leigh disease

Summary

Summary: A group of metabolic disorders primarily of infancy characterized by the subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia, and lactic acidosis. Pathological features include spongy degeneration of the neuropile of the basal ganglia, thalamus, brain stem, and spinal cord. Patterns of inheritance include X-linked recessive, autosomal recessive, and mitochondrial. Leigh disease has been associated with mutations in genes for the PYRUVATE DEHYDROGENASE COMPLEX; CYTOCHROME-C OXIDASE; ATP synthase subunit 6; and subunits of mitochondrial complex I. (From Menkes, Textbook of Child Neurology, 5th ed, p850).

Top Publications

  1. Matthews P, Marchington D, Squier M, Land J, Brown R, Brown G. Molecular genetic characterization of an X-linked form of Leigh's syndrome. Ann Neurol. 1993;33:652-5 pubmed
    ..As the E1 alpha subunit is encoded on the X chromosome, this observation confirms that some patients with Leigh's syndrome may potentially exhibit X-linked inheritance...
  2. Castro Gago M, Blanco Barca M, Campos González Y, Arenas Barbero J, Pintos Martínez E, Eirís Puñal J. Epidemiology of pediatric mitochondrial respiratory chain disorders in northwest Spain. Pediatr Neurol. 2006;34:204-11 pubmed
    ..Sixteen of these patients manifested phenotypic syndromes that have not been previously reported in association with mitochondrial respiratory chain diseases...
  3. Benit P, Slama A, Cartault F, Giurgea I, Chretien D, Lebon S, et al. Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet. 2004;41:14-7 pubmed
    ..The reasons for these differences are uncertain...
  4. Bruno C, Biancheri R, Garavaglia B, Biedi C, Rossi A, Lamba L, et al. A novel mutation in the SURF1 gene in a child with Leigh disease, peripheral neuropathy, and cytochrome-c oxidase deficiency. J Child Neurol. 2002;17:233-6 pubmed
    ..showed a bilateral abnormal signal in the substantia nigra and in the subthalamic nucleus, suggestive of Leigh disease. Histochemical analysis of skeletal muscle showed decreased cytochrome-c oxidase activity...
  5. Van Hove J, Saenz M, Thomas J, Gallagher R, Lovell M, Fenton L, et al. Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy. Pediatr Res. 2010;68:159-64 pubmed publisher
    ..a progressively severe myopathy with pronounced muscle weakness eventually leading to respiratory failure, Leigh disease, and recurrent hepatic failure...
  6. Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol. 2008;39:223-35 pubmed publisher
    ..Associated mutations affect genes of the mitochondrial or nuclear genome. Leigh syndrome and Leigh-like syndrome are the mitochondrial disorders with the largest genetic heterogeneity...
  7. Capková M, Hansikova H, Godinot C, Houst ková H, Houstek J, Zeman J. [A new missense mutation of 574C>T in the SURF1 gene--biochemical and molecular genetic study in seven children with Leigh syndrome]. Cas Lek Cesk. 2002;141:636-41 pubmed
    b>Leigh disease, subacute necrotizing encephalopathy, is a serious mitochondrial disorder of energy-providing metabolism...
  8. McFarland R, Kirby D, Fowler K, Ohtake A, Ryan M, Amor D, et al. De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol. 2004;55:58-64 pubmed
    ..Mitochondrial DNA disease may be considerably more prevalent in the pediatric population than currently predicted and should be considered in patients with infantile mitochondrial encephalopathies and complex I deficiency...
  9. Berger I, Hershkovitz E, Shaag A, Edvardson S, Saada A, Elpeleg O. Mitochondrial complex I deficiency caused by a deleterious NDUFA11 mutation. Ann Neurol. 2008;63:405-8 pubmed publisher
    ..Mutation analysis of the NDUFA11 is warranted in isolated complex I deficiency presenting with infantile lactic acidemia or encephalocardiomyopathy...

More Information

Publications62

  1. Cacic M, Wilichowski E, Mejaski Bosnjak V, Fumic K, Lujic L, Marusić Della Marina B, et al. Cytochrome c oxidase partial deficiency-associated Leigh disease presenting as an extrapyramidal syndrome. J Child Neurol. 2001;16:616-9 pubmed
    b>Leigh disease is a subacute neurodegenerative disorder characterized by symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optical nerves and caused by altered oxidative phosphorylation...
