Leigh Syndrome is a rare, progressive inherited neurometabolic disorder that primarily impacts the central nervous system. It typically manifests in infancy or early childhood, though rare cases can appear in adolescence or adulthood. The condition leads to the progressive deterioration of mental and motor abilities, often starting subtly before a rapid neurological decline. It is a type of mitochondrial disease, stemming from a fundamental problem with the body’s cellular energy production.
Defining Leigh Syndrome and Its Impact
Leigh Syndrome is formally known as subacute necrotizing encephalomyelopathy (SNE), which describes the progressive tissue destruction it causes within the nervous system. The term “necrotizing” refers to the patches of dead tissue, or lesions, that develop symmetrically in specific areas of the brain. These lesions are characteristic hallmarks of the disease, predominantly found in the brainstem and the basal ganglia. Damage to the brainstem, which controls functions like breathing and swallowing, and the basal ganglia, which controls motor function, explains the severe physical symptoms.
The condition results from a failure in the energy metabolism of the central nervous system, one of the body’s most energy-demanding organs. Onset usually occurs between three months and two years of age, a period of rapid development highly vulnerable to energy deprivation. Damage to the brain and spinal cord worsens over time, leading to a steady loss of neurological function. This lack of energy causes brain cells to die, resulting in the characteristic lesions and subsequent neurological dysfunction.
Genetic Basis and Energy Failure
Leigh Syndrome is caused by inherited mutations that disrupt the cell’s ability to generate adenosine triphosphate (ATP), the primary energy currency. This energy defect can arise from mutations in over 110 different genes, making it one of the most genetically diverse disorders of its kind. These genes encode proteins essential for the oxidative phosphorylation (OXPHOS) process, the final and most efficient step of cellular energy production. The resulting ATP deficiency severely affects high-energy organs like the brain, heart, and muscles.
The genetic causes fall into two major categories: mutations in nuclear DNA and mutations in mitochondrial DNA (mtDNA). Nuclear DNA mutations account for 75 to 80 percent of cases and are typically inherited in an autosomal recessive pattern. A common nuclear gene mutation is in the SURF1 gene, which is involved in assembling Complex IV of the electron transport chain. Mutations in mtDNA, inherited solely from the mother, cause 10 to 20 percent of cases, often affecting the MT-ATP6 gene.
Regardless of the specific gene, the mutation impairs crucial enzyme complexes, such as the Pyruvate Dehydrogenase Complex or components of the Electron Transport Chain. When these complexes fail, they cannot efficiently convert nutrients into energy, causing a metabolic bottleneck. This failure leads to a buildup of metabolic byproducts, most notably lactic acid, resulting in episodes of severe lactic acidosis. The chronic lack of energy and the accumulation of toxic metabolites contribute to the progressive cell death seen in the basal ganglia and brainstem.
Clinical Manifestations and Progression
The initial signs of Leigh Syndrome in infants can be subtle, often beginning with feeding difficulties, recurrent vomiting, and diarrhea. These issues lead to a failure to gain weight and grow at the expected rate. Affected children frequently exhibit hypotonia (low muscle tone) and may show psychomotor regression, losing previously acquired motor skills like head control or the ability to sit. The disease often progresses through episodic crises, where symptoms rapidly worsen following periods of illness or metabolic stress.
As the condition advances, more severe neurological symptoms develop, reflecting damage to specific brain regions. Movement disorders are common, including ataxia (lack of coordination) and dystonia (involuntary muscle contractions). Brainstem involvement often results in ophthalmoplegia (paralysis of the eye muscles) and nystagmus (involuntary eye movements). Breathing irregularities, such as periods of rapid or irregular breathing, are also significant complications.
Respiratory failure is the most serious clinical manifestation and the most common cause of death in children with the infantile form of the syndrome. Patients also experience episodes of profound lactic acidosis, a buildup of lactic acid that can overwhelm the body’s systems. The heart can also be affected, with some individuals developing hypertrophic cardiomyopathy, a thickening of the heart muscle. The severity and rate of progression are highly variable, often depending on the specific genetic mutation involved.
Diagnosis and Management Strategies
The diagnosis of Leigh Syndrome relies on a combination of clinical symptoms, specific biochemical findings, and neuroimaging studies. A strong suspicion is raised when an infant presents with developmental regression, hypotonia, and signs of brainstem dysfunction. Laboratory tests often reveal abnormally high levels of lactate in the blood, urine, or cerebrospinal fluid, indicative of the underlying energy metabolism defect.
Magnetic Resonance Imaging (MRI) provides visual confirmation by showing the characteristic bilateral and symmetrical brain lesions. These lesions are typically hyperintense on T2-weighted images and are found in the basal ganglia, brainstem, and sometimes the thalamus. Genetic testing provides the definitive diagnosis by identifying the causative mutation in either nuclear or mitochondrial DNA. Comprehensive genetic sequencing is the preferred method to confirm the diagnosis and determine the specific subtype of the syndrome.
There is currently no curative treatment for Leigh Syndrome, so management focuses on supportive care, symptom relief, and preventing metabolic crises. Treatment involves a multidisciplinary approach, including physical therapy, occupational therapy, and nutritional support. Nutritional support sometimes requires a feeding tube to ensure adequate caloric intake. For patients with Pyruvate Dehydrogenase Complex deficiency, dietary modifications such as a high-fat, low-carbohydrate ketogenic diet may be recommended.
Specific vitamins and cofactors are often administered, such as high-dose thiamine (Vitamin B1) or coenzyme Q10, especially when a patient has a known defect that may respond to these supplements. Medications like sodium bicarbonate or sodium citrate can be used to treat acute episodes of lactic acidosis by buffering the acid in the blood. While these supportive strategies help manage symptoms and improve the quality of life, the prognosis remains poor for the early-onset form, with many children having a shortened lifespan due to respiratory failure.