Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency

Willemijn J van Rijt¹, Emmalie A Jager¹, Derk P Allersma², A Çiğdem Aktuğlu Zeybek³, Kaustuv Bhattacharya⁴, François-Guillaume Debray⁵, Carolyn J Ellaway⁴, Matthias Gautschi⁶, Michael T Geraghty⁷, David Gil-Ortega⁸, Austin A Larson⁹, Francesca Moore¹⁰, Eva Morava^{11

12}, Andrew A Morris^{13

14}, Kimihiko Oishi¹⁵, Manuel Schiff¹⁶, Sabine Scholl-Bürgi¹⁷, Michel C Tchan¹⁸, Jerry Vockley¹⁹, Peter Witters¹², Saskia B Wortmann^{20

21

22}, Francjan van Spronsen¹, Johan L K Van Hove⁹, Terry G J Derks²³

Affiliations

¹ Section of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.
² Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Division of Nutrition and Metabolism, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.
⁴ Genetic Metabolic Disorders Service, Sydney Children's Hospital Network, Disciplines of Genetic Medicine and Child and Adolescent Health, University of Sydney, Sydney, Australia.
⁵ Department of Medical Genetics, CHU of Liège, Liège, Belgium.
⁶ University Hospital Bern, Department of Pediatric Endocrinology, Diabetology and Metabolism and University Institute of Clinical Chemistry, Inselspital, University of Bern, Bern, Switzerland.
⁷ Division of Metabolics and Newborn Screening, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁸ Department of Pediatric Gastroenterology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
⁹ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA.
¹⁰ Biochemical Genetics Laboratory, The Children's Hospital at Westmead, Sydney, Australia.
¹¹ Center of Individualized Medicine, Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
¹² Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium.
¹³ Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
¹⁴ Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
¹⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Reference Centre for Inborn Errors of Metabolism, Robert Debré Univ. Hospital, APHP, INSERM U1141 and Paris Diderot University, Paris, France.
¹⁷ Department of Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
¹⁸ Westmead Hospital, University of Sydney, Sydney, Australia.
¹⁹ Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
²⁰ University Childrens Hospital, Paracelcus Medical University (PMU), Salzburg, Austria.
²¹ Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
²² Institute of Human Genetics, Technische Universität München, Munich, Germany.
²³ Section of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands. t.g.j.derks@umcg.nl.

PMID: 31904027
PMCID: PMC7200590
DOI: 10.1038/s41436-019-0739-z

Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency

Willemijn J van Rijt et al. Genet Med. 2020 May.

. 2020 May;22(5):908-916.

doi: 10.1038/s41436-019-0739-z. Epub 2020 Jan 6.

Authors

Affiliations

¹ Section of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.
² Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Division of Nutrition and Metabolism, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.
⁴ Genetic Metabolic Disorders Service, Sydney Children's Hospital Network, Disciplines of Genetic Medicine and Child and Adolescent Health, University of Sydney, Sydney, Australia.
⁵ Department of Medical Genetics, CHU of Liège, Liège, Belgium.
⁶ University Hospital Bern, Department of Pediatric Endocrinology, Diabetology and Metabolism and University Institute of Clinical Chemistry, Inselspital, University of Bern, Bern, Switzerland.
⁷ Division of Metabolics and Newborn Screening, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁸ Department of Pediatric Gastroenterology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
⁹ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA.
¹⁰ Biochemical Genetics Laboratory, The Children's Hospital at Westmead, Sydney, Australia.
¹¹ Center of Individualized Medicine, Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
¹² Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium.
¹³ Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
¹⁴ Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
¹⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Reference Centre for Inborn Errors of Metabolism, Robert Debré Univ. Hospital, APHP, INSERM U1141 and Paris Diderot University, Paris, France.
¹⁷ Department of Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
¹⁸ Westmead Hospital, University of Sydney, Sydney, Australia.
¹⁹ Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
²⁰ University Childrens Hospital, Paracelcus Medical University (PMU), Salzburg, Austria.
²¹ Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
²² Institute of Human Genetics, Technische Universität München, Munich, Germany.
²³ Section of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands. t.g.j.derks@umcg.nl.

PMID: 31904027
PMCID: PMC7200590
DOI: 10.1038/s41436-019-0739-z

Abstract

Purpose: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking.

Methods: A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients.

Results: Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%).

Conclusion: The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients.

Keywords: D,L-3-hydroxybutyrate treatment; fatty acid oxidation; inborn error of metabolism; ketone bodies; multiple acyl-CoA dehydrogenase deficiency.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Fig. 1. Efficacy of D,L-3-hydroxybutyrate treatment.**
a Proportion of multiple acyl-CoA dehydrogenase deficiency (MADD)(-like) patients with organ based indication and efficacy of D,L-3-hydroxybutyrate treatment, with the numbers presented in the columns. Clinical improvement regarding liver symptoms included hyperammonemia, hypoglycemia, and/or metabolic acidosis; clinical improvement regarding muscle symptoms included exercise intolerance, hypotonia, myopathy, and/or rhabdomyolysis. b Kaplan–Meier curve of the survival in type II (n = 9) and type III (n = 14) MADD(-like) patients treated with D,L-3-HB compared with the survival in historical controls from literature (type I [n = 16], type II [n = 26] and type III [n = 156] MADD) who were not reported to have been treated with D,L-3-HB. c Kaplan–Meier plot that demonstrates the cumulative proportion of MADD(-like) patients with reported clinical improvement upon initiation of D,L-3-HB treatment over time. Calculated from a total of 21 patients with sufficient data. HC historical control. x = censored patient.

**Fig. 2. Safety of D,L-3-hydroxybutyrate treatment.**
The (serious) adverse effects that occurred in a total of 13 multiple acyl-CoA dehydrogenase deficiency (MADD)(-like) patients during the course of D,L-3-HB treatment.

**Fig. 3. D,L-3-Hydroxybutyrate treatment duration.**
Kaplan–Meier plot that demonstrates the cumulative proportion of multiple acyl-CoA dehydrogenase deficiency (MADD)(-like) patients receiving D,L-3-HB treatment over time, categorized according to D,L-3-HB treatment efficacy. Calculated from a total of 23 patients with sufficient data; x = censored patient.

See this image and copyright information in PMC

References

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Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency

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Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency

Authors

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Abstract

Conflict of interest statement

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