COQ8A – Coenzyme Q10 Deficiency

Autosomal recessive primary coenzyme Q10 (CoQ10) deficiency, also known as SCAR9, is caused by bi-allelic mutations in COQ8A leading to impaired mitochondrial respiratory chain function. Nine unrelated probands across six families have been reported to harbor pathogenic COQ8A variants, manifesting with cerebellar ataxia, dysarthria, and variable systemic features (PMID:26818466, PMID:32685350, PMID:35275351, PMID:38229639, PMID:27106809).

The genetic spectrum includes missense, nonsense, frameshift, splice-site, and large intragenic deletions. A recurrent homozygous c.1015G>A (p.Ala339Thr) variant was identified in two siblings with early-onset ataxia and respiratory chain complex II+III deficiency (PMID:32685350). Other alleles include p.Gly272Cys in an Iranian patient with epilepsia partialis continua (PMID:35275351) and p.Arg299Trp among Norwegian families (PMID:27106809).

Segregation studies in two consanguineous sib-pairs confirmed autosomal recessive inheritance, with four additional affected relatives segregating pathogenic COQ8A alleles (PMID:29159460, PMID:24218524).

Functional assessments demonstrated that human COQ8A missense mutations (e.g., p.Arg213Trp, p.Gly272Val, p.Glu605Ter) fail to rescue yeast abc1Δ respiratory growth and markedly reduce ubiquinone synthesis (PMID:18319072). Mammalian cell assays of ADCK3-deficient fibroblasts show decreased CoQ10 content, impaired complex I+III and II+III activities, and oxidative stress (PMID:18319074, PMID:26866375).

A Drosophila Coq8 knockdown model recapitulated locomotor deficits and photoreceptor degeneration, which were rescued by wild-type Drosophila Coq8 but exacerbated by human COQ8A, implicating a dominant-negative effect of hCOQ8A in fly tissues (PMID:35139868).

Collectively, the genetic and experimental data support a Strong gene-disease association. Clinically, early molecular diagnosis enables timely CoQ10 supplementation, which can stabilize or improve neurological outcomes.

References

• Clinical genetics • 2016 • Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3. PMID:26818466
• JIMD reports • 2020 • Early-onset coenzyme Q10 deficiency associated with ataxia and respiratory chain dysfunction due to novel pathogenic COQ8A variants, including a large intragenic deletion. PMID:32685350
• Journal of molecular neuroscience : MN • 2022 • Epilepsia Partialis Continua a Clinical Feature of a Missense Variant in the ADCK3 Gene and Poor Response to Therapy. PMID:35275351
• Annals of Indian Academy of Neurology • 2023 • Stroke-Like Episodes and Epilepsy in a Patient with COQ8A-Related Coenzyme Q10 Deficiency. PMID:38229639
• 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
• Journal of neurology, neurosurgery, and psychiatry • 2014 • Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation. PMID:24218524
• 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
• Molecular brain • 2022 • Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration. PMID:35139868

Evidence Based Scoring (AI generated)