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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
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
Publication status	Published - 6-Jan-2020

Keywords

D,L-3-hydroxybutyrate treatment
fatty acid oxidation
inborn error of metabolism
ketone bodies
multiple acyl-CoA dehydrogenase deficiency
BETA-HYDROXYBUTYRATE
KETONE-BODIES
GLUCOSE-METABOLISM

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Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiencyFinal publisher's version, 514 KBLicence: CC BY-NC-ND

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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

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

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, BETA-HYDROXYBUTYRATE, KETONE-BODIES, GLUCOSE-METABOLISM",

author = "{van Rijt}, {Willemijn J} and Jager, {Emmalie A} and Allersma, {Derk P} and {Aktuğlu Zeybek}, {A {\c C}iğdem} and Kaustuv Bhattacharya and Fran{\c c}ois-Guillaume Debray and Ellaway, {Carolyn J} and Matthias Gautschi and Geraghty, {Michael T} and David Gil-Ortega and Larson, {Austin A} and Francesca Moore and Eva Morava and Morris, {Andrew A} and Kimihiko Oishi and Manuel Schiff and Sabine Scholl-B{\"u}rgi and Tchan, {Michel C} and Jerry Vockley and Peter Witters and Wortmann, {Saskia B} and {van Spronsen}, Francjan and {Van Hove}, {Johan L K} and Derks, {Terry G J}",

year = "2020",

month = jan,

day = "6",

doi = "10.1038/s41436-019-0739-z",

language = "English",

volume = "22",

pages = "908--916",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "5",

}

van Rijt, WJ, Jager, EA, Allersma, DP, Aktuğlu Zeybek, AÇ, Bhattacharya, K, Debray, F-G, 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

TY - JOUR

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 - 2020/1/6

Y1 - 2020/1/6

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.

KW - D,L-3-hydroxybutyrate treatment

KW - fatty acid oxidation

KW - inborn error of metabolism

KW - ketone bodies

KW - multiple acyl-CoA dehydrogenase deficiency

KW - BETA-HYDROXYBUTYRATE

KW - KETONE-BODIES

KW - GLUCOSE-METABOLISM

U2 - 10.1038/s41436-019-0739-z

DO - 10.1038/s41436-019-0739-z

M3 - Article

C2 - 31904027

SN - 1098-3600

VL - 22

SP - 908

EP - 916

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 5

ER -

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

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