Medium-chain acyl-coenzyme A dehydrogenase deficiency

MCADD is caused by mutations in the ACADM gene. This gene gives the body instructions for making an enzyme called medium-chain acyl-CoA dehydrogenase, needed to break down fats called medium-chain fatty acids. These fatty acids are found in foods and the body's tissues, and are an important source of energy for the heart, muscles, liver, and other tissues. Mutations in this gene lead to low levels of the enzyme, which means that medium-chain fatty acids are not broken down properly. They cannot be converted to energy, leading to the symptoms of MCADD.

The false positive rate for medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency varies between screening programs because of differences in analysis of acylcarnitine (a type of fatty acid). Programs that screen for MCAD deficiency but not other fatty acid oxidation disorders often limit their analysis to octanoylcarnitine, the primary screening marker for MCAD deficiency. However, octanoylcarnitine is not specific for MCAD deficiency and is expected to be elevated in several other disorders including glutaric acidemia type II. Consideration of other potential disorders in the differential diagnosis should minimize the false positive rate.

ACADM is the only gene known to be associated with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency. The biochemical diagnosis of MCAD deficiency can be confirmed by measurement of MCAD enzyme activity in fibroblasts or other tissues and/or by genetic testing to detect mutations in the ACADM gene.

For more information on genetic testing for MCAD deficiency, we would recommend you consult with a genetics professional.

A diagnosis of MCADD requires an evaluation of a person's symptoms as well as the interpretation of several tests. Initial testing may include:

• Plasma acylcarnitine
• Urine organic acid
• Urine acylglycine

Further testing to confirm the diagnosis may include molecular genetic testing of the ACADM gene or biochemical genetic testing.

MCADD is included in many newborn screening programs, so a newborn with MCADD who does not yet exhibit symptoms may be diagnosed early. If a newborn screening result for MCADD is not in the normal range ("positive"), additional testing can then be ordered.

Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is inherited in an autosomal recessive manner. This means that to have MCADD, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have this condition.

People with MCADD inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% chance to have the condition
• 50% chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not a carrier

Medium chain acyl-CoA dehydrogenase deficiency is a fatty acid oxidation disorder in which people have problems breaking down fat into energy for the body. It is caused by an enzyme that does not work properly. MCADD occurs when an enzyme, called medium chain acyl-CoA dehydrogenase, is either missing or not working properly. This enzyme’s job is to break down certain fats in food into energy. It also breaks down fat already stored in the body. Energy from fat keeps us going whenever our bodies run low of their main source of energy, a type of sugar called glucose. Our bodies rely on fat when we don’t eat for a stretch of time – like when we miss a meal or when we sleep.

When the medium chain acyl-CoA dehydrogenase enzyme is missing or not working well, the body cannot use certain types of fat for energy, and must rely solely on glucose. Although glucose is a good source of energy, there is a limited amount available. Once the glucose has been used up, the body tries to use fat without success. This leads to low blood sugar, called hypoglycemia, and to the build up of harmful substances in the blood, which can lead to metabolic crises. Symptoms often happen after having nothing to eat for more than a few hours. Hypoglycemia can occur, with or without other symptoms of metabolic crisis, just by going too long without food. Hypoglycemia can cause a person to feel weak, shaky, or dizzy, and to have clammy, cold skin. If not treated, hypoglycemia can lead to coma and even death.

The United Mitochondrial Disease Foundation lists alcohol as a substance that people with mitochondrial disease should avoid, because alcohol has been known to hasten the progression of some mitochondrial disorders. In 2009, Lang reviewed several cases of MCAD deficiency diagnosed in adulthood. Many of these cases had alcohol consumption as a precipitating factor for an episode of metabolic crisis. Alcohol inhibits the breakdown (oxidation) of fatty acids in the liver, which can lead to the toxic accumulation of fatty acids within cells. In the cases reviewed by Lang, the consumption of alcohol also led to vomiting, which may have caused symptoms due to a period of fasting.

