Leigh Syndrome: Neuropathology and Pathogenesis

Journal of Neuropathology and Experimental Neurology

Volumn 74, Issue 6, 2015, Pages 482-492

  Lake, Nicole J ^a,b   Bird, Matthew J ^a,b,c   Isohanni, Pirjo ^d,e   Paetau, Anders ^f  

^a ROYAL CHILDREN'S HOSPITAL   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c UNIVERSITY OF MELBOURNE   (Australia)

^d UNIVERSITY OF HELSINKI   (Finland)

^e UNIVERSITY OF HELSINKI AND HELSINKI UNIVERSITY HOSPITAL   (Finland)

^f HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

Author keywords

ATP depletion; Childhood encephalopathy; Gliosis; Hyperlacticacidemia; Leigh syndrome; Mitochondrial disease; Neuropathology

Indexed keywords

ADENOSINE TRIPHOSPHATE; REACTIVE OXYGEN METABOLITE; NDUFS1 PROTEIN, HUMAN; NDUFV1 PROTEIN, HUMAN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE;

BRAIN BLOOD VESSEL; CENTRAL NERVOUS SYSTEM; DEATH; EXCITOTOXICITY; GENE; GLIOSIS; HUMAN; HYPERLACTATEMIA; HYPOXIC ISCHEMIC ENCEPHALOPATHY; LEIGH DISEASE; MOLECULAR PATHOLOGY; NDUFS1 GENE; NDUFV1 GENE; NEURONAL PRESERVATION; NEUROPATHOLOGY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; ONSET AGE; PRESERVATION; PRIORITY JOURNAL; PROTEIN DEPLETION; REVIEW; ANIMAL; BRAIN; DEFICIENCY; GENETICS; MUTATION; PATHOLOGY;

ADENOSINE TRIPHOSPHATE; ANIMALS; BRAIN; HUMANS; LEIGH DISEASE; MUTATION; NADH DEHYDROGENASE;

EID: 84937965082     PISSN: 00223069     EISSN: 15546578     Source Type: Journal    
DOI: 10.1097/NEN.0000000000000195     Document Type: Review

References (113)

1. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: Clinical features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343-51
2. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951;14:216-21
3. van Erven PM, Cillessen JP, Eekhoff EM, et al. Leigh syndrome, a mitochondrial encephalo(myo)pathy. A review of the literature. Clin Neurol Neurosurg 1987;89:217-30
4. Montpetit VJ, Andermann F, Carpenter S, Fawcett JS, Zborowska-Sluis D, Giberson HR. Subacute necrotizing encephalomyelopathy. A review and a study of two families. Brain 1971;94:1-30
5. Ma YY, Wu TF, Liu YP, et al. Genetic and biochemical findings in Chinese children with Leigh syndrome. J Clin Neurosci 2013;20:1591-94
6. Campbell IC, Durcan MJ, Cohen RM, Pickar D, Chugani D, Murphy DL. Chronic clorgyline and pargyline increase apomorphine-induced stereotypy in the rat. Pharmacol Biochem Behav 1985;23:921-25
7. Sofou K, De Coo IF, Isohanni P, et al. A multicenter study on Leigh syndrome: Disease course and predictors of survival. Orphanet J Rare Dis 2014;9:52
8. Nagashima T, Mori M, Katayama K, et al. Adult Leigh syndrome with mitochondrial DNA mutation at 8993. Acta Neuropathol 1999;97:416-22
9. Chalmers RM, Lamont PJ, Nelson I, et al. A mitochondrial DNA tRNA(Val) point mutation associated with adult-onset Leigh syndrome. Neurology 1997;49:589-92
10. Thorburn DR, Rahman S. Mitochondrial DNAYassociated Leigh syndrome and NARP. In: Pagon RA, Adam MPArdinger HH, et al, eds. GeneReviews [Internet]. Seattle, WA: University of Washington, 1993-2015. http://www.ncbi.nlm.nih.gov/books/NBK1116. Initial Posting: October 30, 2003; Last Update: April 17, 2014.
11. Koopman WJ, Distelmaier F, Smeitink JA, Willems PH. OXPHOS mutations and neurodegeneration. EMBO J 2013;32:9-29
12. Johnson SC, Yanos ME, Kayser EB, et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 2013;342:1524-28
13. Martinelli D, Catteruccia M, Piemonte F, et al. EPI-743 reverses the progression of the pediatric mitochondrial diseaseVgenetically defined Leigh Syndrome. Mol Genet Metab 2012;107:383-88
14. Richter RB. Infantile subacute necrotizing encephalopathy with predilection for the brain stem. J Neuropathol Exp Neurol 1957;16:281-307
15. Cavanagh JB, Harding BN. Pathogenic factors underlying the lesions in Leigh's disease. Tissue responses to cellular energy deprivation and their clinico-pathological consequences. Brain 1994;117:1357-76
16. Willems JL, Monnens LA, Trijbels JM, et al. Leigh's encephalomyelopathy in a patient with cytochrome c oxidase deficiency in muscle tissue. Pediatrics 1977;60:850-57
17. Tsuchiyama A, Oyanagi K, Sogawa H, Nakao T, Ogawa K, Fujita S. Normal activities of hepatic pyruvate dehydrogenase and pyruvate carboxylase in Leigh's syndrome. Tohoku J Exp Med 1983;139:67-72
18. Sedwick LA, Burde RM, Hodges FJ 3rd. Leigh's subacute necrotizing encephalomyelopathy manifesting as spasmus nutans. Arch Ophthalmol 1984;102:1046-48
19. Bekiesinska-Figatowska M, Mierzewska H, Jurkiewicz E. Basal ganglia lesions in children and adults. Eur J Radiol 2013;82:837-49
20. Wells GA, Wells M. Neuropil vacuolation in brain: A reproducible histological processing artefact. J Comp Pathol 1989;101:355-62
21. Feigin I, Wolf A. A disease in infants resembling chronic Wernicke's encephalopathy. J Pediatr 1954;45:243-63
22. Christensen E, Melchior JC, Plum P. Infantile chronic necrotizing encephalopathy. Acta Neurol Scand Suppl 1963;39(Suppl 4):291-93
23. Lewis AJ. Infantile subacute necrotizing encephalopathy. Can Med Assoc J 1965;93:878-81
24. Worsley HE, Brookfield RW, Elwood JS, Noble RL, Taylor WH. Lactic acidosis with necrotizing encephalopathy in two sibs. Arch Dis Child 1965;40:492-501
25. Schwartz WJ, Hutchison HT, Berg BO. Computerized tomography in subacute necrotizing encephalomyelopathy (Leigh disease). Ann Neurol 1981;10:268-71
26. Anzil AP, Weindl A, Struppler A. Ultrastructure of a cerebral white matter lesion in a 41-year-old man with Leigh's encephalomyelopathy (LEM). Acta Neuropathol Suppl 1981;7:233-38