  2. Salviati L, Freehauf C, Sacconi S, DiMauro S, Thoma J, Tsai A. Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome. Am J Med Genet A. 2004;128A:195-8 pubmed
    ..These data confirm that the spectrum of MRI findings in LS is variable and that SURF1 mutations should be considered in patients with encephalomyopathy and COX deficiency even when early MRI findings are negative...
  3. Lebon S, Minai L, Chretien D, Corcos J, Serre V, Kadhom N, et al. A novel mutation of the NDUFS7 gene leads to activation of a cryptic exon and impaired assembly of mitochondrial complex I in a patient with Leigh syndrome. Mol Genet Metab. 2007;92:104-8 pubmed
    ..These results report the first intronic NDUFS7 gene mutation and demonstrate the crucial role of NDUFS7 in the biogenesis of complex I...
  4. Bugiani M, Invernizzi F, Alberio S, Briem E, Lamantea E, Carrara F, et al. Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta. 2004;1659:136-47 pubmed
    ..The latter cases suggest the possibility of unconventional patterns of inheritance in complex I defects...
  5. Bar Meir M, Elpeleg O, Saada A. Effect of various agents on adenosine triphosphate synthesis in mitochondrial complex I deficiency. J Pediatr. 2001;139:868-70 pubmed
    ..The study of adenosine triphosphate production rate in fibroblasts may improve decision-making in treatment design of patients with respiratory chain defects...
  6. Savoiardo M, Zeviani M, Uziel G, Farina L. MRI in Leigh syndrome with SURF1 gene mutation. Ann Neurol. 2002;51:138-9 pubmed
  7. McKenzie M, Tucker E, Compton A, Lazarou M, George C, Thorburn D, et al. Mutations in the gene encoding C8orf38 block complex I assembly by inhibiting production of the mitochondria-encoded subunit ND1. J Mol Biol. 2011;414:413-26 pubmed publisher
    ..We conclude that C8orf38 is a crucial factor required for the translation and/or integration of ND1 into an early-stage assembly intermediate and that mutation of C8orf38 disrupts the initial stages of complex I biogenesis...
  8. Xu F, Morin C, Mitchell G, Ackerley C, Robinson B. The role of the LRPPRC (leucine-rich pentatricopeptide repeat cassette) gene in cytochrome oxidase assembly: mutation causes lowered levels of COX (cytochrome c oxidase) I and COX III mRNA. Biochem J. 2004;382:331-6 pubmed
    ..A more diffuse distribution of LRPPRC in LSFC cells compared with controls was evident when viewed by immunofluorescence microscopy, with less LRPPRC present in peripheral mitochondria...
  9. Di Donato S. Disorders related to mitochondrial membranes: pathology of the respiratory chain and neurodegeneration. J Inherit Metab Dis. 2000;23:247-63 pubmed
    ..To better focus on OXPHOS genotype-phenotype correlations, mutations of the mtDNA-encoded structural genes are also discussed...
  10. Ostergaard E, Bradinova I, Ravn S, Hansen F, Simeonov E, Christensen E, et al. Hypertrichosis in patients with SURF1 mutations. Am J Med Genet A. 2005;138:384-8 pubmed
  11. Poyau A, Buchet K, Bouzidi M, Zabot M, Echenne B, Yao J, et al. Missense mutations in SURF1 associated with deficient cytochrome c oxidase assembly in Leigh syndrome patients. Hum Genet. 2000;106:194-205 pubmed
    ..COX activity could be restored in fibroblasts of the three patients by complementation with a retroviral vector containing normal SURF1 cDNA. These mutations identify domains essential to Surf1 protein structure and/or function...
  12. Zhu Z, Yao J, Johns T, Fu K, De Bie I, MacMillan C, et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet. 1998;20:337-43 pubmed
    ..These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease...
  13. Pecina P, Gnaiger E, Zeman J, Pronicka E, Houstek J. Decreased affinity for oxygen of cytochrome-c oxidase in Leigh syndrome caused by SURF1 mutations. Am J Physiol Cell Physiol. 2004;287:C1384-8 pubmed
    ..These results suggest that at physiologically low intracellular PO2, the depressed oxygen affinity may lead in vivo to limitations of respiration, resulting in impaired energy provision in Leigh syndrome patients...