To learn more about the dietary guidelines for MCAD deficiency, we recommend that you contact the following organizations:

United Mitochondrial Disease Foundation
8085 Saltsburg Road, Suite 201
Pittsburg PA 15239
Toll-free: 1-888-317-UMDF
Telephone: 412-793-8077
Fax: 412-793-6477
E-mail: info@umdf.org
Web site: http://www.umdf.org

FOD (Fatty Oxidation Disorder) Family Support Group
PO Box 54
Okemos, MI 48805-0054
Telephone: 517-381-1940
Fax: 866-290-5206
E-mail: deb@fodsupport.org
Web site: http://www.fodsupport.org

The risk to other family members depends on the status of the individuals most closely related to the affected individual. At conception, the siblings of an affected individual have a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. The risk could be 50% if one of the parents is also affected. Because asymptomatic parents and siblings may have MCAD deficiency, biochemical evaluation and/or molecular genetic testing should be offered to both parents and all siblings.

Your family may benefit from consulting with a genetics professional who can help to determine who may be at risk for medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and who warrants further testing.

Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is an inherited metabolic disorder that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). People with MCADD do not have enough of an enzyme needed to metabolize a group of fats called medium-chain fatty acids. Signs and symptoms usually begin by early childhood and may include vomiting, lack of energy, and low blood sugar (hypoglycemia). Symptoms can be triggered by periods of fasting or by illnesses.

MCADD is caused by mutations in the ACADM gene and inheritance is autosomal recessive. Treatment includes strict avoidance of fasting and avoidance of medium chain triglycerides in the diet. If not treated, people with MCADD are at risk of serious complications including sudden death.

Infants and young children with MCADD need to eat frequently to prevent hypoglycemia or a metabolic crisis. In general, it is often suggested that these infants be fed every four to six hours. Some babies need to eat even more frequently than this. It is also important that infants be fed during the night. They may need to be woken up to eat if they do not wake up on their own. Your metabolic doctor and dietician will give you an appropriate feeding plan for your infant.

A low fat, high carbohydrate food plan is often recommended. Carbohydrates give the body many types of sugar that can be used as energy. For children needing this treatment, most food in the diet should be carbohydrates (bread, pasta, fruit, vegetables, etc.) and protein (lean meat and low-fat dairy foods). Your dietician can create a food plan with the correct type and amount of fat your child needs. Any diet changes should be made under the guidance of an experienced dietician.

We are not aware of an association between white stool and MCADD, or of reports of people with MCADD having white stools.

Stool color is generally influenced by what a person eats, as well as by the amount of bile in the stool. Bile is a yellow-green fluid produced by the liver that digests fats. As bile travels through the gastrointestinal tract, it becomes chemically altered by enzymes, which normally change the color from green to brown.

Light-colored, white, or clay-colored stool could indicate a lack of bile in the stool. This is sometimes due to having a bile duct obstruction, or another problem with how the liver is functioning. Certain medications can also cause light-colored stools such as large doses of bismuth subsalicylate (Kaopectate, Pepto-Bismol) and other anti-diarrheal drugs.

Any sudden, or gradual, persistent changes in stool color should be evaluated by a medical professional to make sure the changes are not caused by an underlying medical problem.

Newborn screening tests look for serious developmental, genetic, and metabolic disorders so that important action can be taken during the critical time before symptoms develop. Screening tests do not diagnose illnesses. They identify which babies need additional testing to confirm or rule out illnesses. Good screening tests have a low false-negative rate (if the test is normal, the child should be healthy), but may have a high false-positive rate (as many affected children as possible should test positive, even if this means many healthy children also test positive).

An abnormal result on a newborn screen means that the child should have additional testing to confirm or rule out the condition. If a disorder is diagnosed on follow-up testing, appropriate treatment can be started right away, before symptoms appear.

Genetic Metabolic Dietitians International (GMDI) has developed nutrition guidelines for this condition.

Wang, et al. Is the G985A Allelic Variant of Medium-Chain Acyl-CoA Dehydrogenase a Risk Factor for Sudden Infant Death Syndrome? A Pooled Analysis. Pediatrics. 2000;105:1175-1176.