# Severe Neurological Presentation in Siblings With COQ5 ‐Related Primary Coenzyme Q10 Deficiency: Expanding Clinical and Molecular Spectrum

## TL;DR

This paper reports two siblings with severe neurological issues caused by a genetic mutation in COQ5, a gene involved in CoQ10 production, and shows that CoQ10 supplementation may help.

## Contribution

The study expands the clinical and molecular spectrum of COQ5-related CoQ10 deficiency and establishes a yeast model to evaluate COQ5 variants.

## Key findings

- Compound heterozygous COQ5 variants were identified in two siblings with severe neurological symptoms.
- A yeast model showed that a missense COQ5 variant failed to rescue CoQ biosynthesis, leading to intermediate accumulation.
- CoQ10 supplementation led to subjective clinical improvement in the proband.

## Abstract

Coenzyme Q10 (CoQ10) is a coenzyme and antioxidant involved in multiple bioenergetic and biosynthetic processes, particularly within mitochondria. The biosynthesis of CoQ10 is a tightly regulated process that involves multiple enzymes, including the methyltransferase COQ5. Genetic defects in COQ5 have recently been associated with autosomal recessive COQ5‐related primary CoQ10 deficiency. The clinical manifestations of seven individuals previously reported were primarily neurological and ophthalmological. Here, we report two siblings with profound developmental delay and brain imaging consistent with multistage strokes. Clinical exome sequencing revealed compound heterozygous variants in COQ5, including one frameshift deletion and one missense variant. Our functional complementation studies demonstrate that a
Saccharomyces cerevisiae COQ5 ortholog harboring the corresponding missense variant fails to fully rescue coq5∆ CoQ6 production, leading to the accumulation of CoQ biosynthetic intermediates. After the diagnosis, CoQ10 supplementation was started on the proband, leading to subjective clinical improvement. We describe new cases of COQ5‐related primary CoQ10 deficiency and expand the phenotypic and molecular spectrum of the disease. We also establish a yeast system to evaluate the effects of the variants in COQ5 and support the use of CoQ10 supplementation for patients with COQ5‐related primary CoQ10 deficiency.