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. More recent reports suggest that the adolescent and adult presentation might be more common that previously thought. [Schatz: 2010] [Lang: 2009] 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 infantile MCADD sufferers do not survive the first attack. [Iafolla: 1994] [Stanley: 2006] The mortality rate for adults is reported to be much higher with a published 50% mortality rate in adults with acutely presenting patients and an overall mortality rate of 29%. [Lang: 2009] Although cardiac and skeletal muscle involvement probably figure prominently in sudden death, chronic involvement of these organ systems is not usually seen. There has been one recent report of a 2 month old presenting with a dilated cardiomyopathy whose twin died several days after birth. The surviving infant was diagnosed with MCADD and started on carnitine, with improvement in cardiac function. Thus, it may be that MCADD can result in chronic cardiac involvement, although cause and effect have not been clearly established in this patient. [Marcì: 2009]

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] It may be prudent to counsel adolescent and adult patients to avoid prolonged fasting and alcohol consumption as there are reports of adults presenting with life-threatening symptoms (encephalopathy, rhabdomyolysis, cardiac failure) after postsurgical fasting, intercurrent illness, strenuous exercise or binge drinking. [Lang: 2009]

Sudden death continues to be reported, despite the advent and acceptance of newborn screening. Yusupov et al published a report describing four patients ranging in age from seven months to 3-1/2 years, preceeded by vomiting and poor oral intake, even with minor illness. There may be some correlation between initial analyte levels, particularly C8,and risk of sudden death, [Yusupov: 2010] although others report that neither genotype nor analyte level have been found to protect against a poor outcome. [Arnold: 2010] These findings tend to emphasize continued adherence to emergency letter protocols, especially in those with initial C8 levels greater than 1.7 umol/L or C8/C10 ratios greater than 4.3 whatever the patient’s age. [Smith: 2010]

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] although this interpretation has recently been challenged as several variants in trans with the c.985A>G have been described with biochemical phenotypes consistent with severe MCADD. [Smith: 2010] 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, regardless of age, is recommended, [Leonard: 2009] 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. Overall, the risk for cognitive impairment or other significant morbidities is very low in this disorder since the introduction of newborn screening. [Wilcken: 2009] [Wilcken: 2010] 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] Thus, MCADD is now recognized as being almost as prevalent as phenylketonuria, the first disorder for which newborn screening was implemented. [Lindner: 2010]

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] The inclusion of MCADD screening has had a positive effect in reducing the impact of the disorder. An Australian study demonstrated a 74% reduction in significant metabolic decompensations and/or death since the implementation of screening. [Wilcken: 2009]

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

Andresen BS, Bross P, Udvari S, Kirk J, Gray G, Kmoch S, Chamoles N, Knudsen I, Winter V, Wilcken B, Yokota I, Hart K, Packman S, Harpey JP, Saudubray JM, Hale DE, Bolund L, Kølvraa S, Gregersen N.
The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?.
Hum Mol Genet. 1997;6(5):695-707. PubMed abstract

Arnold GL, Saavedra-Matiz CA, Galvin-Parton PA, Erbe R, Devincentis E, Kronn D, Mofidi S, Wasserstein M, Pellegrino JE, Levy PA, Adams DJ, Nichols M, Caggana M.
Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.
Mol Genet Metab. 2010;99(3):263-8. PubMed abstract

Bodman M, Smith D, Nyhan WL, Naviaux RK.
Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father.
Arch Neurol. 2001;58(5):811-4. PubMed abstract

Carpenter K, Wiley V, Sim KG, Heath D, Wilcken B.
Evaluation of newborn screening for medium chain acyl-CoA dehydrogenase deficiency in 275 000 babies.
Arch Dis Child Fetal Neonatal Ed. 2001;85(2):F105-9. PubMed abstract / Full Text

Chace DH, Kalas TA, Naylor EW.
The application of tandem mass spectrometry to neonatal screening for inherited disorders of intermediary metabolism.
Annu Rev Genomics Hum Genet. 2002;3:17-45. PubMed abstract

Coates PM, Stanley CA.
Inherited disorders of mitochondrial fatty acid oxidation.
Prog Liver Dis. 1992;10:123-38. PubMed abstract

