Genotypes and Clinical Phenotypes in Children with Cytochrome-cOxidase Deficiency

Abstract

Cytochrome c oxidase (COX) deficiency has been associated with a wide spectrum of clinical features and may be caused by mutations in different genes of both the mitochondrial and the nuclear DNA. In an attempt to correlate the clinical phenotype with the genotype in 16 childhood cases, mtDNA was analysed for deletion, depletion, and mutations in the three genes encoding COX subunits and the 22 tRNA genes. Furthermore, nuclear DNA was analysed for mutations in the SURF1, SCO2, COX10, and COX17 genes and cases with mtDNA depletion were analysed for mutations in the TK2 gene. SURF1-mutations were identified in three out of four cases with Leigh syndrome while a mutation in the mitochondrial tRNA (trp) gene was identified in the fourth. One case with mtDNA depletion had mutations in the TK2 gene. In two cases with leukoencephalopathy, one case with encephalopathy, five cases with fatal infantile myopathy and cardiomyopathy, two cases with benign infantile myopathy, and one case with mtDNA depletion, no mutations were identified. We conclude that COX deficiency in childhood should be suspected in a wide range of clinical settings and although an increasing number of genetic defects have been identified, the underlying mutations remain unclear in the majority of the cases.

Placental Genome and Maternal-Placental Genetic Interactions: A Genome-Wide and Candidate Gene Association Study of Placental Abruption

“…COX10 encodes for the cytochrome C oxidase protein, the terminal component of the mitochondrial respiratory chain that catalyzes the electron transfer from reduced cytochrome C to oxygen. Genetic variations in this gene have been related to several diseases with underlying mitochondrial dysfunction including Alzheimers’ disease, neurodegenerative diseases and other childhood disorders [69] – [71] . The THRB gene encodes a protein that is a receptor for triidothyronine.…”

SURF1 knockout cloned pigs: Early onset of a severe lethal phenotype

“…Mutations in SURF1 account for about one third of LS cases and are by far the most frequent cause of LS associated with isolated COX deficiency [ 5 , 6 ]. Although SURF1 -related LS is a well-established neuropathological and clinical entity, atypical manifestations have been occasionally reported, such as long-surviving cases with scarce brain lesions [ 3 , 7 ], or subjects manifesting predominant demyelinating Charcot-Marie-Tooth disease [ 8 ], villous atrophy, hypertrichosis without the typical brain lesions [ 9 ], or severe renal involvement [ 10 ].…”

Clinical Diagnosis and Treatment of Leigh Syndrome Based on SURF1: Genotype and Phenotype

“…Although LS can be genetically inherited through mutations in the mtDNA and in the PDHA1, SCO1, SCO2 , and COX10 genes, studies [ 13 , 34 , 44 ] next-generation sequencing studies have shown that SURF1 is an important gene for LS. Further, mtDNA mutations account for 25% of LS cases [ 45 ], whereas most patients have nuclear DNA mutations [ 46 ].…”