Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair

Abstract

Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ and the siblings were subsequently established on a therapeutic dose of CoQ with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.

Primary coenzyme Q10 deficiency due to COQ8A gene mutations

“…The dose of oral CoQ10 (ubiquinone, ubiquinol, idebenone, and ubidecarenone) ranged from 5 mg/kg/day to 3000 mg/day in treatment of CoQ10 deficiencies (Musumeci et al, 2001). Most COQ10D4 patients experienced symptomatic improvement (Chang et al, 2018; Mignot et al, 2013; Jacobsen et al, 2018) although some patients with COQ8A mutations showed no satisfactory response (Gerards et al, 2010; Lagier‐Tourenne et al, 2008; Mollet et al, 2008). Early and sustained CoQ10 supplementation appears to be important for a favorable outcome, suggesting that persistent ongoing damage to target tissues and irreversibility of established damages are determinants of therapeutic efficacy (Blumkin et al, 2014).…”

Expression Quantitative Trait Loci in Equine Skeletal Muscle Reveals Heritable Variation in Metabolism and the Training Responsive Transcriptome

“…COQ7 and COQ8A are required for coenzyme Q biosynthesis (Mollet et al, 2008; Stefely et al, 2016). Human patients with COQ8A mutations suffered seizures and other neurological symptoms and showed reduced coenzyme Q within skeletal muscle (Jacobsen et al; Mollet et al, 2008). An eQTL for COQ8A in skeletal muscle has already been identified in horses, with a 227 bp SINE insertion in the promotor region of MSTN (g.66495326_66495327ins227) on ECA18 associated with increased expression of COQ8A (previously known as ADCK3 ) in Thoroughbreds (Rooney et al, 2017).…”

Contaminating DNA in human saliva alters the detection of variants from whole genome sequencing

“…Alignment to the GRCh37 reference genome was performed using the BWA-mem algorithm (version 0.7.17) 29 , followed by de-duplication by Picard MarkDuplicates (version 2.1.0). Variant identification and joint genotyping were performed using the GATK (version 3.7) ‘Haplotype Caller’ and ‘GenotypeGVCFs’ algorithms 30 , as described previously 31 .…”