MCADD - Description

Page Contents

• Other Names
• ICD-9
• Description
• Genetics
• Prognosis
• Prevalence
• Impact
• Pearls And Alerts

Other Names

MCAD, MCADD, medium chain acyl-CoA dehydrogenase deficiency, ACADM, MCADH

ICD-9

277.85, Disorder of fatty acid oxidation

The ICD-9-CM code 277.85 includes several disorders of fatty acid oxidation, of which MCADD is one. Also see MCADD ICD9 ( 55 KB) for codes for related complications.

Description

Medium chain acyl-CoA dehydrogenase deficiency (MCADD), a defect in the catabolism of medium-chain fatty acids, first described in the late 1970’s and early 1980’s, is considered to be the most prevalent of the inherited disorders of fatty acid oxidation. [Gregersen: 1976], [Gregersen: 1982], [Coates: 1992], [Saudubray: 1999] It most commonly affects individuals of northern European extraction. There can be marked phenotypic heterogeneity of the disorder, even within the same family.

During times of fasting, the body uses fat as a major source of energy. Fats are catabolized through a process called beta-oxidation. The overall reaction involves several different enzymes which break down long-chain fats to medium-chain fats, medium-chain fats to short-chain fats, and short-chain fats to ketone bodies and acetyl-CoA. The former are used directly for energy and the latter enter the Kreb cycle to generate ATP and reducing equivalents. Medium-chain fatty acids are broken down through a cycle using the enzyme medium chain acyl-CoA dehydrogenase. Decreased or absent activity of this enzyme results in MCADD.

Individuals with MCADD can present at any age, although acute decompensation is generally thought to be more common within the first two years of life, a period of rapid growth and high energy requirements. There is no "typical" presentation, although prolonged fasting of any type can precipitate an event. Intercurrent illness, which results in increased energy needs, is usually present. With prolonged fasting, greater than 12 to 14 hours, lipolysis and hepatic fatty acid oxidation become activated. Plasma levels of free fatty acids rise but ketones remain inappropriately low. Patients then become hypoglycemic with severe symptoms of lethargy, nausea, and vomiting. Hepatomegaly is sometimes noted. Even if children with MCADD present with glucose levels within the normal range, they can decompensate quickly, as glucose is catabolized instead of fats. Without rapid intervention with IV glucose, patients can rapidly progress to coma within 1 to 2 hours. Seizures may occur and, without appropriate treatment, sudden death from acute cardiorespiratory arrest may follow. Permanent brain damage after successful resuscitation has been described. Up to 25% of undiagnosed MCADD sufferers do not survive the first attack. [Iafolla: 1994], [Stanley: 2006] Although cardiac and skeletal muscle involvement probably figure prominently in sudden death, chronic involvement of these organ systems is not seen.

If treatment for MCADD is initiated prior to the first decompensation, affected individuals generally do well, as fasting tolerance improves with age. Treatment revolves around fasting avoidance and prompt treatment of acute episodes with IV glucose. Chronic treatment strategies include frequent meals, use of cornstarch, and fat restriction. [Solis: 2002] The use of carnitine is somewhat controversial but is definitely indicated when there is a secondary carnitine deficiency. [Walter: 2003] Recent studies have indicated that carnitine may help to improve exercise tolerance in affected adolescents and adults. [Lee: 2005]

Genetics

MCAD deficiency is associated with mutations in the ACADM gene. MCADD is inherited in an autosomal recessive fashion. Over 50% of affected individuals are homozygous for the common c.985A>G (K304E) mutation. [Carpenter: 2001], [Zytkovicz: 2001], [Maier: 2005] This is less than the previously quoted 80-90% and is related to population studies performed since the advent of more universal expanded newborn screening. The allele frequency for this mutation, considered to be a “severe” mutation, is about 71%. Severity of a mutation is defined by its association with an adverse clinical phenotype and more pronounced elevations of biochemical markers. [Waddell: 2006] The carrier frequency for the K304E mutation is between 1:40 and 1:100. [Tanaka: 1997] More pronounced elevations of biochemical markers are seen with homozygosity for this mutation. Rarer mutations tend to have a less severe biochemical phenotype and compound heterozygosity is the rule. [Andresen: 1997] [Maier: 2005], [Tajima: 2005] Severity is difficult to ascertain as individuals homozygous for the C.985A>G mutation may be asymptomatic. Those with rarer mutations should probably be considered at risk for clinical symptoms.

