Handbook of 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 Typical presentation includes hypoketotic hypoglycemia, vomiting, lethargy, seizures, and coma precipitated by prolonged fasting or common illness. 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 Notes The informaiton in this outline was last updated in Feb 2003.