We're celebrating
40 years!
Last updated:
11/17/2023
Years published: 1988, 1989, 1996, 1998, 2005, 2018, 2023
NORD gratefully acknowledges Edward O’Neill, NORD Editorial Intern from the University of Connecticut, and Paldeep S. Atwal, MD, FACMG, FRCP(UK), FRCP(Glasg), Clinical & Biochemical Geneticist, Director, The Atwal Clinic: Genomic & Personalized Medicine, for assistance in the preparation of this report.
Summary
Medium chain acyl-coA dehydrogenase deficiency (MCADD) is a genetic disorder caused by a lower-than-normal level of the medium chain acyl-coenzyme A dehydrogenase enzyme. This enzyme is involved in breaking down fat stores in the body to be used for energy. Symptoms of this disorder generally develop between 1 and 24 months of age, although they can sometimes first appear in adulthood. Individuals with MCADD experience symptoms of metabolic crisis due to low blood sugar (hypoglycemia) after periods of prolonged fasting or in response to a common illness. These may include weakness, vomiting and seizures. Rarely, coma or sudden death may occur. MCADD is inherited in an autosomal recessive pattern.
Introduction
MCADD is usually diagnosed through newborn screening. An early diagnosis of this disorder is important to be able to prevent symptoms from occurring. Treatment involves avoiding long periods of fasting and restricting fat intake. MCADD is a known cause of sudden infant death syndrome (SIDS).
Symptoms of MCADD are metabolic crisis brought about by low blood sugar (hypoglycemia). Because infants are typically weaned from nighttime feedings sometime between 3 and 24 months of age, this is when an infant’s first experience with longer fasting occurs. A previously healthy child with MCADD might suddenly experience severe symptoms at this point. A child could also have symptoms in response to a mild disease like a cold since this can decrease appetite. Alternatively, an individual with a milder form of MCADD might first develop symptoms in adulthood in response to an extreme metabolic stress such as surgery or severe illness. A person with MCADD who never experiences low blood sugar would never develop symptoms of the disease.
During a hypoglycemic crisis, the affected individual could experience tiredness/weakness (lethargy), vomiting (emesis), seizures, coma or sudden death (in 18% of first crises). Additional signs of the disease could include an enlarged liver (hepatomegaly), low blood sugar due to inefficient breakdown of fats (hypoketotic hypoglycemia) and elevated levels of certain substances in the blood or urine (e.g., acylglycines).
Secondary symptoms of MCADD that can develop after a person has experienced one or multiple metabolic crises are caused by damage to body tissues due to the hypoglycemic conditions during the events. These can include lasting muscle weakness and pain as well as reduced tolerance to exercise. Affected individuals may develop an inability to understand or use language (aphasia) and attention deficit disorder due to damage to the brain. Females with MCADD may have pregnancy complications such as HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).
MCADD is a genetic disorder of mitochondrial fatty acid beta-oxidation. This means that fats in the body cannot efficiently be broken down and used for energy. The body relies on glucose (a sugar) for energy, and during times when the amount of glucose in the blood is too low, the body can break down fat stores and convert them to glucose. Enzymes called acyl-coenzyme A dehydrogenases are necessary for one of the steps in the biochemical pathway by which fat is broken down into glucose. Medium chain acyl-coenzyme A dehydrogenase (MCAD) is one of these enzymes.
MCADD is caused by changes (variants) in the ACADM gene that provides instructions for production of the MCAD enzyme. Disease-causing gene variants result in less functional MCAD enzyme in the body. Therefore, medium chained fats cannot be used effectively for energy once blood sugar drops. Since the body’s ability to replenish blood sugar is impaired, hypoglycemic symptoms can develop. Hypoglycemia is the direct cause of the symptoms of MCADD. However, precursor molecules and metabolites that become “stuck” in the biochemical pathway of fat breakdown due to deficient MCAD can build up in the body and also cause health problems.
MCADD is an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
In the general population, MCADD occurs in approximately 1 in 50,000 individuals. The prevalence of MCADD in people of northern European descent has been estimated to be in the range of 1 in 6,400 to 1 in 46,000 individuals. Gypsies of Portugal and Native Americans of California also have a higher-than-average prevalence.
MCADD is usually diagnosed after newborn screening by a blood test. The test measures the amount of chemicals known as acylcarnitines. High levels of a type of acylcarnitine called octanoylcarnitine are characteristic of MCADD, but this is not specific to this disorder. Follow-up testing is needed to confirm the diagnosis. If an infant develops the classic symptoms of MCADD or dies after being otherwise healthy, a diagnosis of MCADD should be considered. This means that vomiting, lethargy and seizures after a period of fasting or a common illness in a previously healthy person would suggest MCADD. Additionally, low blood sugar (hypoketonic hypoglycemia) in response to fasting or illness would be a more measurable sign of the disorder. Genetic testing to identify two disease-causing variants in the ACADM gene can confirm the diagnosis. Genetic counseling is recommended for affected individuals.
Some people with MCADD never develop symptoms and are not diagnosed.
Clinical Testing/Workup
Various biochemical tests can be used to monitor the condition. It is possible to extract cells from the body, grow them in a culture dish and run tests to directly assess the activity of MCAD or the ability of cells to break down fat. Urine tests can be done to test for metabolite markers such as medium chain dicarboxylic acids or organic acids and acylglycines. Blood plasma tests to measure acylcarnitines like octanoylcarnitines (C8) may be done. In all cases, interpretation of these tests should take into consideration the person’s symptoms, because an asymptomatic individual may not show elevated levels of the various indicator molecules in the body.