  14. Cooper M, Qu L, Rohas L, Lin J, Yang W, Erdjument Bromage H, et al. Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1alpha/LRP130 complex. Genes Dev. 2006;20:2996-3009 pubmed
    ..These data link LRP130 and PGC-1alpha to defective hepatic energy homeostasis in LSFC, and reveal a novel regulatory mechanism of glucose homeostasis...
  15. Pagliarini D, Calvo S, Chang B, Sheth S, Vafai S, Ong S, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008;134:112-23 pubmed publisher
    ..Our results have important implications for understanding CI function and pathogenesis and, more generally, illustrate how our compendium can serve as a foundation for systematic investigations of mitochondria...
  16. D Aurelio M, Vives Bauza C, Davidson M, Manfredi G. Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells. Hum Mol Genet. 2010;19:374-86 pubmed publisher
    ..Taken together, these results indicate that the mtDNA background plays an important role in modulating the biochemical defects and clinical outcome in NARP/MILS...
  17. Loeffen J, Smeitink J, Triepels R, Smeets R, Schuelke M, Sengers R, et al. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet. 1998;63:1598-608 pubmed
    ..In the 19 other patients with enzymatic complex I deficiency, no mutations were found in the NDUFS8 cDNA. This article describes the first molecular genetic link between a nuclear-encoded subunit of complex I and Leigh syndrome...
  18. Parfait B, Chretien D, Rotig A, Marsac C, Munnich A, Rustin P. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet. 2000;106:236-43 pubmed
    ..So far, profound deficiencies in complex II activity resulting from mutations in the Fp gene of the SDH present only as LS, a striking observation in view of the ubiquitous expression of this typical housekeeping gene in humans...
  19. Leshinsky Silver E, Lev D, Malinger G, Shapira D, Cohen S, Lerman Sagie T, et al. Leigh disease presenting in utero due to a novel missense mutation in the mitochondrial DNA-ND3. Mol Genet Metab. 2010;100:65-70 pubmed publisher
    ..We emphasize the importance of screening the mtDNA in pediatric patients as the first step in molecular diagnosis of Leigh syndrome...
  20. Wasniewska M, Karczmarewicz E, Pronicki M, Piekutowska Abramczuk D, Zablocki K, Popowska E, et al. Abnormal calcium homeostasis in fibroblasts from patients with Leigh disease. Biochem Biophys Res Commun. 2001;283:687-93 pubmed
    ..In the present work, we examined the activation of SOCs in fibroblasts derived from three patients with Leigh disease (LS). We identified mutations in the SURF-1 gene in all these cells...
  21. Ronchi D, Cosi A, Tonduti D, Orcesi S, Bordoni A, Fortunato F, et al. Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G>A mitochondrial DNA mutation: a case report. BMC Neurol. 2011;11:85 pubmed publisher
    ..Onset is in early infancy and prognosis is poor. Causative mutations have been disclosed in mitochondrial DNA and nuclear genes affecting respiratory chain subunits and assembly factors...
  22. Grafakou O, Oexle K, Van Den Heuvel L, Smeets R, Trijbels F, Goebel H, et al. Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation. Eur J Pediatr. 2003;162:714-8 pubmed
    ..A heterozygous polymorphism was also detected. In the patient's cDNA the I393T mutation and the polymorphism appeared to be homozygous, indicating that the mRNA coming from the IVS9+1G>A mutant allele is not stable...
  23. Leung T, Hui J, Yeung W, Goh K. A Chinese girl with Leigh syndrome: effect of botulinum toxin on dystonia. J Paediatr Child Health. 1998;34:480-2 pubmed
    ..Dystonia persisted despite treatments with muscle relaxants and a ketogenic diet. Intramuscular botulinum toxin resulted in significant relief of dystonia...
  24. Yang Y, Sun F, Zhang Y, Qian N, Yuan Y, Wang Z, et al. Clinical and laboratory survey of 65 Chinese patients with Leigh syndrome. Chin Med J (Engl). 2006;119:373-7 pubmed
    ..In the current study, we performed a retrospective study in 65 patients in order to investigate the clinical and genetic characteristics of Leigh syndrome in Chinese patients...
  25. Pequignot M, Desguerre I, Dey R, Tartari M, Zeviani M, Agostino A, et al. New splicing-site mutations in the SURF1 gene in Leigh syndrome patients. J Biol Chem. 2001;276:15326-9 pubmed
    ..We also show that Surf1 protein is not implicated in the assembly of other respiratory chain complexes or the pyruvate dehydrogenase complex...