27. Reye RDK. Subacute necrotizing encephalomyelopathy. J Pathol Bacteriol 1960;79:165-73
28. Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. White matter involvement in mitochondrial diseases. Mol Genet Metab 2005;84:127-36
29. Saneto RP, Friedman SD, Shaw DW. Neuroimaging of mitochondrial disease. Mitochondrion 2008;8:396-413
30. Burgeois M, Goutieres F, Chretien D, Rustin P, Munnich A, Aicardi J. Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome. Brain Dev 1992;14: 404-8
31. White SL, Collins VR, Wolfe R, et al. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet 1999;65:474-82
32. Shtilbans A, Shanske S, Goodman S, et al. G8363A mutation in the mitochondrial DNA transfer ribonucleic acidLys gene: Another cause of Leigh syndrome. J Child Neurol 2000;15:759-61
33. Monden Y, Mori M, Kuwajima M, Goto T, Yamagata T, Momoi MY. Late-onset Leigh syndrome with myoclonic epilepsy with ragged-red fibers. Brain Dev 2013;35:582-85
34. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001;15:807-26
35. Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol 2008;1:27-36
36. Sun D, Jakobs TC. Structural remodeling of astrocytes in the injured CNS. Neuroscientist 2012;18:567-88
37. Brown GK, Squier MV. Neuropathology and pathogenesis of mitochondrial diseases. J Inherit Metab Dis 1996;19:553-72
38. Brenner O, Wakshlag JJ, Summers BA, de Lahunta A. Alaskan Husky encephalopathyVa canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome). Acta Neuropathol 2000;100:50-62
39. Vernau KM, Runstadler JA, Brown EA, et al. Genome-wide association analysis identifies a mutation in the thiamine transporter 2 (SLC19A3) gene associated with Alaskan Husky encephalopathy. PLoS One 2013; 8:e57195
40. Quintana A, Zanella S, Koch H, et al. Fatal breathing dysfunction in a mouse model of Leigh syndrome. J Clin Invest 2012;122:2359-68
41. Quintana A, Kruse SE, Kapur RP, Sanz E, Palmiter RD. Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome. Proc Natl Acad Sci U S A 2010;107: 10996-1001
42. Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab 2008;7:312-20
43. Leong DW, Komen JC, Hewitt CA, et al. Proteomic and metabolomic analyses of mitochondrial complex IYdeficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene. J Biol Chem 2012;287:20652-63
44. Choi WS, Kruse SE, Palmiter RD, Xia Z. Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat. Proc Natl Acad Sci U S A 2008;105:15136-41
45. Choi WS, Palmiter RD, Xia Z. Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson's disease model. J Cell Biol 2011;192:873-82
46. Bird MJ, Wijeyeratne XW, Komen JC, et al. Neuronal and astrocyte dysfunction diverges from embryonic fibroblasts in the Ndufs4fky/fky mouse. Biosci Rep 2014;34:e00151
47. Dell'agnello C, Leo S, Agostino A, et al. Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. Hum Mol Genet 2007;16:431-44
48. Hegde VR, Vogel R, Feany MB. Glia are critical for the neuropathology of complex I deficiency in Drosophila. Hum Mol Genet 2014;23:4686-92
49. Codeluppi S, Svensson CI, Hefferan MP, et al. The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord. J Neurosci 2009;29:1093-104
50. Sofroniew MV. Reactive astrocytes in neural repair and protection. Neuroscientist 2005;11:400-7
51. Singh S, Swarnkar S, Goswami P, Nath C. Astrocytes and microglia: Responses to neuropathological conditions. Int J Neurosci 2011;121: 589-97
52. Walz W. Role of astrocytes in the clearance of excess extracellular potassium. Neurochem Int 2000;36:291-300
53. Cahoy JD, Emery B, Kaushal A, et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function. J Neurosci 2008;28:264-78
54. Magistretti PJ, Pellerin L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond Ser B Biol Sci 1999;354:1155-63
55. Rohlmann A, Wolff JR. Subcellular Topography and Plasticity of Gap Junction Distribution on Astrocytes. Berlin: Springer, 1996:175-92
56. Sullivan SM, Björkman ST, Miller SM, Colditz PB, Pow DV. Structural remodeling of gray matter astrocytes in the neonatal pig brain after hypoxia/ischemia. Glia 2010;58:181-94
