A number sign (#) is used with this entry because of evidence that mitochondrial complex II deficiency nuclear type 3 (MC2DN3) is caused by homozygous or compound heterozygous mutation in the SDHD gene (602690) on chromosome 11q23.

Mitochondrial complex II deficiency nuclear type 3 (MC2DN3) is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients may have an encephalomyopathic picture with episodic developmental regression, loss of motor skills, hypotonia, ataxia, dystonia, and seizures or myoclonus. Other patients present in infancy with hypertrophic cardiomyopathy, which may be fatal. Laboratory studies show increased serum lactate and mitochondrial complex II deficiency in muscle and fibroblasts (summary by Jackson et al., 2014 and Alston et al., 2015).

For a discussion of genetic heterogeneity of MC2DN, see MC2DN1 (252011).

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. 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. She also had elevated liver enzymes and increased serum creatine kinase. 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. She died at 10 years of age.

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. 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.

The transmission pattern of MC2DN3 in the family reported by Jackson et al. (2014) was consistent with autosomal recessive inheritance.

In a girl, born of unrelated Swiss parents, with MC2DN3, Jackson et al. (2014) identified compound heterozygous mutations in the SDHD gene (E69K, 602690.0029 and X164L, 602690.0030). Each parent was heterozygous for one of the mutations. The variants were not found in 200 control individuals. 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.

In an infant, born of unrelated Irish parents, with mitochondrial complex II deficiency, Alston et al. (2015) identified a homozygous missense mutation in the SDHD gene (D92G; 602690.0031). The parents were heterozygous for the mutation. 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.