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Neurogenetics
Original research
Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes
  1. Lucia Laugwitz1,2,
  2. Annette Seibt3,
  3. Diran Herebian3,
  4. Susana Peralta1,
  5. Imke Kienzle2,
  6. Rebecca Buchert1,
  7. Ruth Falb1,
  8. Darja Gauck1,
  9. Amelie Müller1,
  10. Mona Grimmel1,
  11. Stefanie Beck-Woedel1,
  12. Jan Kern2,
  13. Karim Daliri4,5,
  14. Pegah Katibeh4,
  15. Katharina Danhauser6,7,
  16. Steffen Leiz8,
  17. Viola Alesi9,
  18. Fabian Baertling3,
  19. Gessica Vasco10,
  20. Robert Steinfeld11,
  21. Matias Wagner6,7,
  22. Ahmet Okay Caglayan12,
  23. Hakan Gumus13,
  24. Margit Burmeister14,
  25. Ertan Mayatepek3,
  26. Diego Martinelli15,
  27. Parag Mohan Tamhankar16,
  28. Vasundhara Tamhankar16,
  29. Pascal Joset17,
  30. Katharina Steindl18,
  31. Anita Rauch18,
  32. Penelope E Bonnen19,
  33. Tawfiq Froukh20,
  34. Samuel Groeschel2,
  35. Ingeborg Krägeloh-Mann2,
  36. Tobias B Haack1,21,
  37. Felix Distelmaier3
  1. 1 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
  2. 2 Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Tübingen, Germany
  3. 3 Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
  4. 4 Child Developmental Center, Shiraz University of Medical Sciences, Shiraz, Iran
  5. 5 Institute for Neurophysiology, University of Cologne, Medical Faculty, Cologne, Germany
  6. 6 Institute of Human Genetics, Technische Universität München, Munich, Germany
  7. 7 Helmholtz Zentrum Muenchen, Deutsches Forschungszentrum fuer Gesundheit und Umwelt (GmbH), Neuherberg, Germany
  8. 8 Pediatric Neurology, Department of Pediatrics, Klinikum Dritter Orden, Munich, Germany
  9. 9 Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  10. 10 Department of Neuroscience and Neurorehabilitation, Unit of Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
  11. 11 University Children’s Hospital Zurich, Zurich, Switzerland
  12. 12 Department of Medical Genetics, School of Medicine, Dokuz Eylul University, Izmir, Turkey
  13. 13 Department of Pediatrics, Erciyes University School of Medicine, Kayseri, Turkey
  14. 14 Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA
  15. 15 Division of Metabolism, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
  16. 16 Centre for Medical Genetics, Mulund, Mumbai, India
  17. 17 Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, 4056 Basel, Switzerland
  18. 18 Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
  19. 19 Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  20. 20 Department of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan
  21. 21 Center for Rare Disease, University of Tübingen, Tübingen, Germany
  1. Correspondence to Dr Felix Distelmaier, Department of General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich-Heine-Universitat Düsseldorf, Düsseldorf, Nordrhein-Westfalen, Germany; Felix.Distelmaier{at}med.uni-duesseldorf.de

Abstract

Background Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 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 COQ4. 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 COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 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 COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.

  • nervous system diseases
  • pediatrics
  • epilepsy
  • early diagnosis

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmedgenet-2021-107729

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    Data availability statement

    Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Correction notice Since this article was first published, the institution Institute for Neurophysiology, University of Cologne has been added to Karim Daliri's author affiliations.

    • Contributors Conceptualisation: FD, LL and TBH; data curation and writing the manuscript: LL and FD; biochemical investigations: AS, DH and SP; genetic analyses: LL, TBH, SP, RF, DG, AM, MG, SB-W, MW, AR, KS, PEB, MB and TF; clinical data acquisition: JK, KD, PK, KD, SL, VA, FB, GV, RS and FD; patient evaluation: AOC, HG, DM, PMT, VT, PJ and EM; MRI analyses: IK-M, IK, SG and LL.

    • Funding SG and IK-M are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510.The study was supported by a grant of the German Research Foundation/Deutsche Forschungsgemeinschaft (DI 1731/2-2 to FD) and by a grant from the “Elterninitiative Kinderkrebsklinik e.V.” (Düsseldorf; #701900167).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.