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  • Updated 09.04.2023
  • Released 07.30.1998
  • Expires For CME 09.04.2026

Leigh syndrome



Leigh syndrome is a neurometabolic genetic condition that typically presents during infancy or childhood. It is clinically characterized by progressive neurodegeneration associated with specific neuroradiology or neuropathology findings (symmetric basal ganglia or brainstem abnormalities). Additional organ systems may be affected. Leigh syndrome has been described in association with many nuclear and mitochondrial DNA defects. Treatment includes proactive surveillance for and aggressive management of comorbidities, vitamin or cofactor supplementation when appropriate, and mitigation of physiologic stressors. Specific forms of Leigh syndrome may have particular treatment principles. Genetic counseling is essential.

Key points

• Leigh syndrome is a progressive neurometabolic genetic condition and the most commonly encountered phenotype in patients with primary mitochondrial disease.

• Leigh syndrome typically presents with neurodegeneration during infancy or childhood. However, there may be multisystem manifestations, and onset may occur later in life. It is typically associated with a relapsing-remitting course and an increased risk for mortality.

• The characteristic brain MRI findings include symmetric T1 and T2 prolongation involving the basal ganglia or brainstem. However, other regions of the central nervous system may also be affected.

• The diagnosis can be established based on characteristic clinical, biochemical, and neuroimaging (or histopathologic) findings. Confirmation with genetic testing is recommended because the results may inform management.

• Leigh syndrome has been attributed to various genetic etiologies implicating the nuclear and mitochondrial genomes. A growing number of Leigh-like syndromes and overlap syndromes also have been described.

• Treatment is predominantly supportive. Vitamin or cofactor supplementation may be considered. Some forms of Leigh syndrome may have more targeted approaches to management, which cannot be considered universally helpful and may be harmful in some cases.

Historical note and terminology

In 1951, British neuropathologist Denis Leigh first described subacute necrotizing encephalopathy in an infant with rapidly progressive and ultimately fatal neurodegeneration (47). Autopsy was notable for the finding of bilateral symmetric spongy degeneration with vascular and glio-mesodermal proliferation reminiscent of Wernicke encephalopathy. However, the growing experience with Leigh syndrome was less suggestive of acquired thiamine deficiency and more suggestive of an inborn error of metabolism instead (26). Subsequent reports associated it with lactic acidosis and then with deficiencies of several mitochondrial enzymes, including pyruvate dehydrogenase and cytochrome c oxidase (82; 25; 81). Consequently, it has been recognized for many years that Leigh syndrome may be attributable to various genetic etiologies.

In parallel, it has also been appreciated for many years that Leigh syndrome may present with various neurologic and extraneurologic findings. The characteristic neuropathological findings for 50 cases of Leigh syndrome were first reviewed in detail by Montpetit and colleagues in 1971 (54). However, not all patients for whom the diagnosis of Leigh syndrome is suspected will meet diagnostic criteria. Under these circumstances, the diagnosis of Leigh-like syndrome has been applied (63). For a subset of these cases, the finding of Leigh-like lesions may instead be suggestive of an alternative diagnosis, such as MEGDEL syndrome with the distinctive “putaminal eye” sign (27). Furthermore, some patients with Leigh syndrome may also have findings consistent with an additional diagnosis, such as MELAS (03).

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