# 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.