Leigh syndrome

Redi Rahmani BA (Dr. Rahmani of Dartmouth-Hitchcock Medical Center/Geisel School of Medicine at Dartmouth has no relevant financial relationships to disclose.)
Brandon Root MD (Dr. Root of Dartmouth-Hitchcock Medical Center/Geisel School of Medicine at Dartmouth has no relevant financial relationships to disclose.)
Robert J Singer MD (Dr. Singer of Dartmouth-Hitchcock Medical Center/Geisel School of Medicine at Dartmouth has no relevant financial relationships to disclose.)
Originally released July 30, 1998; last updated September 12, 2016; expires September 12, 2019

This article includes discussion of Leigh syndrome, Leigh disease, Leigh encephalomyelopathy, and subacute necrotizing encephalomyelopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Leigh disease is an expression form of mitochondrial disease, not specific for age, although most patients are infants or children. An ever increasing number of genes are associated with Leigh disease. Leigh disease is characterized by its dramatic and often lethal neurologic regression in a previously healthy baby or child. The author highlights the typical diagnostic findings, including MRI. The underlying cause of Leigh disease is a mutated or deleted gene that affects the pyruvate dehydrogenase complex or the mitochondrial respiratory chain. Genetic counseling of family members and a rational approach to treatment require a molecular diagnosis as a follow-up to clinical diagnosis. This article presents developments in mitochondrial genetics, new emphasis on genetic techniques for diagnosis, and includes an update on available treatments, especially the administration of thiamine and biotin to all patients with suspected Leigh syndrome.

Key points


• Leigh syndrome is a clinical expression of cerebral pathology due to genetic mitochondrial dysfunction that occurs mostly in infancy or childhood. It is named after the first author who described its course and pathology in young infants, which was morphologically similar to adult Wernicke disease.


• Its etiology is a mitochondrial dysfunction due to 1 of several mutations in nuclear mitochondrial DNA.


• Although its presentation and course are generally variable, symptoms may include failure to thrive, weakness/hypotonia, ataxia, oculomotor palsy, seizures, and episodes of lactic acidosis. Its typical course is relapsing, often in response to stress, mostly due to incidental infections. Outcome is often fatal.


• The characteristic finding on MRI is T1 and T2 prolongation, with symmetrical involvement in the putamen, globus pallidus, caudate, thalami, substantia nigra, inferior olivary nuclei, periaqueductal gray matter, superior cerebellar peduncles, tegmentum of the brainstem, and less commonly, periventricular white matter and corpus callosum.


• Treatment generally consists of high dose thiamine (>10-100 mg/kg/day), biotin (>5-10 mg/kg/day), and supportive measures. In some cases, other agents may be useful depending on the specific genetic mutation.

Historical note and terminology

Subacute necrotizing encephalomyelopathy was first described in 1951 by Dr. Denis Leigh, a British neuropathologist who reported the case of an infant with developmental regression at 6.5 months that progressed rapidly and resulted in death over a 6-week period (Leigh 1951). Dr. Leigh performed an extensive autopsy and described multiple bilateral foci of spongy degeneration and microscopic vascular proliferation in the brainstem tegmentum, basal ganglia, thalamus, cerebellum, optic nerves, and spinal cord. He speculated on the pathophysiology, noting the similarity between subacute necrotizing encephalomyelopathy (SNE) and Wernicke syndrome. Wernicke syndrome may arise as a result of thiamine deficiency due to nutritional defects such as in alcoholism. Thiamine is a cofactor of the pyruvate dehydrogenase complex. Inherited pyruvate dehydrogenase deficiency causes brain lesions similar to Wernicke syndrome. Though not appreciated at the time, the similarity between the acquired (Wernicke) and the genetic SNE is due to a shared biochemical mechanism. In 1954 a genetic basis (autosomal recessive) was proposed for the disease with a report of 2 affected siblings with consanguineous parents (Feigin and Wolf 1954). Montpetit and colleagues presented an overview of 50 cases in infants and children studied neuropathologically (Montpetit et al 1971). The lesions were bilateral, sharply delimited, and mainly affected nuclear regions such as basal ganglia, mostly the putamina, and brainstem nuclei. The cerebral cortex was involved only in small minority (10%). The white matter was affected less often, with the internal capsule affected in about one third of cases. The spinal cord was affected in one third of the population, with involvement of both grey and white matter. Subsequent research proved associations with lactic acidosis (Worsley et al 1965) and the first detected mitochondrial enzyme deficiencies: pyruvate dehydrogenase complex (PDHC) deficiency (Farmer et al 1973), and cytochrome C oxidase (COX) deficiency (Willems et al 1977). The last named authors in fact proved that Leigh syndrome was heterogenous in origin. Further developments followed the general progress in mitochondrial research, by which it was shown that Leigh syndrome could be caused by mutations in respiratory chain complex subunits in mitochondrial DNA as well as in nuclear DNA. Diagnosis was facilitated enormously by the introduction of MRI, making diagnosis possible without autopsy confirmation and paving the way for prenatal diagnosis.

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