[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
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
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.
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.