  26. Benit P, Chretien D, Kadhom N, De Lonlay Debeney P, Cormier Daire V, Cabral A, et al. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet. 2001;68:1344-52 pubmed
    ..These results suggest that screening for complex I nuclear gene mutations is of particular interest in patients with complex I deficiency, even when normal respiratory-chain-enzyme activities in cultured fibroblasts are observed...
  27. Procaccio V, Wallace D. Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8 mutations. Neurology. 2004;62:1899-901 pubmed
    ..Western blot analysis revealed a deficiency in the NDUFS8 polypeptide, but also reductions in other nuclear subunits of complex I, suggesting that this subunit is essential for either the assembly or stability of complex I...
  28. Taylor R, Morris A, Hutchinson M, Turnbull D. Leigh disease associated with a novel mitochondrial DNA ND5 mutation. Eur J Hum Genet. 2002;10:141-4 pubmed
    b>Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome...
  29. Hoefs S, Dieteren C, Distelmaier F, Janssen R, Epplen A, Swarts H, et al. NDUFA2 complex I mutation leads to Leigh disease. Am J Hum Genet. 2008;82:1306-15 pubmed publisher
    ..Furthermore, the mutation is associated with a mitochondrial depolarization. The expression and activity of complex I and the depolarization was (partially) rescued with a baculovirus system expressing the NDUFA2 gene...
  30. Moslemi A, Tulinius M, Darin N, Aman P, Holme E, Oldfors A. SURF1 gene mutations in three cases with Leigh syndrome and cytochrome c oxidase deficiency. Neurology. 2003;61:991-3 pubmed
    ..The authors have identified four pathogenic mutations including a novel, in-frame, 15-bp tandem duplication (806-820) in exon 8 and a novel 751+1G>A splice site mutation in SURF1 in three cases of LS with COX deficiency...
  31. McFarland R, Clark K, Morris A, Taylor R, MacPhail S, Lightowlers R, et al. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet. 2002;30:145-6 pubmed
    ..The mother is clinically normal, but a severe biochemical and molecular genetic defect was present in both a fatally affected child and the mother. This family highlights the role of homoplasmic mt-tRNA mutations in genetic disease...
  32. Funalot B, Reynier P, Vighetto A, Ranoux D, Bonnefont J, Godinot C, et al. Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy. Ann Neurol. 2002;52:374-7 pubmed
    ..This Leigh-like encephalopathy appears to be associated with a much more severe outcome than isolated Leber's hereditary optic neuropathy...
  33. Tay S, Sacconi S, Akman H, Morales J, Morales A, De Vivo D, et al. Unusual clinical presentations in four cases of Leigh disease, cytochrome C oxidase deficiency, and SURF1 gene mutations. J Child Neurol. 2005;20:670-4 pubmed
    Mutations in the SURF1 gene are the most frequent causes of Leigh disease with cytochrome c oxidase deficiency...
  34. Lebon S, Rodriguez D, Bridoux D, Zerrad A, Rotig A, Munnich A, et al. A novel mutation in the human complex I NDUFS7 subunit associated with Leigh syndrome. Mol Genet Metab. 2007;90:379-82 pubmed
    ..Identifying nuclear mutations as a cause of respiratory chain disorders will enhance the possibility of prenatal diagnosis and help us to understand how moleculardefects can lead to complex I deficiency...
  35. Weraarpachai W, Antonicka H, Sasarman F, Seeger J, Schrank B, Kolesar J, et al. Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet. 2009;41:833-7 pubmed publisher
  36. Sarzi E, Brown M, Lebon S, Chretien D, Munnich A, Rotig A, et al. A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia. Am J Med Genet A. 2007;143A:33-41 pubmed
    ..These results show that the 10197G>A mutation in the mitochondrial ND3 gene should be considered as a common mtDNA mutation responsible for LS and dystonia...
  37. Wong L. Pathogenic mitochondrial DNA mutations in protein-coding genes. Muscle Nerve. 2007;36:279-93 pubmed
  38. Menezes M, Ouvrier R. Peripheral neuropathy associated with mitochondrial disease in children. Dev Med Child Neurol. 2012;54:407-14 pubmed publisher
    ..We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease...
  39. Lebon S, Chol M, Benit P, Mugnier C, Chretien D, Giurgea I, et al. Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency. J Med Genet. 2003;40:896-9 pubmed
    ..The recurrent mutations consistently involved T-->C transitions (p<10(-4)). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency...