Treatments
The focus of treatment for MCADD is the prevention of symptoms. It is important for patients to maintain blood sugar levels by avoiding fasting for long periods. Frequent feeding is encouraged, and it is helpful for patients to consume foods with complex carbohydrates at bedtime to have a steadier source of glucose overnight. Treatment requirements and recommendations will vary depending upon the severity of the deficiency and how much functional MCAD is present in the body.
It is advisable for patients to consult a genetic metabolic specialist for routine surveillance of the condition. Because of the higher feeding requirements and lower tolerance of exercise associated with MCADD, it is also helpful to talk to a dietician to ensure a patient is consuming a healthful balanced diet, although significant dietary modification is generally not required. In general, feeding infants with formulas high in medium chain fatty acids is inadvisable. In adults, excessive alcohol consumption can lead to a metabolic crisis. In any case, a metabolic crisis can be treated or reverted by consuming a glucose supplement or foods high in sugar. Glucose can be administered directly to the blood (IV) as well.
A few suggestions for treatment of MCADD have been made which are controversial or under-studied. One is the recommendation of a low-fat diet, and another is the recommendation of supplementation with L-carnitine. This supplement could help with the secondary carnitine deficiency that sometimes arises due to MCADD and could help with elimination of toxic metabolites in the body. It could also help improve exercise tolerance. However, studies have not yet been conclusive on this issue, and it is not commonly prescribed in medical practice.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Derks TGJ, Touw CML, Ribas GS, et al. Experimental evidence for protein oxidative damage and altered antioxidant defense in patients with medium-chain acyl-coA dehydrogenase deficiency. Journal of Inherited Metabolic Disease. 2014;37(5):783–789. doi:10.1007/s10545-014-9700-0.
Koster K-L, Sturm M, Herebian D, Smits SHJ, Spiekerkoetter U. Functional studies of 18 heterologously expressed medium-chain acyl-coA dehydrogenase (MCAD) variants. Journal of Inherited Metabolic Disease. 2014;37(6):917–928. doi:10.1007/s10545-014-9732-5.
Rocha H, Castiñeiras D, Delgado C, Egea J, Yahyaoui R, González Y, Conde M, González I, Rueda I, Rello L, Vilarinho L, Cocho J. Birth Prevalence of Fatty Acid β-Oxidation Disorders in Iberia. JIMD Rep. 2014;16:89–94.
Dessein A-F, Fontaine M, Andresen BS, et al. A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: A case report. Orphanet Journal of Rare Diseases. 2010;5(1):26. doi:10.1186/1750-1172-5-26.
Lang TF. Adult presentations of medium-chain acyl-coA dehydrogenase deficiency (MCADD). Journal of Inherited Metabolic Disease. 2009;32(6):675–683. doi:10.1007/s10545-009-1202-0.
Derks TGJ, van Spronsen FJ, Rake JP, van der Hilst CS, Span MM, Smit GPA. Safe and unsafe duration of fasting for children with MCAD deficiency. European Journal of Pediatrics. 2006;166(1):5–11. doi:10.1007/s00431-006-0186-0.
Schowalter DB, Matern D, Vockley J. In vitro correction of medium chain acyl CoA dehydrogenase deficiency with a recombinant adenoviral vector. Molecular Genetics and Metabolism. 2005;85(2):88–95. doi:10.1016/j.ymgme.2005.02.006.
Kurtz DM, Rinaldo P, Rhead WJ, et al. Targeted disruption of mouse long-chain acyl-coA dehydrogenase gene reveals crucial roles for fatty acid oxidation. Proceedings of the National Academy of Sciences. 1998;95(26):15592–15597. doi:10.1073/pnas.95.26.15592.
Gregersen N, Winter V, Curtis D, et al. Medium-chain Acyl-CoA Dehydrogenase (MCAD) deficiency: The prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe. Human Heredity. 1993;43(6):342–350. doi:10.1159/000154157.
Gregersen N, Andresen B, Bross P, et al. Molecular characterization of medium-chain acyl-coA dehydrogenase (MCAD) deficiency: Identification of a lys329 to glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. Coli. Human Genetics. 1991;86(6). doi:10.1007/bf00201539.
Treem WR, Stanley CA, Goodman SI. Medium-chain acyl-coA dehydrogenase deficiency: Metabolic effects and therapeutic efficacy of long-terml-carnitine supplementation. Journal of Inherited Metabolic Disease. 1989;12(2):112–119. doi:10.1007/bf01800712.
Gregersen N, Kelvraa S, Rasmussen K, et al. General (medium-chain) acyl-coA dehydrogenase deficiency (non-ketotic dicarboxylic aciduria): Quantitative urinary excretion pattern of 23 biologically significant organic acids in three cases. Clinica Chimica Acta. 1983;132(2):181–191. doi:10.1016/0009-8981(83)90246-2.
INTERNET
Merritt JL 2nd, Chang IJ. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2000 Apr 20 [Updated 2019 Jun 27]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1424/ Accessed Nov 15, 2023.
Medium-chain acyl-CoA dehydrogenase deficiency.Genetics Home Reference. Reviewed: Feb. 2015. https://ghr.nlm.nih.gov/condition/medium-chain-acyl-coa-dehydrogenase-deficiency# Accessed Nov 15, 2023.
Acyl-Co-A Dehydrogenase, Medium-chain; ACADM. OMIM. Last edit date: 08/12/2021. https://www.omim.org/entry/607008?search=mcadd&highlight=mcadd Accessed Nov 15, 2023.
MCADD. Medical Home Portal. Jan 2023. https://www.medicalhomeportal.org/diagnoses-and-conditions/mcadd#Descriptiontagless Accessed Nov 15, 2023.
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/