3-hydroxybutyrate (3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency: a systematic literature review and international retrospective cohort study

Willemijn J. van Rijt, BSca, Emmalie A. Jager, BSca, Carolyn J. Ellaway, MD PhDb,

Sabine Scholl-Bürgi, MD PhDc, Matthias Gautschi, MD PhDd, François-Guillaume Debray, MD PhDe,

Michel C. Tchan, MD PhDf, Manuel Schiff, MD PhDg, David Gil-Ortega, MD PhDh,

  1. Çiğdem Aktuğlu Zeybek, MD PhDi, Austin A. Larson, MDj,

Johan L. Van Hove, MD PhDj and Terry G.J. Derks, MD PhDa

Affiliations: aSection of Metabolic Diseases, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, Groningen, the Netherlands; bGenetic Metabolic Disorders Service, Sydney Children’s Hospital Network, Disciplines of Genetic Medicine and Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia; cDepartment of Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Tyrol, Austria; dUniversity Children’s Hospital, Department of Pediatric Endocrinology, Diabetology and Metabolism and University Institute of Clinical Chemistry, Inselspital, University of Bern, Bern, Bern, Switzerland; eDepartment of Medical Genetics, CHU of Liège, Liège, Liège, Belgium; fWestmead Hospital, University of Sydney, Sydney, New South Wales, Australia; gRobert Debré Univ. Hospital, APHP, Paris, Île-de-France, France; hDepartment of Pediatric Gastroenterology, Hospital Universitario Virgen de la Arrixaca, Murcia, Murcia, Spain; iDivision of Nutrition and Metabolism, Department of Pediatrics, Cerrahpaşa Medical School, Istanbul University, Istanbul, Istanbul, Turkey; jSection of Clinical Genetics and Metabolism, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado, Aurora, Colorado, United States of America.

Address correspondence to: Terry G. J. Derks, MD, PhD. E-mail: t.g.j.derks@umcg.nl .
Phone: +31 (0)50 3614147.

Abstract

Multiple acyl-CoA dehydrogenase deficiency (MADD; glutaric aciduria type II) is a rare disorder of both mitochondrial fatty acid oxidation and amino acid metabolism. Few case reports describe successful experimental sodium-D,L-3-hydroxybutyrate (3-HB) treatment in severely affected MADD-patients. After 1) an extensive systematic literature review, we are currently performing 2) an international, retrospective questionnaire study on clinical presentation, 3-HB treatment method and (long-term) outcome in MADD(-like)-patients to investigate the efficacy and safety of 3-HB treatment in MADD.

Our systematic review identified 14 MADD(-like)-patients treated with 3-HB. To date, first results of our questionnaire study summarize 13 patients, including four previously reported cases. Median age at first clinical presentation was 5 months (range: 0 days – 26 years), six patients were also identified via abnormal population newborn screening results. Molecular analysis identified five patients with homozygous ETFA (c.1-40G>A; c.797C>T) and ETFDH (c.463A>G; c.1106G>C; c.1141G>C) mutations and three patients with compound heterozygous ETFA (c.200T>C and c.854A>T), ETFDH (c.896T>C and c.1842C>A) and SLC52A3 (c.49T>C and c.639C>G) mutations. Surprisingly, one patient demonstrated two ETFA (c.365G>A and c.809-811delTAG) and ETFB (c.217-4G>T and c.438+20C>T) mutations. Two other patients carry only one ETFDH (c.1774T>C ) and SLC52A3 (c.678-680del) mutation, respectively.

Median age at start of 3-HB treatment was 9 months (2 months – 26 years). Prescribed dosages ranged between 130 and 2600 mg/kg/day in three to six times per day, four patients received 3-HB continuously during the night. Administration methods included oral or nasogastric solution, solution via gastrostomy, oral powder and oral capsules, mostly combined with nutrition. Reported treatment rationales (TR) and clinical improvements (CI) included leukodystrophy (TR n=4; CI n=3), cardiac pathology (TR n=2; CI n=2), muscle pathology (TR n=10; CI n=6 + CI in two additional patients without this original TR), liver pathology (TR n=4; CI n=3), neuropathy (TR n=1; CI n=0) and to prevent complications (TR n=2). Overall, CI was reported in eight patients. Most frequently reported side effects included dehydration, vomiting/nausea, constipation and abdominal pain. Treatment was terminated in six patients due to (a combination of) clinical improvement un-necessitating further 3-HB treatment (n=2), no clinical improvement (n=2), death (n=1), side effects (n=1) or costs (n=1). Median age at termination of 3-HB treatment was 5 years (8 months – 26 years). Median duration of 3-HB treatment was 2 years (1 month – 8 years).

This is the largest international, collaborative cohort study on 3-HB treatment in MADD
(-like)-patients. Based on our preliminary retrospective data, 3-HB can be efficacious and safe in selected MADD-patients. To improve patient monitoring, a clinical severity score for MADD is warranted.

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