57. PeknyM, NilssonM. Astrocyte activation and reactive gliosis. Glia 2005; 50:427-34
58. Perry A, Brat DJ. Practical Surgical Neuropathology: A Diagnostic Approach: A Volume in the Pattern Recognition Series, London: Elsevier Health Sciences, 2010
59. Perlman JM. Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy. Pediatrics 2006;117:S28-33
60. Heinz ER, Provenzale JM. Imaging findings in neonatal hypoxia: A practical review. AJR Am J Roentgenol 2009;192:41-47
61. Fernandez F, Verdu A, Quero J, et al. Cerebrospinal fluid lactate levels in term infants with perinatal hypoxia. Pediatr Neurol 1986;2:39-42
62. Cappellini M, Rapisardi G, Cioni ML, Fonda C. Acute hypoxic encephalopathy in the full-term newborn: Correlation between magnetic resonance spectroscopy and neurological evaluation at short and long term. Radiol Med 2002;104:332-40
63. Fatemi A, Wilson MA, Johnston MV. Hypoxic-ischemic encephalopathy in the term infant. Clin Perinatol 2009;36:835-58, vii
64. Ikonomidou C, Kaindl AM. Neuronal death and oxidative stress in the developing brain. Antioxid Redox Signal 2011;14:1535-50
65. LaiMC, Yang SN. Perinatal hypoxic-ischemic encephalopathy. J Biomed Biotechnol 2011;2011:609813
66. Johnston MV, Trescher WH, Ishida A, Nakajima W. Neurobiology of hypoxic-ischemic injury in the developing brain. Pediatr Res 2001;49: 735-41
67. McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Brain Res Rev 1990;15:41-70
68. Berger R, Garnier Y. Pathophysiology of perinatal brain damage. Brain Res Brain Res Rev 1999;30:107-34
69. Erecinska M, Cherian S, Silver IA. Energy metabolism in mammalian brain during development. Prog Neurobiol 2004;73:397-445
70. Nicholls DG, Budd SL. Mitochondria and neuronal survival. Physiol Rev 2000;80:315-60
71. Mark LP, Prost RW, Ulmer JL, et al. Pictorial review of glutamate excitotoxicity: Fundamental concepts for neuroimaging. AJNR Am J Neuroradiol 2001;22:1813-24
72. Visch HJ, Koopman WJ, Leusink A, et al. Decreased agonist-stimulated mitochondrial ATP production caused by a pathological reduction in endoplasmic reticulum calcium content in human complex I deficiency. Biochim Biophys Acta 2006;1762:115-23
73. Trevelyan AJ, Kirby DM, Smulders-Srinivasan TK, et al. Mitochondrial DNA mutations affect calcium handling in differentiated neurons. Brain 2010;133:787-96
74. McDonald JW, Silverstein FS, Johnston MV. MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur J Pharmacol 1987; 140:359-61
75. Hattori H, Morin AM, Schwartz PH, Fujikawa DG, Wasterlain CG. Posthypoxic treatment with MK-801 reduces hypoxic-ischemic damage in the neonatal rat. Neurology 1989;39:713-18
76. Hagberg H, Gilland E, Diemer NH, Andiné P. Hypoxia-ischemia in the neonatal rat brain: Histopathology after post-treatment with NMDA and non-NMDA receptor antagonists. Biol Neonate 1994;66:205-13
77. Sie LT, van der Knaap MS, Oosting J, de Vries LS, Lafeber HN, Valk J. MR patterns of hypoxic-ischemic brain damage after prenatal, perinatal or postnatal asphyxia. Neuropediatrics 2000;31:128-36
78. Barkovich AJ, Westmark K, Partridge C, Sola A, Ferriero DM. Perinatal asphyxia: MR findings in the first 10 days. AJNR Am J Neuroradiol 1995;16:427-38
79. Cavanagh JB. Is Purkinje cell loss in Leigh's disease an excitotoxic event secondary to damage to inferior olivary nuclei? Neuropathol Appl Neurobiol 1994;20:599-603
80. Distelmaier F, Koopman WJ, van den Heuvel LP, et al. Mitochondrial complex I deficiency: From organelle dysfunction to clinical disease. Brain 2009;132:833-42
81. Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 2001;21:2-14
82. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007;13:688-94
83. Zhu Z, Yao J, Johns T, 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
84. Lin AL, Pulliam DA, Deepa SS, et al. Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice. J Cereb Blood Flow Metab 2013;33:1605-11
85. Goldman SA, Pulsinelli WA, Clarke WY, Kraig RP, Plum F. The effects of extracellular acidosis on neurons and glia in vitro. J Cereb Blood Flow Metab 1989;9:471-77
