carry one altered copy are typically unaffected, and with each pregnancy they have a 25% chance of having an affected child. Mitochondrial inheritance follows a maternal pattern, meaning the condition is passed through the mother. Because mitochondria are inherited almost exclusively from the egg, a mother with a mitochondrial variant can pass it to all of her children, though the severity among those children may differ. Families navigating either inheritance pattern are encouraged to work with a genetic counselor to understand recurrence risks and options for family planning.

Diagnosis of Leigh syndrome typically begins with clinical evaluation of the neurological features and is supported by metabolic testing. Elevated lactate in the blood and cerebrospinal fluid is a key biochemical finding. Brain MRI is an important component of the diagnostic workup, with bilateral symmetric lesions in the basal ganglia and brainstem representing characteristic imaging findings. Molecular genetic testing, including sequencing of the LRPPRC gene and broader mitochondrial and nuclear gene panels, is used to confirm the diagnosis at a molecular level. Because many of these neurological and metabolic features can also be seen in other mitochondrial and metabolic conditions, genetic and biochemical testing is essential to distinguish Leigh syndrome from conditions with similar presentations and to guide appropriate management.

There are currently no FDA-approved disease-modifying therapies for Leigh syndrome, and management focuses on supportive care tailored to each individual's needs. Care typically involves a multidisciplinary team that may include neurologists, metabolic specialists, pulmonologists, ophthalmologists, and feeding and rehabilitation therapists. Nutritional support, management of lactic acidosis, and respiratory support are important components of care. Seizures are managed with appropriate antiepileptic therapy under neurological guidance. Regular surveillance for complications across multiple organ systems, including respiratory, ophthalmologic, and auditory monitoring, is an essential part of long-term management, helping to identify potential problems before they become serious. Several therapies are currently under investigation, including vatiquinone and other compounds targeting mitochondrial function, and additional investigational approaches are in development. Patients should discuss treatment options with their healthcare team to determine which approaches may be appropriate for their specific situation. Genetic counseling is recommended for affected individuals and their families.

The course of Leigh syndrome is variable and depends on the underlying genetic cause, the extent of neurological involvement, and access to specialized supportive care. The condition is associated with significant neurological disability, and respiratory complications represent a major source of morbidity. Outcomes differ considerably among individuals, and the trajectory can range from rapid early progression to a more protracted course in some cases. Supportive care, including careful management of metabolic crises and respiratory function, can influence quality of life and clinical stability. Because natural history data are limited and the condition encompasses genetic heterogeneity, precise predictions about individual outcomes are not possible. Families are encouraged to connect with metabolic neurology specialists and to seek centers with experience in mitochondrial disease management.

Several clinical trials are currently investigating new treatments for Leigh syndrome, reflecting an active and growing research landscape. Investigational approaches include therapies targeting mitochondrial respiratory chain function and gene-based strategies, with orphan drug designations awarded to several compounds including vatiquinone and gene therapy candidates. These efforts represent meaningful progress toward disease-modifying treatment. Individuals and families interested in learning about participation in clinical trials are encouraged to search ClinicalTrials.gov or speak with their care team about eligibility and available studies.