COQ9 deficiency, a rare genetic disorder affecting the coenzyme Q (CoQ) biosynthetic pathway, requires a careful study of its molecular characteristics.
The genetic basis of COQ9 deficiency involves a spectrum of mutations in the COQ9 gene. More than 270 variations have been reported, among them 34 being pathogenic or likely pathogenic. These mutations can be classified as missense mutations, frameshift mutations, and splice site mutations. The diversity of mutation types contributes to the clinical heterogeneity observed in individuals with COQ9 deficiency.
Suspected pathophysiological mechanisms:
While the pathogenesis of the disease is not fully understood, it is thought to be caused by a combination of defects in the oxidative phosphorylation system and increased reactive oxygen metabolites. In cell cultures carrying COQ2 and PDSS2 mutations, which are associated with early onset and multisystemic involvement, a severe deficiency in CoQ levels has been detected. CoQ biosynthesis defects contribute to clinical findings by affecting de novo pyrimidine synthesis and sulfide metabolism. The molecular intricacies of the COQ9 defect extend to its putative pathophysiological mechanisms, which primarily centre on disruption of the CoQ biosynthetic pathway. CoQ, a key component of the mitochondrial electron transport chain, plays a central role in energy production. Defective COQ9 protein inhibits CoQ synthesis, leading to mitochondrial dysfunction, impaired energy production and subsequent cellular damage.
Diagnostic testing:
Advances in next-generation DNA sequencing (NGS) technology have facilitated the diagnosis of many mitochondrial diseases, including CoQ10 deficiencies. Due to the ability to screen for multiple genetic diseases simultaneously and being a less invasive method, genetic analyzes are preferred over invasive procedures such as muscle biopsy nowadays.
If a pathological variant is detected in the COQ genes as a result of genetic examination, family segregation analysis is performed to confirm the variant found. Depending on the results of the variants, subsequent fibroblast studies may be required for functional validation in some cases using gene panels whole exome (WES) or whole genome (WGS).
In addition, the detection of decreased CoQ levels in muscle biopsy, complex I + III or II + III complexes, or decreased CoQ levels in plasma, lymphocytes, and fibroblast cultures can also be a guide in diagnosis.
COQ9