Alternative titles; symbols
SNOMEDCT: 124165006, 237989003; ORPHA: 3208; DO: 0060537;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.33 | Mitochondrial complex II deficiency, nuclear type 1 | 252011 | Autosomal recessive | 3 | SDHA | 600857 |
A number sign (#) is used with this entry because of evidence that mitochondrial complex II deficiency nuclear type 1 (MC2DN1) is caused by homozygous or compound heterozygous mutation in the SDHA gene (600857) on chromosome 5p15.
Heterozygous mutation in the SDHA gene causes neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA; 619259).
Mitochondrial complex II deficiency is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, and muscle with onset in infancy, whereas others have only isolated cardiac or muscle involvement. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013).
Complex II, also known as succinate dehydrogenase, is part of the mitochondrial respiratory chain.
Genetic Heterogeneity of Mitochondrial Complex II Deficiency
See MC2DN2 (619166), caused by mutation in the SDHAF1 gene (612848) on chromosome 19q13; MC2DN3 (619167), caused by mutation in the SDHD gene (602690) on chromosome 11q23; and MC2DN4 (619224), caused by mutation in the SDHB gene (185470) on chromosome 1p36.
Fullerton et al. (2020) reviewed the genetic basis of isolated mitochondrial complex II deficiency.
Riggs et al. (1984) described 2 sibs with deficiency of complex II. A 7-year-old boy and his 9-year-old sister had progressive encephalomyopathy with dementia, myoclonic seizures, and short stature. A muscle biopsy showed mitochondrial aggregates and excessive lipid droplets in muscle fibers. In muscle mitochondria, the activity of succinate cytochrome c reductase was deficient. The activities of NADH-cytochrome c reductase and cytochrome oxidase were normal. The defect was thought to lie somewhere between succinate dehydrogenase and coenzyme Q10 in complex II.
A patient with complex II deficiency reported by Rustin et al. (1993) had isolated hypertrophic cardiomyopathy. Reichmann and Angelini (1994) reported 2 brothers with hypertrophic cardiopathy and skeletal muscle myopathy associated with complex II deficiency.
Bourgeois et al. (1992) reported 2 sisters with a degenerative neurologic disorder presenting clinically as a leukodystrophy. Brain imaging showed symmetric foci of necrosis in the substantia nigra and basal ganglia typical of Leigh syndrome (see 256000). Mitochondria isolated from skeletal muscle, fibroblasts, and lymphocytes showed complex II deficiency. The heart was not involved in these sisters.
Arpa et al. (1994) reviewed 10 previously published cases of succinate dehydrogenase deficiency and reported another case. Their patient was a 22-year-old woman, the daughter of consanguineous parents, with generalized muscle weakness and easy fatigability. She had mild proximal muscle weakness with distal wasting and an elevation of creatine kinase. Histopathologically, there were no ragged-red fibers, but there was a mild excess of neutral lipids and subsarcolemmal granular accumulations. Enzymatic analysis of isolated muscle mitochondria showed mild diminution of all respiratory complexes, most markedly of succinate-cytochrome c reductase. Free carnitine was also reduced.
Alston et al. (2012) reported a boy who presented at 3 months of age with symptoms of dilated cardiomyopathy after a normal neonatal period. He later showed delayed motor development with hypertonia, hyperreflexia, and joint contractures. Speech was delayed. Brain MRI at age 2.5 years showed cystic changes and abnormal symmetric signals in the central cerebral white matter, as well as abnormal signals in the corpus callosum, ventral pons, medulla, and throughout the majority of the gray matter of the spinal cord. Laboratory studies showed normal plasma lactate, but evidence of ketosis and increased urinary lactate and urinary tricarboxylic acid cycle metabolites. Skeletal muscle biopsy showed severe deficiency of mitochondrial complex II activity. Western blot analysis of patient fibroblasts showed decreased amounts of fully assembled complex II with almost complete absence of SDHA.
