Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 May;22(5):908-916.
doi: 10.1038/s41436-019-0739-z. Epub 2020 Jan 6.

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

Willemijn J van Rijt  1 , Emmalie A Jager  1 , Derk P Allersma  2 , A Çiğdem Aktuğlu Zeybek  3 , Kaustuv Bhattacharya  4 , François-Guillaume Debray  5 , Carolyn J Ellaway  4 , Matthias Gautschi  6 , Michael T Geraghty  7 , David Gil-Ortega  8 , Austin A Larson  9 , Francesca Moore  10 , Eva Morava  11   12 , Andrew A Morris  13   14 , Kimihiko Oishi  15 , Manuel Schiff  16 , Sabine Scholl-Bürgi  17 , Michel C Tchan  18 , Jerry Vockley  19 , Peter Witters  12 , Saskia B Wortmann  20   21   22 , Francjan van Spronsen  1 , Johan L K Van Hove  9 , Terry G J Derks  23
Affiliations

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.

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
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
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
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

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Frerman FE, Goodman SI. Chapter 103: defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric acidemia type II. In: Valle D, Beaudet AL, Vogelstein B, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2014.
    1. Olpin SE. Implications of impaired ketogenesis in fatty acid oxidation disorders. Prostaglandins Leukot Essent Fatty Acids. 2004;70:293–308. - PubMed
    1. Bouteldja N, Andersen LT, Moller N, Gormsen LC. Using positron emission tomography to study human ketone body metabolism: a review. Metabolism. 2014;63:1375–1384. - PubMed
    1. Rinaldo P, Matern D, Bennett MJ. Fatty acid oxidation disorders. Annu Rev Physiol. 2002;64:477–502. - PubMed
    1. Bonham JR, Tanner MS, Pollitt RJ, et al. Oral sodium 3-hydroxybutyrate, a novel adjunct to treatment for multiple acyl CoA dehydrogenase deficiency. J Inherit Metab Dis. 1999;22(Suppl 1):101.

Publication types

MeSH terms

Substances