Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency
Marek Böhm1, Ewa Pronicka, Elzbieta Karczmarewicz
1Department of Pediatrics, Faculty of Medicine, Charles University, Prague, Czech Republic.
Insights
Cytochrome c oxidase (COX) deficiency in children often presents early with severe symptoms and has a poor prognosis, with genetic mutations identified in most cases. Specific mutations in SURF1 and SCO2 genes are common, particularly in certain populations.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Cytochrome c oxidase (COX) deficiency is a severe mitochondrial disorder.
- Early onset and high mortality characterize COX deficiency in children.
Purpose of the Study:
- To analyze clinical features, prognosis, and molecular genetic causes of COX deficiency in children.
- To identify common mutations and potential population-specific genetic factors.
Main Methods:
- Retrospective, multicenter study of 180 pediatric patients.
- Clinical data review, biochemical analysis of respiratory chain complexes, and molecular genetic testing (DNA sequencing).
Main Results:
- Most patients presented with failure to thrive, encephalopathy, hypotonia, and/or cardiac/hepatic involvement.
- Two-thirds of patients died; elevated blood and CSF lactate were common.
- Genetic mutations identified in 75 patients, including SURF1 (47 cases, 845-846delCT mutation prevalent) and SCO2 (9 cases, 1541G>A mutation).
- Various mitochondrial DNA mutations and deletions were also found.
Conclusions:
- COX deficiency is a heterogeneous group of diseases with a poor prognosis.
- SURF1 and SCO2 gene mutations are significant causes of COX deficiency, with specific mutations showing high prevalence in a Slavonic population, suggesting regional genetic differences.
Abstract:
A retrospective, multicenter study of 180 children with cytochrome c oxidase (COX) deficiency analyzed the clinical features, prognosis, and molecular bases of the COX deficiency. Clinical symptoms including failure to thrive, encephalopathy, hypotony, Leigh syndrome, cardiac involvement, and hepatopathy appeared in most patients early after birth or in early childhood. Two thirds of all children died. Biochemical examination revealed an isolated COX deficiency in 101 children and COX deficiency combined with disturbances of other respiratory chain complexes in 79 children. Blood and cerebrospinal fluid lactate increased in 85% and 81% of examined cases, respectively. Pathogenic mutations in mitochondrial or nuclear DNA were established in 75 patients. Mutations in surfeit locus protein 1 gene (SURF1) were found in 47 children with Leigh syndrome; 2bp deletion 845-846delCT was found in 89% of independent alleles. Mutations in a mitochondrial copper-binding protein (SCO2) gene were found in nine children with encephalomyopathy and/or cardiomyopathy; all of them were homozygotes or heterozygotes for 1541G>A mutation. Different mitochondrial DNA (mtDNA) deletion or depletion were found in nine children, mtDNA mutation 3243A>G in six, mtDNA mutation 8363G>A in two children with Leigh syndrome and mtDNA mutations 8344A>G, and 9205-9206delTA in one child each. COX deficiency represents a heterogeneous group of diseases with unfavorable prognosis. Marked prevalence of two nuclear DNA mutations (845-846delCT in the SURF1 gene and 1541G>A in the SCO2 gene) associated with COX deficiency in a Slavonic population suggests the existence of regional differences in the genetic basis of COX deficiency.