If a child is identified as having MCAD deficiency, then it is assumed that both parents are carriers. Testing of asymptomatic siblings is recommended, although offering carrier testing or biochemical testing for parents is recommended by some because "asymptomatic" parents who are homozygous for ACADM gene mutations have been described. [Duran: 1986], [Kelly: 1990], [Andresen: 1997], [Bodman: 2001] Parents are counseled that there is, with each pregnancy, a 25% chance of having an affected baby, a 50% chance of having a baby who is a carrier, and a 25% chance of having a baby who is neither affected nor a carrier. Unaffected siblings have a 2/3 chance of being carriers for the disorder. All of the children of an affected individual will be, at the least, carriers. The probability of having an affected child depends on the carrier status of the spouse. Genetic counseling is recommended for affected individuals when they reach reproductive age. Prenatal diagnosis by either molecular genetic or biochemical testing is possible. However, this must be done by either amniocentesis or chorionic villus sampling (CVS). It is felt that there is no advantage to prenatal testing if prompt postnatal testing by measurement of plasma acylcarnitines and urine acylglycines is obtained in at-risk pregnancies. [Matern: 2005]

Prognosis

Prognosis is generally good if the disorder is identified early, treatment is implemented, and prompt interventions during times of intercurrent illness are implemented. However, in one study, chronic muscular weakness was described in about 18% of those with recurrent episodes of metabolic decompensation. [Iafolla: 1994] Other sequelae after acute decompensation have also been described, including loss of developmental milestones, aphasia, and attention deficit disorder, which are probably associated with brain injury during the event. All patients should have an emergency treatment letter which can be presented at the Emergency Department in case of illness. A medical alert bracelet or necklace can be worn to alert providers that they have MCADD but is not a substitution for the emergency letter.

Prevalence

MCADD is considered to be the most prevalent inherited inborn error of fatty acid oxidation in those with Caucasian, northern European ancestry. Although there is some regional variability in prevalence, most specifically in Europe, in the United States, the overall incidence is about 1:16,000 live births. [Chace: 2002] A recent study [Maier: 2005] suggests that in the United States, the overall incidence might be as high as 1 in 8500 births. It has been reported that the incidence in Hispanic, African-American, Native American and Asian populations is lower. Internationally, the average incidence is reported to be about 1 in 14,600 births. [Rhead: 2006]

Impact

MCADD is a common disorder and prior to its identification and to expanded newborn screening, symptomatic individuals often died at presentation and were given either the diagnosis of Sudden Infant Death Syndrome or Reye Syndrome. See Reye syndrome. Prior to identification by expanded newborn screening, up to 25% of undiagnosed patients may have died during the first decompensation. [Stanley: 2006] Those who survive an acute episode of decompensation may develop mild to severe sequelae. Iafolla et al. reported on 120 patients with follow-up of 97 surviving patients. They found that developmental and behavioral problems, cerebral palsy, chronic muscle weakness and failure to thrive were associated morbidities. [Iafolla: 1994] Derks et al. in a natural history study in the Netherlands, found that the most common morbidities included obesity, fatigue, muscle pain, and reduced exercise tolerance. More severe sequlae, found in individuals who had survived an acute decompensation included severe psychomotor developmental delays, behavioral problems, hemiplegia, and speech delays. [Derks: 2006]

Pearls And Alerts

MCADD Module Authors

The authors listed above are responsible for the overall MCADD Module. Authors contributing to individual pages in the module are listed on those pages.

Funding/Support

This module was developed in partnership with the Heartland Regional Genetics and Newborn Screening Collaborative and was funded in part by a Health Resources Services Administration (HRSA) cooperative agreement (U22MC03962).

Page Bibliography

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