Neuropediatrics 2025; 56(S 01): S1-S24
DOI: 10.1055/s-0045-1812125
Neuromuscular Disorders

Preclinical and First-in-Human Evidence Supporting 4-Hydroxybenzoic Acid as a Treatment for COQ2-associated Mitochondrial Disease

Authors

  • F. Distelmaier

    1   Universitätsklinikum Düsseldorf, Allgemeine Pädiatrie, Düsseldorf, Germany

  • J. Corral-Sarasa

    2   Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain

  • L. Jiménez-Sánchez

    2   Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain

  • M. E. Díaz-Casado

    2   Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain

  • M. Rohmann

    3   Department of Pediatrics, Pediatric Nephrology, Jena University Hospital, Jena, Germany

  • A. Seibt

    1   Universitätsklinikum Düsseldorf, Allgemeine Pädiatrie, Düsseldorf, Germany

  • D. Herebian

    1   Universitätsklinikum Düsseldorf, Allgemeine Pädiatrie, Düsseldorf, Germany

  • S. Smits

    4   Institute of Biochemistry and Center for Structural Studies, Heinrich-Heine-University, Düsseldorf, Germany

  • J. Münch

    1   Universitätsklinikum Düsseldorf, Allgemeine Pädiatrie, Düsseldorf, Germany

  • E. Mayatepek

    1   Universitätsklinikum Düsseldorf, Allgemeine Pädiatrie, Düsseldorf, Germany

  • J. Breitkreutz

    5   Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Düsseldorf, Germany

  • R. Husain

    6   Department of Neuropediatrics, Jena University Hospital, Center for Inborn Metabolic Disorders, Jena, Germany

  • S. López-Herrador

    2   Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain

  • P. González-García

    7   Departamento de Fisiología, Universidad de Granada, Facultad de Medicina, Granada, Germany

  • L. López

    2   Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain
Further Information
Also available at
 

Background/Purpose: Primary coenzyme Q (CoQ) deficiency is a mitochondrial disorder with variable clinical presentation and limited response to standard CoQ10 supplementation. Recent studies suggest that 4-hydroxybenzoic acid (4-HBA), a biosynthetic precursor of CoQ, may serve as a substrate enhancement treatment in cases caused by pathogenic variants in COQ2, a gene encoding a key enzyme in CoQ biosynthesis. However, it remains unclear whether 4-HBA is required throughout life to maintain health, whether it offers advantages over CoQ10 treatment, and whether these findings are translatable to humans.

Methods: We investigated the effects of 4-HBA supplementation in a murine model carrying the pathogenic Coq2A252V variant. Moreover, we initiated a first-in-human individual therapeutic trial with 4-HBA in a 3-year-old boy with genetically confirmed primary CoQ10 deficiency due to compound heterozygous pathogenic COQ2 variants and a Leigh-like syndrome phenotype.

Results: We demonstrate that lifelong 4-HBA supplementation in the murine COQ2 model is well tolerated and prevents the onset of mitochondrial encephalopathy. In contrast, withdrawal of 4-HBA leads to progressive neurological decline. Four-HBA treatment in a COQ2 patient induced rapid and sustained remission of proteinuria, improved renal hyperfiltration, and a gradual increase in serum CoQ10 concentrations. No adverse effects were observed during a 6-month follow-up. Clinically, the patient showed notable improvements in motor skills, language acquisition, cognitive alertness, and overall development, accompanied by significant gains in growth and nutritional status.

Conclusion: Our findings support 4-HBA as a promising targeted metabolic treatment for COQ2-related CoQ deficiency and highlight the need for further clinical investigation.



Publication History

Article published online:
26 September 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany