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.