86. Siesjo BK. Acidosis and ischemic brain damage. Neurochem Pathol 1988;9:31-88
87. Sauer SW, Okun JG, Schwab MA, et al. Bioenergetics in glutarylcoenzyme A dehydrogenase deficiency: A role for glutaryl-coenzyme A. J Biol Chem 2005;280:21830-36
88. Strauss KA, Lazovic J, Wintermark M, Morton DH. Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency. Brain 2007;130:1905-20
89. Galluzzi L, Kepp O, Kroemer G. Mitochondria: Master regulators of danger signalling. Nat Rev Mol Cell Biol 2012;13:780-88
90. Bourgeron T, Rustin P, Chretien D, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 1995;11:144-49
91. Beal MF, Brouillet E, Jenkins BG, et al. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 1993;13:4181-92
92. Brouillet E, Hantraye P, Ferrante RJ, et al. Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc Natl Acad Sci U S A 1995;92:7105-9
93. Uemura Y, Kowall NW, Beal MF. Selective sparing of NADPHdiaphoraseYsomatostatinYneuropeptide Y neurons in ischemic gerbil striatum. Ann Neurol 1990;27:620-25
94. Ferriero DM, Arcavi LJ, Sagar SM, McIntosh TK, Simon RP. Selective sparing of NADPH-diaphorase neurons in neonatal hypoxia-ischemia. Ann Neurol 1988;24:670-76
95. Behrens MI, Koh JY, Muller MC, Choi DW. NADPH diaphoraseY containing striatal or cortical neurons are resistant to apoptosis. Neurobiol Dis 1996;3:72-75
96. KissG, Konrad C, Pour-Ghaz I, et al. Mitochondrial diaphorases as NAD+ donors to segments of the citric acid cycle that support substrate-level phosphorylation yielding ATP during respiratory inhibition. FASEB J 2014;28:1682-97
97. Elphick MR. Localization of nitric oxide synthase using NADPH diaphorase histochemistry. Methods Mol Biol 1997;72:153-58
98. Clerc P, Rigoulet M, Leverve X, Fontaine E. Nitric oxide increases oxidative phosphorylation efficiency. J Bioenerg Biomembr 2007;39:158-66
99. Wei T, Chen C, Hou J, Xin W, Mori A. Nitric oxide induces oxidative stress and apoptosis in neuronal cells. Biochim Biophys Acta 2000;1498: 72-79
100. Dawson VL, Dawson TM. Nitric oxide neurotoxicity. J Chem Neuroanat 1996;10:179-90
101. Harris JJ, Attwell D. The energetics of CNS white matter. J Neurosci 2012;32:356-71
102. Sokoloff L, Reivich M, Kennedy C, et al. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: Theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 1977;28:897-916
103. Chugani HT, Phelps ME, Mazziotta JC. Positron emission tomography study of human brain functional development. Ann Neurol 1987;22:487-97
104. Kinnala A, Suhonen-Polvi H, Aärimaa T, et al. Cerebral metabolic rate for glucose during the first six months of life: An FDG positron emission tomography study. Arch Dis Child Fetal Neonatal Ed 1996;74:F153-57
105. Chugani HT, Phelps ME. Maturational changes in cerebral function in infants determined by 18FDG positron emission tomography. Science 1986;231:840-43
106. Harding BN. Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): A personal review. J Child Neurol 1990;5:273-87
107. Cohen BH, Naviaux RK. The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods 2010;51:364-73
108. Taanman JW, Rahman S, Pagnamenta AT, et al. Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. Hum Mutat 2009;30:248-54
109. Marin SE, Mesterman R, Robinson B, Rodenburg RJ, Smeitink J, Tarnopolsky MA. Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations in NDUFV1 and NDUFS2. Gene 2013;516:162-67
110. Breningstall GN, Shoffner J, Patterson RJ. Siblings with leukoencephalopathy. Semin Pediatr Neurol 2008;15:212-15
111. Lieber DS, Calvo SE, Shanahan K, et al. Targeted exome sequencing of suspected mitochondrial disorders. Neurology 2013;80:1762-70
112. Tuppen HA, Hogan VE, He L, et al. The p.M292T NDUFS2 mutation causes complex IYdeficient Leigh syndrome in multiple families. Brain 2010;133:2952-63
113. Hoefs SJ, Skjeldal OH, Rodenburg RJ, et al. Novel mutations in the NDUFS1 gene cause low residual activities in human complex I deficiencies. Mol Genet Metab 2010;100:251-56