COQ4 Mutations Cause a Broad Spectrum of Mitochondrial Disorders Associated with CoQ10 Deficiency

Abstract

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

“…Three genes in our epilepsy cohort (COQ4, DNM1, and PURA), accounting for 14% (3/21) of all novel genetic etiologies identified in patients with epilepsy, were subsequently confirmed in independent publications. 16,[33][34][35][36] Although it is difficult to assess to what extent this frequency is higher than would be expected by chance, we feel reassured by the fact that approximately 15% of all genes that were reported as potential novel disease genes received subsequent independent confirmation without knowledge of our prior report. This number may provide a baseline for future studies examining the role of diagnostic novel gene reporting.…”

Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9

“…The case, together with the description of Duncan et al, places COQ9 deficiency among the most severe forms of CoQ 10 metabolism disorders, comparable to descriptions in patients with defects in COQ2 or COQ4. 6,13,14 However, further clinical descriptions will be required to evaluate the specific clinical spectrum of patients with COQ9 mutations. As suggested by Duncan et al, 6 CoQ 10 treatment might be helpful in COQ9-deficient children.…”

Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus

“…The complex pathway of coenzyme Q 10 biosynthesis has not yet been fully delineated in humans, but eight genetic defects of CoQ 10 synthesis have been described, six of which are associated with epilepsy [35][36][37]. Patients with ADCK3 mutations have seizures associated with autosomal recessive cerebellar ataxia [38,39], while those with COQ6 mutations present with nephrotic syndrome which may or may not be associated with seizures [40].…”