ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis

Johan L K Van Hove; Marisa W Friederich; Daniella H Hock; David A Stroud; Nikeisha J Caruana; Uwe Christians; Björn Schniedewind; Cole R Michel; Richard Reisdorph; Edwin D J Lopez Gonzalez; Charles Brenner; Tonia E Donovan; Jessica C Lee; Kathryn C Chatfield; Austin A Larson; Peter R Baker 2nd; Shawn E McCandless; Meghan F Moore Burk

doi:10.1016/j.mito.2024.101905

ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis

Mitochondrion. 2024 Sep:78:101905. doi: 10.1016/j.mito.2024.101905. Epub 2024 May 24.

Authors

Johan L K Van Hove¹, Marisa W Friederich², Daniella H Hock³, David A Stroud³, Nikeisha J Caruana⁴, Uwe Christians⁵, Björn Schniedewind⁵, Cole R Michel⁶, Richard Reisdorph⁶, Edwin D J Lopez Gonzalez⁷, Charles Brenner⁷, Tonia E Donovan⁸, Jessica C Lee⁹, Kathryn C Chatfield¹⁰, Austin A Larson⁹, Peter R Baker 2nd⁹, Shawn E McCandless⁹, Meghan F Moore Burk¹¹

Affiliations

¹ Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO 80045, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA. Electronic address: Johan.Vanhove@childrenscolorado.org.
² Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO 80045, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA.
³ Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
⁴ Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia.
⁵ iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁶ Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷ Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
⁸ Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA.
⁹ Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO 80045, USA.
¹⁰ Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO 80045, USA; Department of Pediatrics, Section of Cardiology, University of Colorado, Aurora, CO, USA.
¹¹ Department of Physical Medicine and Rehabilitation, Children's Hospital Colorado, 13121 East 16(th) Avenue, Aurora, CO, USA.

PMID: 38797357
PMCID: PMC11390326 (available on 2025-09-01)
DOI: 10.1016/j.mito.2024.101905

Abstract

Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC₅₀. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.

Keywords: ACAD9 disorder; Bezafibrate; Cardiomyopathy; Mitochondrial disease; Nicotinamide riboside; Treatment; complex I deficiency.

Publication types

Case Reports

MeSH terms

Acidosis, Lactic* / diagnosis
Acidosis, Lactic* / drug therapy
Acidosis, Lactic* / genetics
Acidosis, Lactic* / metabolism
Acyl-CoA Dehydrogenases* / genetics
Acyl-CoA Dehydrogenases* / metabolism
Acyl-CoA Dehydrogenases* / pharmacology
Acyl-CoA Dehydrogenases* / therapeutic use
Bezafibrate* / pharmacology
Bezafibrate* / therapeutic use
Biomarkers
Cardiomyopathies* / drug therapy
Cardiomyopathies* / genetics
Cardiomyopathies* / metabolism
Cardiomyopathies* / physiopathology
Drug Combinations
Echocardiography
Humans
Infant
Male
Niacinamide* / pharmacology
Niacinamide* / therapeutic use
Proteomics
Pyridinium Compounds* / pharmacology
Pyridinium Compounds* / therapeutic use

Substances

ACAD9 protein, human
Acyl-CoA Dehydrogenases
Bezafibrate
Biomarkers
Drug Combinations
Niacinamide
nicotinamide-beta-riboside
Pyridinium Compounds

Supplementary concepts

Lactic Acidosis, Fatal Infantile

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding