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  • Updated 11.25.2018
  • Released 07.30.1998
  • Expires For CME 11.25.2021

Leigh syndrome

Introduction

Overview

The diagnosis of Leigh syndrome refers to a neurometabolic disorder affecting the central nervous system, with effects on cognition, development, and motor skills. Leigh syndrome generally presents in infancy or childhood, though older ages of presentation are possible. Clinically, Leigh syndrome is often characterized by dramatic neurologic regression in a previously healthy baby or child with high morbidity and mortality. Pathogenic variants in a multitude of genes involved in mitochondrial energy production (mitochondrial respiratory chain, pyruvate dehydrogenase, etc.) have been reported to be causative for Leigh disease. Treatment of patients includes aggressive management of comorbidities, vitamin cofactor supplementation where appropriate (biotin, thiamine), and management of physiologic stress, among other management approaches. Genetic counseling of family members is also essential, including guidance on personal and reproductive/recurrence risks.

Key points

• Leigh syndrome is a genetic neurometabolic disorder resulting from defects in mitochondrial energy production that most often presents in infancy or childhood.

• Leigh syndrome affects children usually in early years of life, presenting an estimated average of 1 per 34,000 births during the preschool period (04).

• Symptoms may include failure to thrive, weakness/hypertonia, ataxia, oculomotor palsy, seizures, and episodes of lactic acidosis, among other features.

• The course of Leigh syndrome is usually relapsing, often in response to physiologic stress (ie, respiratory or gastrointestinal infections). The outcome is often fatal.

• The diagnosis can be made based on the neuroimaging presentation (see below), but genetic confirmation is recommended.

• 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 may consist 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 (78). On autopsy, Dr. Leigh 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 noted the similarity between subacute necrotizing encephalomyelopathy (SNE) and Wernicke syndrome (which arises as a result of nutritional thiamine deficiency). Notably, thiamine is a cofactor of the pyruvate dehydrogenase complex, mutations in which are now known to be 1 cause of Leigh disease. Thus, the parallels in neuropathology between Wernicke disease and Leigh disease, at their core, share a similar cellular pathological mechanism.

An autosomal recessive mechanism for the inheritance of Leigh disease was reported in 1954 based on a report of 2 affected siblings with consanguineous parents (49). A more complete review of neuropathological findings in Leigh disease were described by Montpetit and colleagues who in 1971 presented an overview of 50 cases in infants and children (93). Lesions were described as 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 10% of cases. 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.

Since these early case and neuropathological reports, pathological genetic variants in many genes have been reported.

Leigh syndrome was first associated with lactic acidosis by Worsley and colleagues (134). The first detected mitochondrial enzyme deficiency reported by Farmer and associates was pyruvate dehydrogenase complex deficiency (47). Willems and colleagues in 1977 showed that Leigh syndrome was heterogenous in origin as well as having association with cytochrome C oxidase (COX) deficiency (133). Subsequent research proved associations of Leigh syndrome with smallest subunit of cytochrome c oxidase, COX8A (60) and hemizygous NDUFA1 mutation (92).

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