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

Willemijn J. van Rijt; Emmalie A. Jager; Derk P. Allersma; A. Çiğdem Aktuğlu Zeybek; Kaustuv Bhattacharya; François Guillaume Debray; Carolyn J. Ellaway; Matthias Gautschi; Michael T. Geraghty; David Gil-Ortega; Austin A. Larson; Francesca Moore; Eva Morava; Andrew A. Morris; Kimihiko Oishi; Manuel Schiff; Sabine Scholl-Bürgi; Michel C. Tchan; Jerry Vockley; Peter Witters; Saskia B. Wortmann; Francjan van Spronsen; Johan L.K. Van Hove; Terry G.J. Derks

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, Emmalie A. Jager, Derk P. Allersma, A. Çiğdem Aktuğlu Zeybek, Kaustuv Bhattacharya, François Guillaume Debray, Carolyn J. Ellaway, Matthias Gautschi, Michael T. Geraghty, David Gil-Ortega, Austin A. Larson, Francesca Moore, Eva Morava, Andrew A. Morris, Kimihiko Oishi, Manuel Schiff, Sabine Scholl-Bürgi, Michel C. Tchan, Jerry Vockley, Peter WittersSaskia B. Wortmann, Francjan van Spronsen, Johan L.K. Van Hove, Terry G.J. Derks

Medical Genetics

Research output: Contribution to journal › Article

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.

Original language	English (US)
Pages (from-to)	908-916
Number of pages	9
Journal	Genetics in Medicine
Volume	22
Issue number	5
DOIs	https://doi.org/10.1038/s41436-019-0739-z
State	Published - May 1 2020

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Keywords

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

ASJC Scopus subject areas

Genetics(clinical)

Cite this

van Rijt, W. J., Jager, E. A., Allersma, D. P., Aktuğlu Zeybek, A. Ç., Bhattacharya, K., Debray, F. G., Ellaway, C. J., Gautschi, M., Geraghty, M. T., Gil-Ortega, D., Larson, A. A., Moore, F., Morava, E., Morris, A. A., Oishi, K., Schiff, M., Scholl-Bürgi, S., Tchan, M. C., Vockley, J., ... Derks, T. G. J. (2020). Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency. Genetics in Medicine, 22(5), 908-916. https://doi.org/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. / van Rijt, Willemijn J.; Jager, Emmalie A.; Allersma, Derk P.; Aktuğlu Zeybek, A. Çiğdem; Bhattacharya, Kaustuv; Debray, François Guillaume; Ellaway, Carolyn J.; Gautschi, Matthias; Geraghty, Michael T.; Gil-Ortega, David; Larson, Austin A.; Moore, Francesca; Morava, Eva; Morris, Andrew A.; Oishi, Kimihiko; Schiff, Manuel; Scholl-Bürgi, Sabine; Tchan, Michel C.; Vockley, Jerry; Witters, Peter; Wortmann, Saskia B.; van Spronsen, Francjan; Van Hove, Johan L.K.; Derks, Terry G.J.

In: Genetics in Medicine, Vol. 22, No. 5, 01.05.2020, p. 908-916.

Research output: Contribution to journal › Article

van Rijt, WJ, Jager, EA, Allersma, DP, Aktuğlu Zeybek, AÇ, Bhattacharya, K, Debray, FG, Ellaway, CJ, Gautschi, M, Geraghty, MT, Gil-Ortega, D, Larson, AA, Moore, F, Morava, E, Morris, AA, Oishi, K, Schiff, M, Scholl-Bürgi, S, Tchan, MC, Vockley, J, Witters, P, Wortmann, SB, van Spronsen, F, Van Hove, JLK & Derks, TGJ 2020, 'Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency', Genetics in Medicine, vol. 22, no. 5, pp. 908-916. https://doi.org/10.1038/s41436-019-0739-z

van Rijt, Willemijn J. ; Jager, Emmalie A. ; Allersma, Derk P. ; Aktuğlu Zeybek, A. Çiğdem ; Bhattacharya, Kaustuv ; Debray, François Guillaume ; Ellaway, Carolyn J. ; Gautschi, Matthias ; Geraghty, Michael T. ; Gil-Ortega, David ; Larson, Austin A. ; Moore, Francesca ; Morava, Eva ; Morris, Andrew A. ; Oishi, Kimihiko ; Schiff, Manuel ; Scholl-Bürgi, Sabine ; Tchan, Michel C. ; Vockley, Jerry ; Witters, Peter ; Wortmann, Saskia B. ; van Spronsen, Francjan ; Van Hove, Johan L.K. ; Derks, Terry G.J. / Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency. In: Genetics in Medicine. 2020 ; Vol. 22, No. 5. pp. 908-916.

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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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T1 - Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency

AU - van Rijt, Willemijn J.

AU - Jager, Emmalie A.

AU - Allersma, Derk P.

AU - Aktuğlu Zeybek, A. Çiğdem

AU - Bhattacharya, Kaustuv

AU - Debray, François Guillaume

AU - Ellaway, Carolyn J.

AU - Gautschi, Matthias

AU - Geraghty, Michael T.

AU - Gil-Ortega, David

AU - Larson, Austin A.

AU - Moore, Francesca

AU - Morava, Eva

AU - Morris, Andrew A.

AU - Oishi, Kimihiko

AU - Schiff, Manuel

AU - Scholl-Bürgi, Sabine

AU - Tchan, Michel C.

AU - Vockley, Jerry

AU - Witters, Peter

AU - Wortmann, Saskia B.

AU - van Spronsen, Francjan

AU - Van Hove, Johan L.K.

AU - Derks, Terry G.J.

PY - 2020/5/1

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N2 - 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.

AB - 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.

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KW - inborn error of metabolism

KW - ketone bodies

KW - multiple acyl-CoA dehydrogenase deficiency

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