Alternative titles; symbols
SNOMEDCT: 29570005; ORPHA: 506; DO: 3652;
A number sign (#) is used with this entry because of evidence that nuclear Leigh syndrome (NULS) can be caused by mutations in several different nuclear-encoded genes, indicating substantial genetic heterogeneity.
Leigh syndrome is a clinical diagnosis based primarily on characteristic brain imaging findings associated with progressive and severe neurodegenerative features with onset within the first months or years of life, sometimes resulting in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation (summary by Lake et al., 2015).
Genetic Heterogeneity of Nuclear Leigh Syndrome
Leigh syndrome is a presentation of numerous genetic disorders resulting from defects in the mitochondrial OXPHOS complex. Accordingly, the genes implicated in Leigh syndrome most commonly encode structural subunits of the OXPHOS complex or proteins required for their assembly, stability, and activity. Mutations in both nuclear and mitochondrial genes have been identified. For a discussion of genetic heterogeneity of mitochondrial Leigh syndrome, see MILS (500017).
Nuclear Leigh syndrome can be caused by mutations in nuclear-encoded genes involved in any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), and complex V deficiency (see 604273) (summary by Lake et al., 2015). Some forms of combined oxidative phosphorylation deficiency (COXPD) can present as Leigh syndrome (see, e.g., 617664).
Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502). Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome.
This condition was first described by Leigh (1951) in a patient with foci of necrosis and capillary proliferation in the brainstem. Feigin and Wolf (1954) observed 2 affected sibs from a consanguineous mating. Because of similarity to Wernicke encephalopathy (277730), they suggested that a genetic defect in some way related to thiamine was present (see HISTORY). Ford (1960) referred to 2 affected sibs, and Clark (1964) pictured the histopathology of 1 of them. The main biochemical findings were high pyruvate and lactate in the blood and slightly low glucose levels in blood and cerebrospinal fluid. Hommes et al. (1968), who studied a family with 3 affected sibs, found absence of pyruvate carboxylase in the liver and concluded that gluconeogenesis was impaired. Clayton et al. (1967) demonstrated therapeutic benefit of lipoic acid. Montpetit et al. (1971) pointed out similarity in the distribution and histology of the lesions of SNE to those of Wernicke disease. They tabulated instances of affected sibs and consanguineous parents. Kohlschutter et al. (1978) reported 2 sisters and a brother born of consanguineous parents.
Gordon et al. (1974) noted that since oxidation of pyruvate is dependent on a multienzyme complex (the pyruvate dehydrogenase complex), it is likely that a number of apoenzyme and coenzyme deficiencies could lead to this disorder. Whereas Kustermann-Kuhn et al. (1984) had found that activity of the pyruvate dehydrogenase complex was not deficient in the brain of 3 autopsied cases of Leigh disease, Kretzschmar et al. (1987) reported a patient with well-documented clinical and biochemical pyruvate dehydrogenase complex deficiency who at postmortem examination was found to have the specific CNS pathologic changes of Leigh disease.
Rutledge et al. (1981) pointed out that hypertrophic cardiomyopathy (CMH; see 192600) is a frequent associated finding in Leigh syndrome. Of 12 autopsy cases, 7 (including a pair of sibs) had hypertrophic cardiomyopathy, and 4 of these had asymmetric septal hypertrophy. The authors suggested that this feature may be useful in premortem diagnosis.
Van Erven et al. (1987) reported 4 sibs (1 male, 3 female) of unrelated parents with what the authors considered to be an autosomal recessive juvenile form of Leigh syndrome. They detected no abnormalities of pyruvate metabolism in urine and serum, but all patients had marked elevations of CSF pyruvate and lactate concentrations. Although the affected sibs lived to adulthood, they were severely affected and 1 of them died at age 17 years. The mother had the onset of neurologic signs and symptoms at age 56 years. The authors suggested a defect restricted to the brain.
DiMauro and De Vivo (1996) reviewed the genetic heterogeneity of Leigh syndrome and noted that multiple defects had been described in association with Leigh syndrome, including mutations in PDHA1, mutations in the mitochondrial MTATP6 gene, and defects in complex IV. Thus, there are at least 3 major causes of Leigh syndrome, each transmitted by a different mode of inheritance: X-linked recessive, mitochondrial, and autosomal recessive.