  40. Bernier F, Boneh A, Dennett X, Chow C, Cleary M, Thorburn D. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology. 2002;59:1406-11 pubmed
    ..Respiratory chain (RC) disorders are clinically, biochemically, and molecularly heterogeneous. The lack of standardized diagnostic criteria poses difficulties in evaluating diagnostic methodologies...
  41. Ogawa Y, Naito E, Ito M, Yokota I, Saijo T, Shinahara K, et al. Three novel SURF-1 mutations in Japanese patients with Leigh syndrome. Pediatr Neurol. 2002;26:196-200 pubmed
  42. Rahman S, Brown R, Chong W, Wilson C, Brown G. A SURF1 gene mutation presenting as isolated leukodystrophy. Ann Neurol. 2001;49:797-800 pubmed
  43. Rahman S, Blok R, Dahl H, Danks D, Kirby D, Chow C, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39:343-51 pubmed
    ..A specific defect must be identified if reliable genetic counseling is to be provided...
  44. Yuksel A, Seven M, Cetincelik U, Yeşil G, Koksal V. Facial dysmorphism in Leigh syndrome with SURF-1 mutation and COX deficiency. Pediatr Neurol. 2006;34:486-9 pubmed
    ..SURF-1 gene mutations must be particularly reviewed in such patients...
  45. Mannan A, Sharma M, Shrivastava P, Ralte A, Gupta V, Behari M, et al. Leigh's syndrome. Indian J Pediatr. 2004;71:1029-33 pubmed
  46. Pronicki M, Matyja E, Piekutowska Abramczuk D, Szymanska Debinska T, Karkucinska Wieckowska A, Karczmarewicz E, et al. Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease. J Clin Pathol. 2008;61:460-6 pubmed
    ..The aim of the present work is to assess the skeletal muscle morphology coexisting with SURF1 mutations from our own research and in the literature...
  47. Ugalde C, Triepels R, Coenen M, van den Heuvel L, Smeets R, Uusimaa J, et al. Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene. Ann Neurol. 2003;54:665-9 pubmed
  48. Rossi A, Biancheri R, Bruno C, Di Rocco M, Calvi A, Pessagno A, et al. Leigh Syndrome with COX deficiency and SURF1 gene mutations: MR imaging findings. AJNR Am J Neuroradiol. 2003;24:1188-91 pubmed
    ..MR imaging pattern recognition can suggest an underlying COX deficiency and should prompt investigators to search for SURF1 gene mutations...
  49. Chol M, Lebon S, Benit P, Chretien D, de Lonlay P, Goldenberg A, et al. The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. J Med Genet. 2003;40:188-91 pubmed
  50. Lee N, Daly M, Delmonte T, Lander E, Xu F, Hudson T, et al. A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16. Am J Hum Genet. 2001;68:397-409 pubmed
    ..Although the LSFC gene remains to be elucidated, the present study demonstrates the feasibility of using a genomewide LD strategy to localize the critical region for a rare genetic disease in a founder population...
  51. Martin M, Blazquez A, Gutierrez Solana L, Fernandez Moreira D, Briones P, Andreu A, et al. Leigh syndrome associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFS1 gene. Arch Neurol. 2005;62:659-61 pubmed
    ..Mutations in the nuclear-encoded subunits of complex I of the mitochondrial respiratory chain are a recognized cause of Leigh syndrome (LS). Recently, 6 mutations in the NDUFS1 gene were identified in 3 families...
  52. Malojcic B, Brinar V, Poser C, Djakovic V. An adult case of Leigh disease. Clin Neurol Neurosurg. 2004;106:237-40 pubmed
    ..results of muscle biopsy and the lack of response to corticosteroid treatment, led to the correct diagnosis of Leigh disease. Initiation of a ketogenic diet resulted in a rapid partial response...
  53. Benit P, Steffann J, Lebon S, Chretien D, Kadhom N, de Lonlay P, et al. Genotyping microsatellite DNA markers at putative disease loci in inbred/multiplex families with respiratory chain complex I deficiency allows rapid identification of a novel nonsense mutation (IVS1nt -1) in the NDUFS4 gene in Leigh syndrome. Hum Genet. 2003;112:563-6 pubmed
    ..More generally, we suggest giving consideration to a more systematic microsatellite analysis of putative disease loci for identification of disease genes in inbred/multiplex families affected with genetically heterogeneous conditions...