Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes.

TitleHuman COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes.
Publication TypeJournal Article
Year of Publication2022
AuthorsLaugwitz, L, Seibt, A, Herebian, D, Peralta, S, Kienzle, I, Buchert, R, Falb, R, Gauck, D, Müller, A, Grimmel, M, Beck-Woedel, S, Kern, J, Daliri, K, Katibeh, P, Danhauser, K, Leiz, S, Alesi, V, Baertling, F, Vasco, G, Steinfeld, R, Wagner, M, Caglayan, AOkay, Gumus, H, Burmeister, M, Mayatepek, E, Martinelli, D, Tamhankar, PMohan, Tamhankar, V, Joset, P, Steindl, K, Rauch, A, Bonnen, PE, Froukh, T, Groeschel, S, Krägeloh-Mann, I, Haack, TB, Distelmaier, F
JournalJ Med Genet
Date Published2022 Sep
KeywordsCell Line, Child, Humans, Infant, Newborn, Mitochondrial Proteins, Neuroimaging, Phenotype, Ubiquinone

BACKGROUND: Human coenzyme Q4 (COQ4) is essential for coenzyme Q (CoQ) biosynthesis. Pathogenic variants in cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency.

METHODS: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed.

RESULTS: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in . Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.

CONCLUSION: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of variants. Due to the insufficient clinical response to oral CoQ supplementation, alternative treatment strategies are warranted.

Alternate JournalJ Med Genet
PubMed ID34656997
PubMed Central IDPMC9807242
Grant ListR01 NS083726 / NS / NINDS NIH HHS / United States

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