Rahman et al. (1996) investigated Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups: in 80% of the tightly defined group and 41% of the 'Leigh-like' group. Enzyme defects were found in 29 patients: in respiratory chain complex I in 13, in complex IV in 9, and in the pyruvate dehydrogenase complex (PDHC) in 7. Complex I deficiency (see 252010) was more common than had previously been recognized. Eleven patients had mitochondrial mutations, including point mutations in the MTATP6 gene (e.g., 516060.0001) a mutation in the gene encoding mitochondrial transfer RNA-lysine (MTTK) (590060.0001), which is common in MERRF syndrome (545000), and a mitochondrial deletion. In 6 of the 7 PDHC-deficient patients, mutations were identified in the X-linked E1-alpha subunit of PDHC (PDHA1; 300502). Rahman et al. (1996) found no strong correlation between the clinical features and basic defects. Parental consanguinity suggested autosomal recessive inheritance in 2 complex IV-deficient sibships. An assumption of autosomal recessive inheritance would have been wrong in nearly one-half of those in whom a cause was found: 11 of 28 tightly defined and 18 of 41 total patients. The experience illustrated that a specific defect must be identified if reliable genetic counseling is to be provided.
Morris et al. (1996) reviewed the clinical features and biochemical cause of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of the pedigrees, and in 74% of the 19 pedigrees with pathologically confirmed Leigh disease. Mutation in the MTATP6 gene (516060.0001) was found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid.
Morris et al. (1996) described complex I deficiency (see 252010) as an important cause of Leigh syndrome. Identified in 7 of 25 patients, it was the second most common biochemical abnormality after complex IV deficiency.
Dahl (1998) reviewed mutations of respiratory chain-enzyme genes that cause Leigh syndrome.
In a review of the mechanisms of mitochondrial respiratory chain diseases, DiMauro and Schon (2003) diagrammed the defects resulting from mutations in complexes I, II, III, IV, and V, all of which had Leigh syndrome as one of their pathologic consequences.
Associations Pending Confirmation
For discussion of a possible association between a neurodegenerative disorder with clinical features of Leigh syndrome and variation in the GYG2 gene, see 300198.0001.
For discussion of a possible association between Leigh syndrome and variation in the IARS2 gene, see 612801.0002.
Denis Leigh was a registrar in the Department of Neuropathology, Institute of Psychiatry, Maudsley Hospital, London, at the time he described this condition and named it subacute necrotizing encephalomyelopathy, or SNE (Leigh, 1951). He pronounced his name 'Lee,' not 'Lay'(McHugh, 1993).
It was originally suggested that the biochemical defect in Leigh syndrome was a block in thiamine metabolism. Cooper et al. (1969, 1970) found that patients with SNE elaborate a factor, found in the blood and urine, that inhibits the synthesis of thiamine triphosphate (TTP) in brain tissue. The enzyme responsible for TTP synthesis is called thiamine pyrophosphate-adenosine triphosphate phosphoryl transferase. TTP was completely absent in postmortem brain. They suggested that an assay for the inhibitor of TTP synthesis could be performed on urine or blood for diagnostic purposes. In the urine of obligatory or presumptive heterozygotes, Murphy (1973) found an inhibitor of thiamine triphosphate synthesis in vitro. Pincus et al. (1969) had described the inhibitor in untreated patients. Thiamine derivatives in therapy were studied by Pincus et al. (1973). By direct examination of amniotic fluid for the inhibitor of TTP synthesis, Murphy et al. (1975) suggested that Leigh syndrome could probably be diagnosed antenatally.
Plaitakis et al. (1980) studied the family of a patient who died at age 21 years. The patient came from an isolated Greek island with a population of 1,200. Studies of the family showed inhibitor of adenosine triphosphate-thiamine diphosphate phosphoryltransferase in several members of the family and many of these had a chronic neurologic illness compatible with Leigh disease. Several sibships had more than 1 affected member and the parents were demonstrably consanguineous in several instances.
