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Leigh syndrome
Specialty	Neurology

Leigh disease, also known as Subacute Necrotizing Encephalomyelopathy (SNEM), is a rare neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh (1916-1998), a British psychiatrist who first described the condition in 1951.

Causes

It is an inherited disorder that usually affects infants between the age of three months and two years, but, in rare cases, teenagers and adults as well. In the case of the disease, mutations in mitochondrial DNA (mtDNA) or in nuclear DNA (gene SURF1 and some COX assembly factors) cause degradation of motor skills and eventually death.

Mitochondria are an essential organelle in eukaryotic cells. Their function is to convert the potential energy of glucose, amino acids, and fatty acids into adenosine triphosphate (ATP). Mitochondria carry their own DNA, called mitochondrial DNA . The information stored in the mtDNA is used to produce several of the enzymes essential to the production of ATP.

Disorders of oxidative phosphorylation may be caused by mutations in either mtDNA or in nuclear encoded genes. The latter account for the majority of Leigh disease, although it is not always possible to identify the specific mutation responsible for the condition in a particular individual.

Regardless of the genetic basis, the effect is that mitochondria fail or function improperly. In the case of Leigh disease, crucial cells in the brain stem and basal ganglia are affected. This causes a chronic lack of energy in the cells, which, in turn, affects the central nervous system and inhibits motor functions.

Signs and Symptoms

The disease is characterized by movement disorders. In one case review, 22 of 34 patients had evidence of a movement disorder. Dystonia, occurring in 19 patients, was the most common movement disorder. The dystonia was usually multifocal at onset and showed progression in six patients. Rigidity, tremor, chorea, hypokinesia, myoclonus, and tics were also noted (Macaya et al.). As it progresses rapidly, the earliest signs may be poor sucking ability and loss of head control and motor skills. Other symptoms include loss of appetite, vomiting, irritability, continuous crying (in infants), and seizures. A later sign can also be episodes of lactic acidosis, which can lead to impairment of respiratory and kidney function. Some children can present with loss of development skills or developmental regression and have often had investigations for failure to thrive. As the disease progresses in adults, it may also cause general weakness, kidney failure, and heart problems. Life expectancy is unpredictable, although survival beyond a few years is uncommon if the first symptoms develop in infancy. Acute fulminating illness of a few days and prolonged survival have been reported.

Treatment

Leigh disease is an extremely rare disorder. There is currently no effective treatment. A high-fat, low-carbohydrate diet may be recommended. Various combinations of vitamins and other 'cofactors' may be given, but there is no evidence of efficacy. Thiamin (vitamin B₁) may be given if a deficiency of pyruvate dehydrogenase is known or suspected.

X-linked Leigh disease

Leigh disease can also be caused by deficiency of the pyruvate dehydrogenase complex (PDHC), most commonly involving a PDHC subunit which is encoded by an X-linked gene (OMIM 308930). The neurological features of Leigh disease caused by PDHC deficiency are indistinguishable from other forms. However, non-neurological features (other than lactic acidosis) are not seen in PDHC deficiency.

References

1. "Obituaries" (PDF). Psychiatric Bulletin (1998). Retrieved 1 Aug 2020.
2. Pronicki M, Matyja E, Piekutowska-Abramczuk D; et al. (2008). "Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease". J. Clin. Pathol. 61 (4): 460–6. doi:10.1136/jcp.2007.051060. PMC 2571978. PMID 17908801. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

4. Macaya A, Munell F, Burke RE, De Vivo DC. Disorders of movement in Leigh syndrome. Neuropediatrics 1993;4(2):60-7.

External links

• GeneReviews/NCBI/NIH/UW entry on Mitochondrial DNA-Associated Leigh Syndrome and NARP
• OMIM entries on Mitochondrial DNA-Associated Leigh Syndrome and NARP
• Leigh syndrome; Subacute necrotizing encephalopathy; Leigh's disease at NIH's Office of Rare Diseases
• leighsdisease at NINDS
• Maternally Inherited Leigh Syndrome at NIH's Office of Rare Diseases

• Mitochondrial diseases
• Neurological disorders
• Neurological disorders in children
• Rare diseases
• TCA and ETC metabolism disorders