Leigh syndrome
Leigh syndrome is a rare neurological disorder primarily affecting infants and young children, characterized by degeneration of the brain's gray matter, particularly in regions like the basal ganglia and brain stem. This condition arises from mutations in mitochondrial or, less frequently, nuclear genes, leading to disruptions in the cellular processes that generate energy from sugars and fats. Symptoms can vary significantly, ranging from mild to severe, and may include seizures, poor muscle coordination, visual disturbances, and developmental delays. The disorder is typically diagnosed through clinical observation in early childhood, as there are no specific screening tests available.
Leigh syndrome has a genetic basis, with over fifty mutations identified in mitochondrial genes and several in nuclear genes related to energy production. Although the condition is currently incurable, treatments focus on managing symptoms and may include medications to alleviate seizures and other neurological issues. The prognosis for children with Leigh syndrome is generally poor, with many not surviving past age five; however, some individuals have been known to survive into adulthood with varying degrees of health. Further research continues to explore potential therapeutic options, as well as the genetic heterogeneity of this complex disorder.
Leigh syndrome
ALSO KNOWN AS: Subacute necrotizing encephalopathy
DEFINITION Leigh syndrome is a brain disorder arising from a mutation in a mitochondrial gene (usually) or a nuclear gene (less frequently). The genetic defect disrupts the series of chemical reactions that release, from sugars and fats, the energy needed to power the cell. The result is degeneration of the gray matter of the brain, primarily in the basal ganglia, thalamus, and brain stem. (In contrast, Kearns-Sayre syndrome, also a mitochondrial disorder, produces abnormalities of the brain’s white matter.)
Risk Factors
No risk factors are known.
Etiology and Genetics
The first chemical reactions that release energy from food (primarily glucose) occur in the cytoplasm of the cell, but most take place in the mitochondria. Mitochondria are cellular structures outside the nucleus. They have their own genes (more than a dozen are known), independent of the genes of the nucleus. Mitochondrial genes are part of the egg; thus, the offspring inherits mitochondrial genes solely from its mother.
The reactions that release energy for cellular use involve many substrates, enzymes, and intermediate products, all of which lead to the production of the high-energy phosphate compound ATP. ATP is the cell’s main energy source. Leigh syndrome occurs when certain substances needed to produce ATP are absent, inactive, or present in insufficient quantities. (Those substances may be the pyruvate dehydrogenase, coenzyme Q, or certain complexes of the respiratory chain, which is a series of reactions in the Krebs cycle.) These biochemical deficits have the greatest impact on organs that require the most energy—primarily the brain, muscles, sensory organs, liver, and kidneys.
Leigh syndrome (and several related syndromes) exhibit the greatest genetic heterogeneity of all the mitochondrial disorders. Mutations have been identified in both mitochondrial (usually) and nuclear (less frequently) genes. The mitochondrial genes ND1-ND6, COX, and ATP code for subunits of the complexes I, IV, and V of the respiratory chain. About fifty specific mutations of those genes have been reported in association with Leigh syndrome. The mitochondrial gene tRNA codes for transfer RNA, which plays a role in protein synthesis. A dozen mutations of tRNA have been implicated in Leigh syndrome cases. The mutations of nuclear genes suspected in cases of Leigh syndrome include various forms of NDUFS, NDUFV, SDH, COX, and SURF; those genes encode for various subunits of respiratory-chain complexes I, II, and IV; CoQ, which directs the formation of coenzyme Q; PDH, which controls the synthesis of pyruvate dehydrogenase, an enzyme required for glucose in the cytoplasm; and several other genes of varying biochemical functions designated EFG1, EFTu, LRP130, SUCLA2, and BTD.
Kearns-Sayre syndrome results from a mutation in a mitochondrial gene, but it affects primarily the white matter and differs from Leigh syndrome in its clinical features. It usually affects the eyes, with degeneration of the retina and weakness of eye muscles commonly reported. Other symptoms may include difficulty swallowing, muscle weakness, hearing loss, poor coordination, and heart defects.
Symptoms
Symptoms vary from absent to severe. Central nervous system abnormalities may include an overall slowing of physical and mental activity, seizures, poor coordination of muscle action, poor muscle tone, and difficulty swallowing. Visual anomalies may include paralysis or weakness of eye muscles, degeneration of the optic nerve, or nystagmus (rhythmic, oscillating motions of the eyes). Some patients also exhibit structural and functional abnormalities of the peripheral nerves. Retinitis pigmentosa and deafness have been reported, as have anomalous facial features, excessive hair, and diverse defects of the heart and digestive tract.
Screening and Diagnosis
No screening test is available. Leigh syndrome is usually diagnosed symptomatically in infancy or early childhood. It is distinguished from Kearns-Sayre syndrome by the type of brain lesions observable in pathological examinations. Leigh syndrome causes a loss of specific groups of neurons in the brain’s gray matter, cell death, and structural abnormalities at several sites. The white matter degeneration of Kearns-Sayre syndrome is characterized by the absence of a myelin sheath around nerves and spongy degeneration of neuronal tissue.
According to 2023 statistics, Leigh syndrome affected 1 in 40,000 infants, with the condition being more prevalent in some localized communities. For example, Leigh syndrome occurred in about 1 in 2,000 infants in the Saguenay Lac-Saint-Jean region of Quebec, Canada, and in 1 in 1,700 in the Faroe Islands.
Treatment and Therapy
No cure is available for Leigh syndrome. To prevent sudden death, physicians closely monitor respiration and use magnetic resonance imaging (MRI), auditory-evoked brain stem potentials, somatosensory-evoked potentials, blink reflexes, or polysomnography to assess brain stem function.
Treatment is symptomatic and directed toward the alleviation of seizures, headaches, confusion, involuntary muscular contractions, tremors, elevated levels of lactic acid, or depression. Experiments with high doses of thiamine, coenzyme-Q, or L-carnitine have yielded some positive outcomes for small numbers of patients. In one study, a high-fat diet appeared to improve eye-muscle control. Treatments with various substances including dichhloroacetate, cholinesterase inhibitors, memantine, riboflavin, biotin, creatine, succinate, and idebenone have effected improvements in isolated cases.
Prevention and Outcomes
No preventive measures are known. Acute respiratory failure occurs in about two-thirds of all cases. Most affected children die before age five, usually from respiratory failure, although affected individuals are now surviving into adulthood in increasing numbers. In one patient, spontaneous resolution to a near-normal neurological profile was observed by age eighteen, so researchers advise caution in counseling patients and their families.
Bibliography
Baldo, Manuela Schubert and Laura Vilarinho. "Molecular Basis of Leigh Syndrome: A Current Look." Orphanet Journal of Rare Diseases, 29 Jan. 2020, doi.org/10.1186/s13023-020-1297-9. Accessed 4 Sept. 2024.
Finsterer, Josef. “Leigh and Leigh-Like Syndrome in Children and Adults.” Pediatric Neurology 39 (2008): 223-235.
Lee, H. F., et al. “Leigh Syndrome: Clinical and Neuroimaging Follow-up.” Pediatric Neurology 40 (February 2009): 88-93.
“Leigh Syndrome." Medline Plus, 28 Apr. 2023, medlineplus.gov/genetics/condition/leigh-syndrome/. Accessed 4 Sept. 2024.