Clark, D. B. Infantile subacute necrotizing encephalopathy. In: Nelson, W. E. (ed.): Textbook of Pediatrics. (8th ed.) Philadelphia: W. B. Saunders (pub.) 1964.
Clayton, B. E., Dobbs, R. H., Patrick, A. D. Leigh's subacute necrotizing encephalopathy: clinical and biochemical study, with special reference to therapy with lipoate. Arch. Dis. Child. 42: 467-478, 1967. [PubMed: 4862967] [Full Text: https://doi.org/10.1136/adc.42.225.467]
Cooper, J. R., Itokawa, Y., Pincus, J. H. Thiamine triphosphate deficiency in subacute necrotizing encephalomyelopathy. Science 164: 74-75, 1969. [PubMed: 5773712] [Full Text: https://doi.org/10.1126/science.164.3875.74]
Cooper, J. R., Pincus, J. H., Itokawa, Y., Piros, K. Experience with phosphoryl transferase inhibition in subacute necrotizing encephalomyelopathy. New Eng. J. Med. 283: 793-795, 1970. [PubMed: 5456237] [Full Text: https://doi.org/10.1056/NEJM197010082831506]
Dahl, H.-H. Getting to the nucleus of mitochondrial disorders: identification of respiratory chain-enzyme genes causing Leigh syndrome. (Editorial) Am. J. Hum. Genet. 63: 1594-1597, 1998. [PubMed: 9837811] [Full Text: https://doi.org/10.1086/302169]
David, R. B., Gomez, M. R., Okazaki, H. Necrotizing encephalomyelopathy (Leigh). Dev. Med. Child Neurol. 12: 436-445, 1970. [PubMed: 5457539] [Full Text: https://doi.org/10.1111/j.1469-8749.1970.tb01937.x]
DiMauro, S., De Vivo, D. C. Genetic heterogeneity in Leigh syndrome. (Letter) Ann. Neurol. 40: 5-7, 1996. [PubMed: 8687192] [Full Text: https://doi.org/10.1002/ana.410400104]
DiMauro, S., Schon, E. A. Mitochondrial respiratory-chain diseases. New Eng. J. Med. 348: 2656-2668, 2003. [PubMed: 12826641] [Full Text: https://doi.org/10.1056/NEJMra022567]
Feigin, I., Wolf, A. A disease in infants resembling chronic Wernicke's encephalopathy. J. Pediat. 45: 243-263, 1954. [PubMed: 13202022] [Full Text: https://doi.org/10.1016/s0022-3476(54)80188-0]
Ford, F. R. A disease resembling Wernicke's encephalopathy (Feigen and Wolf). Diseases of the Nervous System in Infancy, Childhood and Adolescence. (4th ed.) Springfield, Ill.: Charles C Thomas (pub.) 1960. Pp. 407-410.
Gordon, N., Marsden, H. B., Lewis, D. M. Subacute necrotizing encephalomyelopathy in three siblings. Dev. Med. Child Neurol. 16: 64-78, 1974. [PubMed: 4813493] [Full Text: https://doi.org/10.1111/j.1469-8749.1974.tb02713.x]
Hommes, F. A., Polman, H. A., Reerink, J. D. Leigh's encephalomyelopathy: an inborn error of gluconeogenesis. Arch. Dis. Child. 43: 423-426, 1968. [PubMed: 4873809] [Full Text: https://doi.org/10.1136/adc.43.230.423]
Kohlschutter, A., Kraus-Ruppert, R., Rohrer, T., Herschkowitz, N. N. Myelin studies in a case of subacute necrotizing encephalomyelopathy (SNE). J. Neuropath. Exp. Neurol. 37: 155-164, 1978. [PubMed: 632845] [Full Text: https://doi.org/10.1097/00005072-197803000-00004]
Kretzschmar, H. A., DeArmond, S. J., Koch, T. K., Patel, M. S., Newth, C. J. L., Schmidt, K. A., Packman, S. Pyruvate dehydrogenase complex deficiency as a cause of subacute necrotizing encephalopathy (Leigh disease). Pediatrics 79: 370-373, 1987. [PubMed: 3103091]
Kustermann-Kuhn, B., Harzer, K., Schroder, R., Permanetter, W., Peiffer, J. Pyruvate dehydrogenase activity is not deficient in the brain of three autopsied cases with Leigh disease (subacute necrotizing encephalomyelopathy, SNE). Hum. Genet. 68: 51-53, 1984. [PubMed: 6437963] [Full Text: https://doi.org/10.1007/BF00293871]
Lake, N. J., Compton, A. G., Rahman, S., Thorburn, D. R. Leigh syndrome: one disorder, more than 75 monogenic causes. Ann. Neurol. 79: 190-203, 2015. [PubMed: 26506407] [Full Text: https://doi.org/10.1002/ana.24551]
Leigh, D. Subacute necrotizing encephalomyelopathy in an infant. J. Neurol. Neurosurg. Psychiat. 14: 216-221, 1951. [PubMed: 14874135] [Full Text: https://doi.org/10.1136/jnnp.14.3.216]
McHugh, P. R. Personal Communication. Baltimore, Md. 12/1/1993.
