Leigh syndrome is a severe, progressive neurological disorder that typically becomes apparent during infancy or early childhood. This condition is characterized by a deterioration of mental and movement abilities, which worsens over time. The root cause of Leigh syndrome is genetic defects that cause a failure of energy production within the body’s cells. This cellular energy crisis primarily affects the brain and central nervous system, which are the organs with the highest energy demands.
The Core Biological Mechanism of Leigh Syndrome
The pathology of Leigh syndrome centers on the malfunction of mitochondria. These specialized organelles are responsible for converting energy from food into adenosine triphosphate (ATP), the primary energy currency used to fuel cellular processes. This energy production occurs mainly through oxidative phosphorylation (OXPHOS), which involves a series of protein complexes known as the electron transport chain (ETC).
When a genetic defect disrupts the ETC or other upstream metabolic pathways, ATP production significantly drops. A common alternative cause is a defect in the pyruvate dehydrogenase complex (PDC), an enzyme system that processes carbohydrates before they enter the energy-generating cycles. Both ETC and PDC failures result in insufficient energy supply for the cell, leading to cell death in high-demand tissues.
The brain is particularly vulnerable to this energy deficit, explaining the severe neurological symptoms that define Leigh syndrome. Specific brain regions, including the brainstem and the basal ganglia, are preferentially affected, developing characteristic patches of damaged tissue known as lesions. Damage to the brainstem impairs basic life functions like breathing and swallowing, while damage to the basal ganglia affects movement coordination. The failure of the ETC also leads to an accumulation of lactic acid in the body, a condition called lactic acidosis, which further stresses the compromised metabolic system.
Genetic Causes Originating in Nuclear DNA
The majority of Leigh syndrome cases, estimated to be about 80%, stem from mutations in genes located within the cell’s nucleus. These nuclear genes encode hundreds of proteins necessary for the structure and function of the mitochondria. A defect in a nuclear gene can prevent the proper assembly or function of the ETC or PDC complexes.
Inheritance of these forms is typically autosomal recessive, meaning a child must inherit one copy of the defective gene from each parent to develop the disorder. For carrier parents, there is a 25% chance with each pregnancy that their child will inherit both mutated copies and be affected by Leigh syndrome.
These nuclear gene mutations frequently target components of the ETC, particularly Complex I and Complex IV. Complex I is the most common site of failure, accounting for nearly one-third of all Leigh syndrome cases. Mutations can also affect the assembly factors required to build the complexes correctly, or the genes for the PDC components, all of which lead to systemic energy failure.
Genetic Causes Originating in Mitochondrial DNA
A smaller proportion of Leigh syndrome cases, approximately 20%, is caused by mutations in the mitochondrial DNA (mtDNA). Unlike nuclear DNA, mtDNA is inherited exclusively from the mother. This pattern is known as maternal inheritance, meaning all children of an affected or carrier mother are at risk.
Mitochondrial DNA primarily codes for some of the core structural subunits of the ETC complexes. A unique feature of mtDNA disorders is heteroplasmy, which refers to the co-existence of both mutated and healthy mtDNA copies within the same cell. The severity of Leigh syndrome is often directly related to the percentage of mutated mtDNA inherited.
If the proportion of mutated mtDNA is low, a person may remain asymptomatic or exhibit a milder, related disorder. However, if the percentage crosses a certain threshold, mitochondrial energy production is too compromised, and the child develops severe symptoms. The most common mtDNA mutation associated with the syndrome affects the gene MT-ATP6, which codes for a subunit of Complex V, a final step in ATP synthesis.
Physiological Triggers of Symptom Onset
While the underlying genetic defect creates chronic energy insufficiency, the onset or acute worsening of Leigh syndrome symptoms is often precipitated by specific physiological stressors. These stressors push the energy-starved cells past their point of tolerance, leading to rapid neurological decline.
Routine childhood illnesses, such as viral infections, are common triggers for sudden deterioration. The increased energy required by the immune system to fight the infection, combined with the metabolic stress of fever, can overwhelm the limited capacity of the dysfunctional mitochondria. Similarly, periods of trauma or prolonged fasting can cause an acute metabolic crisis.
The inability of the body to meet the temporary surge in energy demand results in an acute exacerbation of symptoms, often presenting as a sudden regression of motor skills, increased seizures, or respiratory distress. This physiological link between illness and symptom onset helps explain why the disorder frequently manifests after a seemingly mild, common childhood ailment.