[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
van Rijt, Willemijn J.
Jager, Emmalie A.
Allersma, Derk P.
Aktuğlu Zeybek, A. Çiğdem
Bhattacharya, Kaustuv
Debray, François-Guillaume ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Maladies métaboliques d'origine génétique
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, et al., editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2004. http://ommbid.mhmedical.com/content.aspx?bookid=2709§ionid=225088261. Accessed 19 August 2019.
Olpin SE. Implications of impaired ketogenesis in fatty acid oxidation disorders. Prostaglandins Leukot Essent Fatty Acids. 2004;70:293–308.
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.
Rinaldo P, Matern D, Bennett MJ. Fatty acid oxidation disorders. Annu Rev Physiol. 2002;64:477–502.
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.
Van Hove JL, Grunewald S, Jaeken J, et al. D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD). Lancet. 2003;361:1433–1435.
Van Rijt WJ, Heiner-Fokkema MR, du Marchie Sarvaas GJ, et al. Favorable outcome after physiologic dose of sodium-D,L-3-hydroxybutyrate in severe MADD. Pediatrics. 2014;134:e1224–8.
Gautschi M, Weisstanner C, Slotboom J, Nava E, Zurcher T, Nuoffer JM. Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy. Pediatr Res. 2015;77:91–98.
Fischer T, Och U, Marquardt T. Long-term ketone body therapy of severe multiple acyl-CoA dehydrogenase deficiency: a case report. Nutrition. 2018;60:122–128.
van Spronsen FJ, de Weerd W, Goorhuis J, et al. Respiratory insufficiency as first presentation of multiple acyl-CoA dehydrogenase deficiency (MADD). J Inherit Metab Dis. 2005;28 Suppl 1:115.
Bosch AM, Abeling NG, Ijlst L, et al. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J Inherit Metab Dis. 2011;34:159–164.
van Rijt WJ, Ferdinandusse S, Giannopoulos P, et al. Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency: a retrospective and laboratory cohort study. J Inherit Metab Dis. 2019;42:878–889.
Van Hove J, Jaeken J, Lagae L, Demaerel P, Bourdoux P, Niezen-Koning K. Multiple acyl-CoA dehydrogenase deficiency: acquired leukodystrophy treated with D,L-3-hydroxybutyrate. J Inherit Metab Dis. 2001;24 Suppl 1:72.
Grunewald S, Marek J, Deanfield J, Olpin S, Leonard JV. Five year follow up of D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD). J Inherit Metab Dis. 2008;31 Suppl 1:36.
Al-Hertani W, Mineyko A, Humphreys P, Chakraborty P, Geraghty MT. Glutaric aciduria type II presenting with lipid myopathy, progressive leukodystrophy; intrafamilial variation in two siblings. Presentation at: 58th Annual Meeting of The American Society of Human Genetics; 2008; Philadelphia, PA.
Marquardt T, Harms E. Ketone body therapy of severe multiple acyl-CoA dehydrogenase deficiency (MADD). Mol Genet Metab. 2009;98:57.
Dalkeith T, Dennison B, Wilcken B, et al. Difficulties in the dietetic management of patients with early childhood onset: multiple acyl co-A dehydrogenase deficiency (MADD). J Inherit Metab Dis. 2010;33 Suppl 1:173.
Dalkeith T, Ellaway C, Thompson S, et al. The use of 3-hydroxybutyrate in patients with fat oxidation disorders. J Inherit Metab Dis. 2013;36 Suppl 2:94.
Hale S, Hahn S, Merritt JLI. Novel therapies in treatment of presumptive multiple acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2011;102:288.
Van I, Landy C, Corriol O, De Lonlay P, Touaty G, Bourget P. Use of sodium D,L-3-hydroxybutyrate in metabolic diseases. Pharm World Sci. 2010;32:219.
Valayannopoulos V, Bajolle F, Arnoux JB, et al. Successful treatment of severe cardiomyopathy in glycogen storage disease type III with D,L-3-hydroxybutyrate, ketogenic and high-protein diet. Pediatr Res. 2011;70:638–641.
