Mitochondrial Complex Ii Deficiency

A number sign (#) is used with this entry because of evidence that mitochondrial complex II deficiency is caused by homozygous or compound heterozygous mutation in the nuclear-encoded SDHA gene (600857) on chromosome 5p, the nuclear-encoded SDHAF1 gene (612848) on chromosome 19q, or the nuclear-encoded SDHD gene (602690) on chromosome 11q23.

Complex II, also known as succinate dehydrogenase (EC 1.3.5.1), is part of the mitochondrial respiratory chain.

Description

Mitochondrial complex II deficiency is an autosomal recessive disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. 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).

Clinical Features

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.

Rivner et al. (1989) reported a 25-year-old woman with Kearns-Sayre syndrome (530000) and isolated complex II deficiency. She had short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia, and cardiac conduction defects. Muscle biopsy showed ragged-red fibers and increased number of mitochondria with abnormal structure and paracrystalline inclusions. 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 (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.

Brockmann et al. (2002) reported 3 patients, 2 Turkish sibs and an unrelated Norwegian boy, with isolated complex II deficiency with decreased activities of succinate dehydrogenase and succinate:cytochrome c oxidoreductase. The patients presented in infancy and very early childhood with neurologic symptoms, including loss of motor skills and spastic paresis, and leukoencephalopathy on MRI. Proton MRS showed strongly elevated concentrations of succinate in white matter and CSF.

Ghezzi et al. (2009) provided follow-up of the consanguineous Turkish family reported by Brockmann et al. (2002) and an Italian family reported by Bugiani et al. (2006). The 3 Italian patients originated from a small village in Lombardy, Italy. Two of the patients were clearly related and the other was believed to be related. Onset of the disorder became apparent in the first year of life, manifest as acute psychomotor regression and poor growth with lack of speech development. All patients developed severe spastic quadriplegia with partial loss of postural control and dystonia. Brain imaging studies showed leukoencephalopathy with sparing of the peripheral U-fibers and basal ganglia and increased lactate and succinate. Lactate and pyruvate were variably elevated in blood. Most had relative stabilization of their clinical conditions, with survival beyond the first decade of life in several cases, although growth was consistently and severely impaired. Biochemical analysis of mitochondrial respiratory chain complexes in muscle and fibroblasts showed 20 to 30% residual activity of SDH and succinate-CoQ reductase (SCoQR) and decreased protein levels.

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. Genetic analysis identified compound heterozygosity for 2 mutations in the SDHA gene (600857.0006 and 600857.0007).

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.

Jain-Ghai et al. (2013) reviewed 36 cases of complex II deficiency from the literature. The phenotype was highly variable: some patients had multisystem involvement of the brain, heart, muscle, liver, and kidneys 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.

Jackson et al. (2014) reported a girl, born of unrelated Swiss parents, with encephalomyopathy and biochemical evidence of isolated mitochondrial complex II deficiency. The patient showed developmental regression with reduced motor development at age 3 months of age after a respiratory infection. Thereafter, she showed severely delayed psychomotor development associated with hypotonia, nystagmus, secondary microcephaly, ataxia, dystonia, and deteriorating vision. Laboratory studies were normal, excluding severe catabolic episodes. After 4.5 years of age, she developed seizures and myoclonic movements. During an illness at age 7, the patient underwent laboratory studies that showed lactic acidosis, ketonuria, and Krebs cycle intermediates, suggesting a mitochondrial defect. Biochemical assays of skin fibroblasts and muscle homogenates indicated isolated mitochondrial complex II deficiency (5% residual activity) and defective oxygen consumption; immunoblotting showed impaired complex II assembly. Genetic analysis identified compound heterozygous mutation in the SDHD gene (602690.0029 and 602690.0030). Cellular complementation studies showed that the SDHD variants were unable to rescue the complex II assembly defect, whereas wildtype SDHD was able to rescue it.

Alston et al. (2015) reported an infant, born of unrelated Irish parents, with fatal cardiomyopathy associated with mitochondrial complex II deficiency. The patient was noted prenatally to have dilated cardiomyopathy with mitral regurgitation and left ventricular systolic dysfunction. He died on the first day of life. Postmortem examination showed noncompaction of the hypertrophic left ventricle and an underdeveloped right ventricle. Genetic analysis identified a homozygous missense mutation in the SDHD gene (D92G; 602690.0031). Patient skeletal muscle sample showed isolated complex II deficiency (30% residual activity), as well as a significant decrease in SDHD protein levels and a decrease in fully assembled complex II. Complementation studies in yeast deficient in the homologous SDH4 gene showed that the mutation was unable to rescue the oxidative growth defect, consistent with a loss of function.

Clinical Management

Bugiani et al. (2006) reported favorable results with oral riboflavin treatment in 2 Italian patients with complex II deficiency. The patients showed acute psychomotor regression in the first year of life, followed by rapidly progressive neurologic deterioration, spastic quadriparesis with dystonic posturing, and mental impairment. One patient was blind. Complex II deficiency was demonstrated in muscle and fibroblasts. Treatment with oral riboflavin resulted in stabilization of the clinical condition and moderate improvement in cognitive and communicative abilities. Riboflavin supplementation to the growth medium of cultured fibroblasts resulted in a 2-fold increase of complex II activity in patient cells but not control cells.

Molecular Genetics

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 (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 affected members of an Italian and Turkish family with mitochondrial complex II deficiency, Ghezzi et al. (2009) identified 2 different homozygous mutations in the SDHAF1 gene (612848.0001 and 612848.0002, respectively). Some of patients had been reported by Brockmann et al. (2002) and Bugiani et al. (2006).

Associations Pending Confirmation

For discussion of a possible association between mitochondrial complex II deficiency and variation in the SDHB gene, see 185470.0020; for discussion of a possible association with variation in the SDHD gene, see 602690.0029.