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

Similar Publications

Rhie A, Nurk S, Cechova M, Hoyt SJ, Taylor DJ, Altemose N, et al.. The complete sequence of a human Y chromosome. Nature. 2023;621(7978):344-354.
Chen F, Zhang Y, Chandrashekar DS, Varambally S, Creighton CJ. Global impact of somatic structural variation on the cancer proteome. Nat Commun. 2023;14(1):5637.
Saengboonmee C, Sorin S, Sangkhamanon S, Chomphoo S, Indramanee S, Seubwai W, et al.. γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus. World J Gastroenterol. 2023;29(28):4416-4432.
Wojcik MH, Reuter CM, Marwaha S, Mahmoud M, Duyzend MH, Barseghyan H, et al.. Beyond the exome: What's next in diagnostic testing for Mendelian conditions. Am J Hum Genet. 2023;110(8):1229-1248.
Chin C-S, Behera S, Khalak A, Sedlazeck FJ, Sudmant PH, Wagner J, et al.. Multiscale analysis of pangenomes enables improved representation of genomic diversity for repetitive and clinically relevant genes. Nat Methods. 2023;20(8):1213-1221.
Walker KA, Chen J, Shi L, Yang Y, Fornage M, Zhou L, et al.. Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Sci Transl Med. 2023;15(705):eadf5681.
Zhao N, Teles F, Lu J, Koestler DC, Beck J, Boerwinkle E, et al.. Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study. J Clin Periodontol. 2023;50(9):1140-1153.
Harris RA, McAllister JM, Strauss JF. Single-Cell RNA-Seq Identifies Pathways and Genes Contributing to the Hyperandrogenemia Associated with Polycystic Ovary Syndrome. Int J Mol Sci. 2023;24(13).
Qian X, Srinivasan T, He J, Chen R. The Role of Ceramide in Inherited Retinal Disease Pathology. Adv Exp Med Biol. 2023;1415:303-307.
Calame DG, Guo T, Wang C, Garrett L, Jolly A, Dawood M, et al.. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease. Am J Hum Genet. 2023;110(8):1394-1413.