Montpetit, V. J. A., Andermann, F., Carpenter, S., Fawcett, J. S., Zborowska-Sluis, D., Giberson, H. R. Subacute necrotizing encephalomyelopathy: a review and a study of two families. Brain 94: 1-30, 1971. [PubMed: 5552162] [Full Text: https://doi.org/10.1093/brain/94.1.1]
Morris, A. A. M., Leonard, J. V., Brown, G. K., Bidouki, S. K., Bindoff, L. A., Woodward, C. E., Harding, A. E., Lake, B. D., Harding, B. N., Farrell, M. A., Bell, J. E., Mirakhur, M., Turnbull, D. M. Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann. Neurol. 40: 25-30, 1996. [PubMed: 8687187] [Full Text: https://doi.org/10.1002/ana.410400107]
Murphy, J. V., Craig, L. J., Diven, W. F. Prenatal detection of Leigh's disease: current status. (Abstract) Am. J. Hum. Genet. 27: 68A only, 1975.
Murphy, J. V. Subacute necrotizing encephalomyelopathy (Leigh's disease): detection of the heterozygous carrier state. Pediatrics 51: 710-715, 1973. [PubMed: 4697519]
Pincus, J. H., Cooper, J. R., Murphy, J. V., Rabe, E. F., Lonsdale, D., Dunn, H. G. Thiamine derivatives in subacute necrotizing encephalomyelopathy. Pediatrics 51: 716-721, 1973. [PubMed: 4697520]
Pincus, J. H., Itokawa, Y., Cooper, J. R. Enzyme-inhibiting factor in subacute necrotizing encephalomyelopathy. Neurology 19: 841-845, 1969. [PubMed: 5816876] [Full Text: https://doi.org/10.1212/wnl.19.9.841]
Plaitakis, A., Whetsell, W. O., Jr., Cooper, J. R., Yahr, M. D. Chronic Leigh disease: a genetic and biochemical study. Ann. Neurol. 7: 304-310, 1980. [PubMed: 6246834] [Full Text: https://doi.org/10.1002/ana.410070404]
Rahman, S., Blok, R. B., Dahl, H.-H. M., Danks, D. M., Kirby, D. M., Chow, C. W., Christodoulou, J., Thorburn, D. R. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann. Neurol. 39: 343-351, 1996. [PubMed: 8602753] [Full Text: https://doi.org/10.1002/ana.410390311]
Richter, R. B. Infantile subacute necrotizing encephalopathy with predilection for the brain stem. J. Neuropath. Exp. Neurol. 16: 281-307, 1957. [PubMed: 13439393] [Full Text: https://doi.org/10.1097/00005072-195707000-00001]
Rutledge, J. C., Haas, J. E., Monnat, R. Hypertrophic cardiomyopathy is a feature of subacute necrotizing encephalomyelopathy. (Abstract) Am. J. Hum. Genet. 33: 89A only, 1981.
van Erven, P. M. M., Gabreels, F. J. M., Ruitenbeek, W., Renier, W. O., Lamers, K. J. B., Slooff, J. L. Familial Leigh's syndrome: association with a defect in oxidative metabolism probably restricted to brain. J. Neurol. 234: 215-219, 1987. [PubMed: 3612192] [Full Text: https://doi.org/10.1007/BF00618253]