What is Leigh's Syndrome?

Leigh’s syndrome (LS) or subacute necrotizing encephalomyelopathy was first described by the neuropathologist Denis Leigh in a 7-month infant who had died of the disease, and on whom he performed an autopsy. It occurs quite rarely, in about 1 in 40,000 births, and may be due to either a mitochondrial DNA (mtDNA) or nuclear mutation. Two ethnic populations have a high incidence (1 in 2,000 to 1 in 2,500 births).

The nuclear mutations, which are present in 75% of patients, are heritable in an autosomal recessive or X-linked fashion, but the mtDNA mutations, which are present in 25% of patients, are harder to identify.

More than 35 different genes have been found to be mutated in LS, and all involve the mitochondrial respiratory chain, affecting the fundamental process of energy production in the body.

Clinical Features

Symptoms typically set in during the first year of life, but the time of onset may range from the fetal period to the third decade of life. Early infancy symptoms include head floppiness and delayed motor milestones. Infections or a seizure episode may precipitate sudden cognitive impairment due to the buildup of lactate in blood and cerebrospinal fluid (CSF).

Moreover, the brain deterioration may be enhanced by malnutrition as the child finds it difficult to feed. Around this time slowing of growth becomes obvious.

Similar difficulties manifest with childhood onset LS as well. The typical sign is diffuse hypotonia. Complications include dystonic posturing, persistent breathing difficulties, and very often, death due to respiratory failure owing to weakness of the respiratory muscles.

The median survival is only 2.4 years. The prognosis becomes more dismal with the presence of early disease, genetic mutations, seizures (in about 40%), lesions in the brainstem (typically spongiform with demyelination) visible on neuroimaging, failure to thrive and the need for ICU admission.

The involvement of the cerebellum and basal ganglia, in addition to the brainstem, causes the cranial nerve palsy, ataxia and/or movement abnormalities (such as chorea) in this disorder. The presence of encephalopathy is manifested by the decline in cognitive capabilities, feeding problems and seizures, as well as delayed motor development. The heart, kidneys, liver and skeletal muscle are sometimes also affected. Temporary remissions may occur, but the condition is progressive.

Another clinical form of LS is NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa). This includes weakness of the proximal muscles, sensory abnormalities, along with the last two conditions, often with early onset during childhood. Learning difficulties are common. The course is often episodic, with exacerbations following viral infections.

Diagnosis and Management

The diagnosis is made on the basis of the symptoms and signs, with typical findings on neuroimaging with MRI, the detection of high lactate levels in the blood and CSF, and genetic testing to identify the specific mutation in the nuclear genome or exclude mutations in mtDNA. If these are not typical the condition is classified as Leigh-like syndrome. This may include single genes tested serially, the use of a multiple gene panel, or genomic testing.

Specific management is possible for the underlying defect in the nuclear-encoded Leigh-like syndromes by lifelong supplementation of biotin, thiamine and/or coenzyme Q10, which prevents clinical manifestations by bypassing the biochemical defect.

However, all other cases of LS require intensive support of respiration, prevention and treatment of metabolic acidosis, seizure treatment, and management of dystonia and cardiomyopathy as well as attention to nutrition. Precautions with such children include the avoiding of anesthetics whenever feasible as well as certain antiepileptic drugs, such as valproate, because these agents may suppress the respiratory drive, or further inhibit mitochondrial respiration.