Parfait et al. (2000) reported a girl with complex II deficiency presenting as Leigh syndrome. The patient was the first child of unrelated healthy parents and was born at term after a normal pregnancy and delivery. She developed normally until 9 months of age, when psychomotor delay was noted. She could not sit unaided before 16 months of age, when truncal ataxia and cerebellar syndrome were noticed. There was mild hyperlactatemia, and cerebrospinal fluid lactate was mildly elevated. Magnetic resonance imaging showed necrotic lesions in the basal ganglia compatible with the diagnosis of Leigh syndrome.
Van Coster et al. (2003) reported a female infant, born of first-cousin parents, with mitochondrial complex II deficiency who died at 5.5 months of age following a respiratory infection. Although her clinical course differed from that in the patients reported by Bourgeron et al. (1995) and Parfait et al. (2000), Van Coster et al. (2003) noted that she died before any sign of Leigh syndrome could develop.
Jain-Ghai et al. (2013) reviewed 36 published cases of complex II deficiency. The phenotype was highly variable: some patients had multisystem involvement of the brain, heart, and muscle, sometimes resulting in death in infancy, whereas others had only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Neurologic findings, although variable, included developmental delay or regression following infection, hypotonia, hypertonia, and spasticity. Ophthalmologic features included ophthalmoplegia, retinopathy, nystagmus, optic atrophy, and blindness. Measurement of complex II activity in muscle was the most reliable means of diagnosis; however, there was no correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin had some clinical benefit.
The transmission pattern of MC2DN1 in the sibs reported by Bourgeois et al. (1992) and Bourgeron et al. (1995) was consistent with autosomal recessive inheritance.
In 2 sibs with complex II deficiency presenting as Leigh syndrome reported by Bourgeois et al. (1992), Bourgeron et al. (1995) identified a homozygous mutation in the SDHA gene (R554W; 600857.0001). Bourgeron et al. (1995) claimed that this was the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans.
In a girl with mitochondrial complex II deficiency manifesting as Leigh syndrome, Parfait et al. (2000) identified compound heterozygous mutations in the SDHA gene (A524V, 600857.0002; M1L, 600857.0003).
In a female infant who died at 5.5 months of age following a respiratory infection and was found to have MC2DN1, Van Coster et al. (2003) identified homozygosity for a missense mutation in the SDHA gene (G555E; 600857.0004). The authors noted that the patient died in infancy before signs of Leigh syndrome could develop.
Pagnamenta et al. (2006) reported a 10-year-old Palestinian boy with MC2DN1 manifest as Leigh syndrome in whom they identified homozygosity for the G555E mutation in the SDHA gene. Pagnamenta et al. (2006) noted that the patient previously reported by Van Coster et al. (2003) with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation.
In a boy with complex II deficiency who presented with cardiomyopathy and leukodystrophy, Alston et al. (2012) identified compound heterozygous mutations in the SDHA gene (T508I, 600857.0006 and S509L, 600857.0007). Each parent was heterozygous for one of the mutations.
Genetic Heterogeneity
Jain-Ghai et al. (2013) reported a female infant, born of unrelated parents of Middle Eastern descent, with complex II deficiency. She was born at 28 weeks' gestation due to preeclampsia. Echocardiogram showed dilated cardiomyopathy and left ventricular noncompaction, and laboratory studies showed increased serum lactate. The patient later showed developmental delay, failure to thrive, and hypotonia. She died at age 13 months. Electron microscopic analysis of muscle biopsy showed mitochondria with a dense array of parallel cristae and matrix granules, isolated complex II deficiency, and low levels of SDHA protein (24%) compared to controls. However, genetic analysis did not reveal mutations in the SDHA, SDHAF1, or ISCU (611911) genes. Jain-Ghai et al. (2013) postulated that this patient had a novel genetic defect.
Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W. Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J. Med. Genet. 49: 569-577, 2012. [PubMed: 22972948] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101146]
Arpa, J., Campos, Y., Gutierrez-Molina, M., Cruz-Martinez, A., Arenas, J., Caminero, A. B., Palomo, F., Morales, C., Barreiro, P. Benign mitochondrial myopathy with decreased succinate cytochrome C reductase activity. Acta Neurol. Scand. 90: 281-284, 1994. [PubMed: 7839816] [Full Text: https://doi.org/10.1111/j.1600-0404.1994.tb02722.x]
Bourgeois, 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. 14: 404-408, 1992. [PubMed: 1492653] [Full Text: https://doi.org/10.1016/s0387-7604(12)80349-4]
Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genet. 11: 144-149, 1995. [PubMed: 7550341] [Full Text: https://doi.org/10.1038/ng1095-144]
Fullerton, M., McFarland, R., Taylor, R. W., Alston, C. L. The genetic basis of isolated mitochondrial complex II deficiency. Molec. Genet. Metab. 131: 53-65, 2020. [PubMed: 33162331] [Full Text: https://doi.org/10.1016/j.ymgme.2020.09.009]
Jain-Ghai, S., Cameron, J. M., Al Maawali, A., Blaser, S., MacKay, N., Robinson, B., Raiman, J. Complex II deficiency--a case report and review of the literature. Am. J. Med. Genet. 161A: 285-294, 2013. [PubMed: 23322652] [Full Text: https://doi.org/10.1002/ajmg.a.35714]
Martin, J. J., Van de Vyver, F. L., Scholte, H. R., Roodhooft, A. M., Cevterick, C., Martin, L., Luyt-Houwen, J. E. M. Defect in succinate oxidation by isolated muscle mitochondria in a patient with symmetrical lesions in the basal ganglia. J. Neurol. Sci. 84: 189-200, 1988. [PubMed: 3379446] [Full Text: https://doi.org/10.1016/0022-510x(88)90124-4]
Pagnamenta, A. T., Hargreaves, I. P., Duncan, A. J., Taanman, J.-W., Heales, S. J., Land, J. M., Bitner-Glindzicz, M., Leonard, J. V., Rahman, S. Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II. Molec. Genet. Metab. 89: 214-221, 2006. [PubMed: 16798039] [Full Text: https://doi.org/10.1016/j.ymgme.2006.05.003]
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. 106: 236-243, 2000. [PubMed: 10746566] [Full Text: https://doi.org/10.1007/s004390051033]
Reichmann, H., Angelini, C. Single muscle fibre analyses in 2 brothers with succinate dehydrogenase deficiency. Europ. Neurol. 34: 95-98, 1994. [PubMed: 8174601] [Full Text: https://doi.org/10.1159/000117016]
Riggs, J. E., Schochet, S. S., Jr., Fakadej, A. V., Papadimitriou, A., DiMauro, S., Crosby, T. W., Gutmann, L., Moxley, R. T. Mitochondrial encephalomyopathy with decreased succinate-cytochrome-c-reductase activity. Neurology 34: 48-53, 1984. [PubMed: 6318158] [Full Text: https://doi.org/10.1212/wnl.34.1.48]
Rustin, P., Lebidois, J., Chretien, D., Bourgeron, T., Piechaud, J.-F., Rotig, A., Sidi, D., Munnich, A. The investigation of respiratory chain disorders in heart using endomyocardial biopsies. J. Inherit. Metab. Dis. 16: 541-544, 1993. [PubMed: 7609447] [Full Text: https://doi.org/10.1007/BF00711676]
Van Coster, R., Seneca, S., Smet, J., Van Hecke, R., Gerlo, E., Devreese, B., Van Beeumen, J., Leroy, J. G., De Meirleir, L., Lissens, W. Homozygous gly555-to-glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II. Am. J. Med. Genet. 120A: 13-18, 2003. [PubMed: 12794685] [Full Text: https://doi.org/10.1002/ajmg.a.10202]