COQ8A – Autosomal Recessive Ataxia Due to Ubiquinone Deficiency

COQ8A encodes an atypical mitochondrial kinase essential for coenzyme Q10 (CoQ10) biosynthesis. Biallelic loss-of-function variants in COQ8A cause autosomal recessive spinocerebellar ataxia type 9 (SCAR9; MONDO:0012784, HGNC:16812), clinically characterised by cerebellar ataxia, exercise intolerance, and multisystem involvement.

Genetic evidence derives from multiple cohorts. In 2008, four patients from three independent families harboured missense (e.g., c.637C>G (p.Arg213Gly)) and frameshift (c.1813dup (p.Glu605fs)) variants that abolished CoQ10 synthesis in yeast models (PMID:18319072). A contemporaneous genome-wide scan in a large consanguineous pedigree identified a homozygous splice-site mutation in COQ8A, and five additional variants in sporadic cases, all associated with reduced fibroblast CoQ10 and impaired ubiquinone synthesis (PMID:18319074).

Subsequent case reports reinforced an autosomal recessive inheritance. A single patient with homozygous c.1218_1219del (p.Cys406_Glu436del) presented with cerebellar ataxia, hypophosphatemia and renal phosphate wasting, improving with CoQ10 and phosphate repletion (PMID:37529414). Two siblings carrying p.Ser616LeufsTer114 manifested ataxia and myoclonus, and four patients with c.895C>T (p.Arg299Trp) exhibited ataxia plus epilepsy (PMID:24218524; PMID:27106809). Compound heterozygotes (p.Leu277Pro, c.1506+1G>A) and early-onset frameshift or stop variants further expand the allelic spectrum (PMID:29159460; PMID:30968303).

Biochemical assays consistently demonstrate decreased CoQ10 levels and complex II+III defects in patient tissues and fibroblasts, with partial restoration upon exogenous CoQ10 supplementation (PMID:23150520; PMID:30968303).

Functional characterisation in model systems corroborates haploinsufficiency. Yeast complementation of missense alleles confirmed loss of function (PMID:18319072); Drosophila Coq8 knockdown induced locomotor and photoreceptor defects reversible by wild-type Coq8 (PMID:35139868); mammalian ADCK3-deficient cells display oxidative stress, mitochondrial dysregulation and lysosomal accumulation (PMID:26866375).

Together, over 40 pathogenic COQ8A variants in more than 30 unrelated probands, segregation in consanguineous and multiplex families, and robust functional concordance establish a definitive gene–disease relationship. Early molecular diagnosis enables targeted CoQ10 and phosphate repletion therapy, yielding measurable ataxia improvement (e.g., SARA score reduction).

Key Take-home: COQ8A genetic testing is critical for the diagnosis and management of SCAR9, guiding CoQ10 and phosphate supplementation strategies.

References

• American Journal of Human Genetics • 2008 • CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures PMID:18319072
• American Journal of Human Genetics • 2008 • ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency PMID:18319074
• Neurology: Genetics • 2023 • Autosomal Recessive Spinocerebellar Ataxia Type 9 With a Response to Phosphate Repletion: A Case Report PMID:37529414
• Journal of Neurology, Neurosurgery & Psychiatry • 2014 • Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation PMID:24218524
• European Journal of Neurology • 2016 • ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic? PMID:27106809
• JIMD Reports • 2018 • Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair PMID:29159460
• Neurochemical Research • 2019 • Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants, Studies in Fibroblasts and Review of Literature PMID:30968303
• Molecular Brain • 2022 • Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration PMID:35139868
• PLoS One • 2016 • AarF Domain Containing Kinase 3 (ADCK3) Mutant Cells Display Signs of Oxidative Stress, Defects in Mitochondrial Homeostasis and Lysosomal Accumulation PMID:26866375

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