Leigh's disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Leigh's disease, a form of Leigh syndrome, also known as Subacute Necrotizing Encephalomyelopathy (SNEM), is a rare, inherited neurodegenerative disorder that mainly affects the central nervous system and becomes apparent during infancy, often after a viral illness. There is progressive loss of mental and movement abilities (psychomotor regression) and often leads to death within 2-3 years, usually due to respiratory failure.

Historical Perspective

Leigh's Syndrome was first described by Archibald Denis Leigh, a British neuropsychiatrist, in 1951.

Pathophysiology

It is thought that manifestation of Leigh's syndrome is caused by brain lesion at different parts including brainstem, basal ganglia, cerebellum, and other regions of the brain. Brain lesions may be present in different forms such as demyelination, gliosis, spongiosis, necrosis and capillary proliferation. Due to demyelination, neurons in brain loses their ability to communicate with other neurons which hampers basic life functions, movements and balance. Lactic acidosis may be observed in some patients with pyruvate buildup, due to defective oxidative phosphorylation.

Causes

Leigh's syndrome may be caused by mutations of any of 30 different genes, present in nuclear DNA. The most common cause of Leigh's syndrome is mutations in a gene called SURF1 (surfeit1) among nuclear DNA genes. Around 20 % of the cases are found to be due to mutation in mitochondrial DNA. Among mitochondrial DNA genes, mutations in MT-ATP6 gene, that codes for ATP synthase is most common cause known to cause the disease.

Epidemiology and Demographics

The prevalence of Leigh's Syndrome is approximately 1 per 40,000 live births individuals worldwide.

Differential diagnosis

Leigh's disease must be differentiated from other diseases that cause neurological manifestations in infants. Leigh's disease must be differentiated from birth asphyxia, kernicterus, encephalitis, thiamine deficiency, Wilson's disease, biotin-responsive basal ganglia disease. Birth asphyxia and hyperbilirubinemia can cause damage to thalamus and basal ganglia, which can cause lesions similar to leigh's disease.

Diagnosis

The diagnosis of Leigh's syndrome is suggested based on the clinical findings, confirmed through laboratory and genetic testing.

Diagnostic study of Choice

Magnetic resonance imaging (MRI) of the brain may reveal abnormal areas in certain parts of the brain including basal ganglia, brain stem, and grey matter.

History and Symptoms

Symptoms began to appear from infancy that begins with vomiting, diarrhoea, and poor sucking that leads to failure to thrive. On progressive note, muscular system involved leading to hypotonia (decrease tone), dystonia (sustained spasm) and ataxia (loss of control over movements). Muscles that controls eye movement get affected leading to ophthalmoparesis and nystagmus (involuntary eye movement). Lungs and heart can be involved leading to hypertrophic cardiomyopathy and respiratory failure, most common cause of death. Peripheral neuropathy have been noted in some cases of Leigh's syndrome. Hypertrichosis can be seen in some patient due SURF1 nuclear gene mutation.

Physical Examinations

Common physical examination findings of Leigh's syndrome include dystonia, nystagmus, autonomic dysfunction (due to damage to basal ganglia and brain stem).

Laboratory Findings

Laboratory findings consistent with the diagnosis of Leigh's syndrome include high levels of acidic waste products in the blood (lactic acidosis) as well as elevated levels of pyruvate and alanine.

Treatment

There is no treatment for Leigh's syndrome; the mainstay of therapy is supportive care. Anti-epileptic drugs can be used to manage patient who present with epilepsy. In addition, coenzyme Q10, thiamine and biotin can be used to supplement deficiencies.