Leigh syndrome is a severe neurological disorder caused primarily by defects in the mitochondria, the energy-producing structures within cells. These defects disrupt the ability of cells to generate energy efficiently, especially in the brain and nervous system, leading to progressive damage and dysfunction.
At its core, Leigh syndrome results from mutations in genes that affect mitochondrial function. These mutations can be found either in the mitochondrial DNA (mtDNA), which is inherited maternally, or in nuclear DNA, which follows other inheritance patterns such as autosomal recessive or X-linked. Because mitochondria are responsible for producing the majority of cellular energy through a process called oxidative phosphorylation, any disruption in this process can severely impact tissues with high energy demands, like the brain.
The genetic causes of Leigh syndrome are diverse and complex. Mutations can occur in genes encoding components of the mitochondrial respiratory chain complexes, which are essential for energy production. For example, mutations in the ND3 gene, part of complex I of the respiratory chain, have been identified as causes of severe Leigh syndrome with early lethality. Other genes involved include those encoding mitochondrial ribosomal proteins, such as MRPS36, which are crucial for mitochondrial protein synthesis. When these proteins are defective, the mitochondria cannot produce the enzymes needed for energy generation, leading to cellular energy failure.
Inheritance patterns vary depending on the specific genetic mutation. When caused by mitochondrial DNA mutations, Leigh syndrome is maternally inherited because mitochondria are passed from mother to offspring. This form is sometimes called Maternally Inherited Leigh Syndrome (MILS). Alternatively, mutations in nuclear genes can be inherited in an autosomal recessive manner, meaning a child must inherit defective copies from both parents to develop the disease. Some cases are linked to X-linked inheritance, affecting mostly males.
The onset of Leigh syndrome typically occurs in infancy or early childhood, usually between 3 months and 2 years of age. The disease manifests as progressive neurological decline, including symptoms such as abnormal muscle tone, loss of motor skills (ataxia), seizures, impaired vision and hearing, developmental delays, and respiratory difficulties. These symptoms reflect the widespread energy deficiency in brain regions critical for movement, coordination, and autonomic functions.
At the molecular level, the energy deficit caused by mitochondrial dysfunction leads to the accumulation of toxic metabolites and insufficient ATP (adenosine triphosphate), the cell’s energy currency. This energy shortage particularly affects neurons, which are highly dependent on aerobic metabolism. The brain lesions seen in Leigh syndrome are typically symmetrical and located in areas such as the basal ganglia, brainstem, and cerebellum, which explains the characteristic neurological symptoms.
Leigh syndrome is not caused by a single mutation but rather a broad spectrum of genetic abnormalities affecting mitochondrial function. This genetic heterogeneity contributes to the variability in clinical presentation and severity. Some mutations lead to rapid progression and early death, while others may cause milder symptoms or later onset.
In addition to genetic causes, environmental factors or secondary mitochondrial dysfunction can sometimes exacerbate the condition, but the primary cause remains genetic mutations impairing mitochondrial energy production.
Understanding the causes of Leigh syndrome is critical for diagnosis and potential therapeutic approaches. Genetic testing can identify specific mutations, guiding prognosis and family counseling. Although there is currently no cure, research into mitochondrial biology and gene therapy holds promise for future treatments.
In summary, Leigh syndrome arises from inherited mutations affecting mitochondrial genes, disrupting energy production in cells, especially neurons. This leads to progressive neurological deterioration beginning in infancy or early childhood, with a wide range of genetic causes and inheritance patterns contributing to the disease’s complexity.
