Genetic counseling: Medium-chain acyl-coenzyme A dehydrogenase Deficiency

Medium-chain acyl-coenzyme A dehydrogenase Deficiency

Overview

 * Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is an enzyme involved in mitochondrial fatty acid b-oxidation (FAO). Fatty acid oxidation provides energy for peripheral tissues when glycogen is depleted through hepatic ketogenesis. A defect in the MCAD enzyme causes accumulation of medium-chain fatty acids, metabolized to glycine- and carnitine-esters and dicarboxylic acids, and hypoketonia.

Genetics

 * MCAD deficiency is caused by a mutation in the ACADM gene
 * Chromosomal locus 1p31
 * 31 known disease causing mutations
 * 1 common mutation, K304E, accounts for 76% of alleles

Incidence

 * Common in Caucasians, especially with Northern European ancestry
 * Disease incidence 1:4,900 to 1:17,000
 * Carrier frequency 1:40 to 1:100
 * Less common among Hispanics
 * Rare in African-American, and Native-American populations

Diagnosis

 * Metabolic testing
 * Symptomatic individuals should have plasma acylcarnitines, plasma fatty acids, urine organic acids, and urine acylclycines analyzed and interpreted.
 * Enzymatic testing
 * MCAD enzyme activity should be measured in fibroblasts or other tissues to confirm diagnosis
 * Molecular testing
 * Molecular genetic testing by mutation analysis (for K204E) or sequence analysis of the ACADM gene can confirm diagnosis
 * Newborn screening
 * MCAD is part of the newborn screening panel in 9 states (IA, ME, MA, NC, OH, SC, SD, WI, WY).
 * Prenatal testing
 * Enzymatic or molecular testing can be performed prenatally; however, there is limited benefit to prenatal vs. newborn testing.
 * Carrier testing
 * Only molecular testing can determine carrier status.

Clinical Features
seizures, and coma precipitated by prolonged fasting or common illness.
 * Typical presentation includes hypoketotic hypoglycemia, vomiting, lethargy,
 * Hepatomegaly and acute liver disease may also be present.
 * Sudden, unexplained death may be first symptom (18%).

Natural History

 * Typically normal at birth following uneventful pregnancy
 * Most present with symptoms between 3 and 24 months in response to prolonged fasting or infection
 * Initial presentation in adulthood also possible
 * Affected individuals may lose developmental milestones or acquire aphasia or ADD as a result of acute metabolic event
 * Individuals identified as newborns typically develop normally under treatment

Inheritance

 * MCAD deficiency is an autosomal recessive disorder.

Testing

 * Enzymatic and Molecular testing can confirm diagnosis.
 * Both mutation and sequence analysis are available on a clinical basis.

Management & Treatment

 * MCAD is a highly treatable condition- good prognosis when managed
 * Avoidance of fasting is key-
 * Infants should be fed frequently
 * Toddlers should be given 2 g/kg uncooked cornstarch before bed
 * Low-fat diet and carnitine supplementation may be beneficial

Differential Diagnosis

 * Other disorders of acyl-CoA dehydrogenase (ACAD) gene family
 * Other disorders of fatty acid b-oxidation

Psychosocial Issues

 * Parental guilt over allowing too long of time between feedings which triggered onset of symptoms
 * Parental guilt over passing gene to child
 * When presenting symptom is sudden death, loss of seemingly healthy child can be devastating
 * Parent or sibling may be identified as a homozygote during carrier testing
 * Family planning- risk for future offspring/siblings of affected individual

Patient Resources

 * FOD (Fatty Oxidation Disorder) Family Support Group
 * 805 Montrose Drive
 * Greensboro, NC 27410
 * Phone: (336) 547-8682
 * Email: deb@fodsupport.org
 * Web: www.fodsupport.org


 * Organic Acidemia Association
 * 13210 35th Avenue North
 * Plymouth, MN 55441
 * Phone; (763) 556-1797
 * Email: OAANews@aol.com
 * Web: www.oaanews.org


 * United Mitochondrial Disease Foundation
 * 8085 Saltsburg Road, Suite 201
 * Pittsburgh, PA 15239
 * Phone: (412) 793-8077
 * Email: info@umdf.org
 * Web: www.umdf.org