May 24, 2018
Years published: 1988, 1989, 1996, 1998, 2005, 2018
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.
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 as autosomal recessive genetic condition.
MCADD is usually diagnosed through newborn screening. An early diagnosis of this disorder is important in order 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 characterized by 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 the infant’s first experience with longer fasting would occur. Being previously healthy, a child with MCADD might suddenly experience severe symptoms at this point. A child could also have symptoms in response to a common and normally mild disease like a cold, since it can decrease appetite and increase the body’s metabolic requirements. 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 entered a low blood sugar state would never experience the symptoms of the disease.
In the event of a hypoglycemic crisis, the affected individual might 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 acquire such brain disorders as an inability to understand or use language (aphasia) and attention deficit disorder due to damage to the brain. Women with MCADD may experience 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.
In MCADD, the gene that codes for the MCAD enzyme (called ACADM) is altered, and too little functional MCAD enzyme is present in the body. This means that medium chained fats cannot be used effectively for energy once blood sugars drop. Since the body’s ability to replenish blood sugars 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 cause some oxidative damage.
MCADD is an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one 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 altered gene and have an affected child is 25% with each pregnancy. The risk to have 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. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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.
There are no other known disorders caused by abnormalities with the ACADM gene. However, MCADD is in a family of enzymes that are all important in the breakdown of fat for energy. For example, short-, long-, and very long- chain acyl-CoA dehydrogenases. It is possible of any one of these enzymes to be dysfunctional due to a defect in the gene that codes for it. Such a defect could lead to a disorder similar to MCADD, and collectively these are known as fatty acid oxidation disorders. Many such disorders involve symptoms that are similar to MCADD, but they tend to have their own specific symptoms that help to distinguish them. For example, in terms of MCADD-like symptoms, the addition of heart problems or lung issues would be more indicative of a deficiency in another type of enzyme, rather than MCADD. (For more information on such alternate disorders, choose “Acyl CoA Dehydrogenase” as your search term in the Rare Disease Database.)
MCADD is usually diagnosed through newborn screening by a blood test. The test looks for 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. Moreover, if an infant develops the classic symptoms or dies after being otherwise healthy, a diagnosis of MCADD would be considered. This means that vomiting, lethargy, and seizures after a period of fasting or a common illness in a previously healthy individual would suggest MCADD. Additionally, low blood sugar (hypoketonic hypoglycemia) in response to fasting or illness would be a more measurable sign of the disorder. It is also prudent to consider family genetic history when making a diagnosis. Some individuals may never develop symptoms of MCADD or be diagnosed.
Various biochemical analyses can be used to further confirm the diagnosis of MCADD and to monitor the condition. Genetic testing to identify two copies of the pathogenic version (allele) of the ACADM gene may be done. 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 cells’ ability to break down fat. Furthermore, urine analysis can be done to test for such metabolite markers 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 symptomatic state of the person, as an asymptomatic individual may not show elevated levels of the various indicator molecules in the body. The results of the testing and confirmed diagnosis would provide valuable information for the genetic counseling of the individual’s family and any potential reproductive partner.
The focus of treatment for MCADD is the prevention of the symptoms. It is important to maintain blood sugar levels by avoiding fasting for long periods. Frequent feeding is encouraged, and it is helpful to consume sources of complex carbohydrates at bedtime in order to supply a steadier source of glucose overnight. Treatment requirements and recommendations will vary depending upon the severity of the deficiency—how much functional MCAD is present in the body.
It is advisable to consult a genetic metabolic specialist and undergo 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 in order to ensure one 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 sugars. 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. The supplementation 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 not commonly prescribed in medical practice.
Gene therapy techniques—editing the DNA sequence itself—for treating MCADD have been showing promise in human cells grown in culture. However, these techniques have not yet been tested in people. One particular pathogenic variation of the ACADM gene could possibly be treated by a medication called Ravicti, and clinical trials are currently in progress.
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