Mitochondrial complex III deficiency nuclear type 6 (MC3DN6) is an autosomal recessive disorder caused by mitochondrial dysfunction. It is characterized by onset in early childhood of episodic acute lactic acidosis, ketoacidosis, and insulin-responsive hyperglycemia, usually associated with infection. ... Mitochondrial complex III deficiency nuclear type 6 (MC3DN6) is an autosomal recessive disorder caused by mitochondrial dysfunction. It is characterized by onset in early childhood of episodic acute lactic acidosis, ketoacidosis, and insulin-responsive hyperglycemia, usually associated with infection. Laboratory studies show decreased activity of mitochondrial complex III. Psychomotor development is normal (summary by Gaignard et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Gaignard et al. (2013) reported 2 unrelated patients, both born of consanguineous parents, with mitochondrial complex III deficiency. The families were of Lebanese and Sri Lankan descent, respectively. Both patients had recurrent episodes of lactic acidosis and metabolic ... Gaignard et al. (2013) reported 2 unrelated patients, both born of consanguineous parents, with mitochondrial complex III deficiency. The families were of Lebanese and Sri Lankan descent, respectively. Both patients had recurrent episodes of lactic acidosis and metabolic decompensation usually associated with intercurrent illness. One child, a boy, first presented at age 5 months with severe metabolic ketoacidosis, increased serum lactate, and hyperammonemia, whereas the other, a girl, first presented at age 2.5 years with neurologic deterioration resulting in coma. She had hyperglycemic ketoacidosis with increased serum lactate, liver failure, and hyperammonemia. In both patients, hyperglycemia during these episodes was responsive to insulin therapy. Biochemical studies of fibroblasts and skeletal muscle samples from both patients showed isolated decreases in mitochondrial complex III activity; liver biopsy in 1 patient also showed decreased complex III activity. Both children had subsequent normal psychomotor development, and were 34 months and 18 years of age, respectively, at the time of the report. The older patient still had rare episodes of metabolic decompensation.
In 2 unrelated patients with mitochondrial complex III deficiency, Gaignard et al. (2013) identified 2 different homozygous missense mutations in the CYC1 gene (123980.0001 and 123980.0002) that segregated with the disorder in the families. One of the mutations ... In 2 unrelated patients with mitochondrial complex III deficiency, Gaignard et al. (2013) identified 2 different homozygous missense mutations in the CYC1 gene (123980.0001 and 123980.0002) that segregated with the disorder in the families. One of the mutations was found by whole-exome sequencing and the other by candidate gene sequencing. Immunoblot analysis of patient fibroblasts and skeletal muscle samples showed a severe reduction in CYC1 protein levels (less than 10% of controls), suggesting that the mutant proteins were unstable. There was also a decrease in assembly-dependent complex III subunits, which correlated with significantly decreased complex III activity in patient cells. Expression of a single copy of the orthologous mutations in Cyc1-null yeast resulted in decreased amounts of mutant protein and failed to rescue the growth defect, but the growth defect could be partially rescued in transformants harboring multiple copies of the mutant genes. Similar effects were observed with patient fibroblasts, indicating that the mutations cause a deleterious effect on complex III assembly or stability. Crystal structure analysis indicated that both mutations occurred in the extramembrane domain, which is thought to play a role in structural and functional integrity of complex III.