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

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Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-01-06 , DOI: 10.1038/s41436-019-0739-z
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 ₁

Affiliation

Section of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Division of Nutrition and Metabolism, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.
Genetic Metabolic Disorders Service, Sydney Children's Hospital Network, Disciplines of Genetic Medicine and Child and Adolescent Health, University of Sydney, Sydney, Australia.
Department of Medical Genetics, CHU of Liège, Liège, Belgium.
University Hospital Bern, Department of Pediatric Endocrinology, Diabetology and Metabolism and University Institute of Clinical Chemistry, Inselspital, University of Bern, Bern, Switzerland.
Division of Metabolics and Newborn Screening, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
Department of Pediatric Gastroenterology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, USA.
Biochemical Genetics Laboratory, The Children's Hospital at Westmead, Sydney, Australia.
Center of Individualized Medicine, Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Reference Centre for Inborn Errors of Metabolism, Robert Debré Univ. Hospital, APHP, INSERM U1141 and Paris Diderot University, Paris, France.
Department of Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
Westmead Hospital, University of Sydney, Sydney, Australia.
Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
University Childrens Hospital, Paracelcus Medical University (PMU), Salzburg, Austria.
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Institute of Human Genetics, Technische Universität München, Munich, Germany.

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.

中文翻译：

D,L-3-羟基丁酸 (D,L-3-HB) 治疗多种酰基辅酶 A 脱氢酶缺乏症的疗效和安全性。

目的多酰基辅酶 A 脱氢酶缺乏症 (MADD) 是一种危及生命的极其罕见的先天性代谢缺陷。病例报告描述了 D,L-3-羟基丁酸 (D,L-3-HB) 对严重受影响的 MADD 患者的成功治疗，但缺乏关于疗效和安全性的系统数据。方法对 MADD 类患者的临床表现、D,L-3-HB 治疗方法和结局进行系统文献回顾和国际回顾性队列研究。结果我们的研究总结了 23 例 MADD（类似）患者，其中包括 14 例新病例。临床发病时的中位年龄为两个月（四分位数范围 [IQR]：8 个月）。开始 D,L-3-HB 的中位年龄为 7 个月（IQR：4.5 岁）。 D,L-3-HB 剂量范围为 100 至 2600 mg/kg/天。据报道，16 名患者 (70%) 的心肌病、脑白质营养不良、肝脏症状、肌肉症状和/或呼吸衰竭的临床改善。 D,L-3-HB 似乎对神经病变无效。与历史对照相比，D,L-3-HB 的生存期似乎更长。第一次临床改善的中位时间为一个月，最长可达六个月。报告的副作用包括腹痛、便秘、脱水、腹泻和呕吐/恶心。中位 D,L-3-HB 治疗持续时间为两年（IQR：6 年）。 12 名患者 (52%) 停止 D,L-3-HB 治疗。结论本研究的优势在于国际数据汇集证明 D,L-3-HB 治疗对于 MADD（类似）患者是有效且安全的。

更新日期：2020-01-06

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