Genetics of Coenzyme Q10 Deficiency

Abstract

Coenzyme Q₁₀ (CoQ₁₀) is an essential component of eukaryotic cells and is involved in crucial biochemical reactions such as the production of ATP in the mitochondrial respiratory chain, the biosynthesis of pyrimidines, and the modulation of apoptosis. CoQ₁₀ requires at least 13 genes for its biosynthesis. Mutations in these genes cause primary CoQ₁₀ deficiency, a clinically and genetically heterogeneous disorder. To date mutations in 8 genes (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) have been associated with CoQ₁₀ deficiency presenting with a wide variety of clinical manifestations. Onset can be at virtually any age, although pediatric forms are more common. Symptoms include those typical of respiratory chain disorders (encephalomyopathy, ataxia, lactic acidosis, deafness, retinitis pigmentosa, hypertrophic cardiomyopathy), but some (such as steroid-resistant nephrotic syndrome) are peculiar to this condition. The molecular bases of the clinical diversity of this condition are still unknown. It is of critical importance that physicians promptly recognize these disorders because most patients respond to oral administration of CoQ₁₀.

Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content

“…7 This is the base of understanding that a defective biosynthesis of CoQ 10 by mutations in any COQ genes, and secondary deficiencies by defects of respiratory chain complexes functions such as mtDNA depletions 14 or proteins involved in mitochondrial homeostasis cause mitochondrial diseases mainly with neuromuscular phenotype. 5 The two patients presented here showed a similar phenotype to those described in encephalomyopathy, mainly ataxia, associated to primary or secondary CoQ 10 deficiency but in these cases CoQ 10 levels were elevated in both muscle and fibroblasts, corresponding to the increase of mitochondrial mass, showing mitochondrial dysfunction with low efficiency on ATP biosynthesis. A similar condition of defective respiration in the presence of high content of CoQ has been described in COQ10 null mutant yeast strain, 15 indicating that CoQ is one major component in respiratory chain but requires proteins for its electron carrier transport to properly prevent defective electrons leaking for ROS production.…”

“…7 Furthermore, mutations of genes that are not part of respiratory chain also cause mitochondrial dysfunctions and may induce an adaptive decrease of CoQ 10 , named secondary deficiency, although the mechanisms are totally unknown. 4,5 In contrast to the already described cases of mitochondrial diseases showing CoQ 10 deficiency, we describe here two unrelated children that present a fatal neurological disorder, associated to genetic variants in PDH genes. The two cases presented high levels of both CoQ 10 and mitochondria in fibroblasts and skeletal muscle, with low efficient mitochondria that show defective homeostasis, and high levels of antioxidant enzymes.…”

“…4 Primary deficiencies are due to mutations of genes involved in its biosynthesis, a very complex pathway not completely known, whose regulation has started to be described. 5 In mammals, CoQ levels are tissue specific and its concentration in mitochondria is very much balanced with electron chain complexes, contributing to prevent endogenous oxidative stress. 6 Among tissues, CoQ content in brain is very stable and highly independent of environment.…”

Steroid-resistant nephrotic syndrome caused by co-inheritance of mutations at <i>NPHS1</i> and <i>ADCK4</i> genes in two Chinese siblings

“…CoQ10 requires at least 13 genes for its biosynthesis (21). Mutations in these genes cause primary CoQ10 deficiency, a clinically and genetically heterogeneous disorder.…”

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

“…To date, defects in eight of these genes were identified as a cause of primary CoQ 10 deficiency disorders (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4 and COQ9), a clinically heterogeneous group of diseases, which frequently manifests in childhood. 3,4 According to Quinzii et al, 5 five major clinical phenotypes can be distinguished: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) nephropathy, (4) cerebellar ataxia and (5) isolated myopathy. Identification of CoQ 10 deficiency is important because CoQ 10 supplementation can be beneficial in certain conditions.…”