Francois B, Bachmann C, Schutgens RBH. Glucose metabolism in a child with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. J Inherit Metab Dis. 1981;4:163–164.
Bhattacharya K, Ho G, Dalkeith T, Dennison B, Thompson S, Christodoulou J. Improvement in severe HMG co-lyase deficiency with fat restriction and 3-hydroxybutyrate therapy. J Inherit Metab Dis. 2010;33 Suppl 1:62.
Bougneres PF, Ferre P, Chaussain JL, Job JC. Glucose metabolism in hyperinsulinemic infants: the effects of fasting and sodium DL-beta-hydroxybutyrate on glucose production and utilization rates. J Clin Endocrinol Metab. 1983;57:1054–1060.
Plecko B, Stoeckler-Ipsiroglu S, Schober E, et al. Oral beta-hydroxybutyrate supplementation in two patients with hyperinsulinemic hypoglycemia: monitoring of beta-hydroxybutyrate levels in blood and cerebrospinal fluid, and in the brain by in vivo magnetic resonance spectroscopy. Pediatr Res. 2002;52:301–306.
Bougneres PF, Lemmel C, Ferre P, Bier DM. Ketone body transport in the human neonate and infant. J Clin Invest. 1986;77:42–48.
Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15:412–426.
Stubbs BJ, Cox PJ, Evans RD, et al. On the metabolism of exogenous ketones in humans. Front Physiol. 2017;8:848.
Koper JW, Lopes-Cardozo M, Van Golde LM. Preferential utilization of ketone bodies for the synthesis of myelin cholesterol in vivo. Biochim Biophys Acta. 1981;666:411–417.
Newman JC, Verdin E. Beta-hydroxybutyrate: a signaling metabolite. Annu Rev Nutr. 2017;37:51–76.
Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25:262–284.
Wang SJ, Wu WM, Yang FL, Hsu GS, Huang CY. Vitamin B2 inhibits glutamate release from rat cerebrocortical nerve terminals. Neuroreport. 2008;19:1335–1338.
Marashly ET, Bohlega SA. Riboflavin has neuroprotective potential: focus on Parkinson's disease and migraine. Front Neurol. 2017;8:333.
O'Callaghan B, Bosch AM, Houlden H. An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency. J Inherit Metab Dis. 2019;42:598–607.
Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience. 2007;145:256–264.
Webber RJ, Edmond J. Utilization of L(+)-3-hydroxybutyrate, D(-)-3-hydroxybutyrate, acetoacetate, and glucose for respiration and lipid synthesis in the 18-day-old rat. J Biol Chem. 1977;252:5222–5226.
Broer S, Schneider HP, Broer A, Rahman B, Hamprecht B, Deitmer JW. Characterization of the monocarboxylate transporter 1 expressed in xenopus laevis oocytes by changes in cytosolic pH. Biochem J. 1998;333 Pt 1:167–174.
Reed WD, Ozand PT. Enzymes of L-(+)-3-hydroxybutyrate metabolism in the rat. Arch Biochem Biophys. 1980;205:94–103.
Swiatek KR, Dombrowski GJ Jr, Chao KL. The metabolism of D- and L-3-hydroxybutyrate in developing rat brain. Biochem Med. 1984;31:332–346.
Lincoln BC, Des Rosiers C, Brunengraber H. Metabolism of S-3-hydroxybutyrate in the perfused rat liver. Arch Biochem Biophys. 1987;259:149–156.
Desrochers S, David F, Garneau M, Jette M, Brunengraber H. Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats. Biochem J. 1992;285 Pt 2:647–653.
Wilkinson MD, Dumontier M, Aalbersberg IJ, et al. The FAIR guiding principles for scientific data management and stewardship. Sci Data. 2016;3:160018.
Simoens S. Pricing and reimbursement of orphan drugs: the need for more transparency. Orphanet J Rare Dis. 2011;6:42–1172-6-42.
Luzzatto L, Hyry HI, Schieppati A, et al. Outrageous prices of orphan drugs: a call for collaboration. Lancet. 2018;392:791–794.
Fair Medicine. https://www.fairmedicine.eu/en/. Accessed 27 March 2019.