Derks TG, Reijngoud DJ, Waterham HR, Gerver WJ, van den Berg MP, Sauer PJ, Smit GP.
The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome.
J Pediatr. 2006;148(5):665-670. PubMed abstract

Duran M, Hofkamp M, Rhead WJ, Saudubray JM, Wadman SK.
Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency.
Pediatrics. 1986;78(6):1052-7. PubMed abstract

Gregersen N, Lauritzen R, Rasmussen K.
Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria.
Clin Chim Acta. 1976;70(3):417-25. PubMed abstract

Gregersen N, Wintzensen H, Christensen SK, Christensen MF, Brandt NJ, Rasmussen K.
C6-C10-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects.
Pediatr Res. 1982;16(10):861-8. PubMed abstract

Iafolla AK, Thompson RJ Jr, Roe CR.
Medium-chain acyl-coenzyme A dehydrogenase deficiency: clinical course in 120 affected children.
J Pediatr. 1994;124(3):409-15. PubMed abstract

Kelly DP, Whelan AJ, Ogden ML, Alpers R, Zhang ZF, Bellus G, Gregersen N, Dorland L, Strauss AW.
Molecular characterization of inherited medium-chain acyl-CoA dehydrogenase deficiency.
Proc Natl Acad Sci U S A. 1990;87(23):9236-40. PubMed abstract / Full Text

Lang TF.
Adult presentations of medium-chain acyl-CoA dehydrogenase deficiency (MCADD).
J Inherit Metab Dis. 2009;32(6):675-83. PubMed abstract

Lee PJ, Harrison EL, Jones MG, Jones S, Leonard JV, Chalmers RA.
L-carnitine and exercise tolerance in medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency: a pilot study.
J Inherit Metab Dis. 2005;28(2):141-52. PubMed abstract

Leonard JV, Dezateux C.
Newborn screening for medium chain acyl CoA dehydrogenase deficiency.
Arch Dis Child. 2009;94(3):235-8. PubMed abstract

Lindner M, Hoffmann GF, Matern D.
Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting.
J Inherit Metab Dis. 2010;. PubMed abstract

Maier EM, Liebl B, Röschinger W, Nennstiel-Ratzel U, Fingerhut R, Olgemöller B, Busch U, Krone N, v Kries R, Roscher AA.
Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency.
Hum Mutat. 2005;25(5):443-52. PubMed abstract

Marcì M, Ajovalasit P.
Medium-Chain Acyl-CoA Dehydrogenase Deficiency in an Infant with Dilated Cardiomyopathy.
Cardiol Res Pract. 2009;2009:281389. PubMed abstract / Full Text

Matern D, Rinaldo P .
Medium-chain acyl-coenzyme A dehydrogenase deficiency.
NCBI/NIH; (2005) http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mcad.

Rhead WJ.
Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective.
J Inherit Metab Dis. 2006;29(2-3):370-7. PubMed abstract

Saudubray JM, Martin D, de Lonlay P, Touati G, Poggi-Travert F, Bonnet D, Jouvet P, Boutron M, Slama A, Vianey-Saban C, Bonnefont JP, Rabier D, Kamoun P, Brivet M.
Recognition and management of fatty acid oxidation defects: a series of 107 patients.
J Inherit Metab Dis. 1999;22(4):488-502. PubMed abstract

Schatz UA, Ensenauer R.
The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population.
J Inherit Metab Dis. 2010;. PubMed abstract

Smith EH, Thomas C, McHugh D, Gavrilov D, Raymond K, Rinaldo P, Tortorelli S, Matern D, Highsmith WE, Oglesbee D.
Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.
Mol Genet Metab. 2010;100(3):241-50. PubMed abstract

Solis JO, Singh RH.
Management of fatty acid oxidation disorders: a survey of current treatment strategies.
J Am Diet Assoc. 2002;102(12):1800-3. PubMed abstract

Stanley, CA, Editors: Fernandes J, Saudubray JM, vand den Berghe G, Walter JH .
Disorders of fatty acid oxidation.
Inborn Metabolic Diseases: Diagnosis and Treatment. 2006; 4th Edition:175-190.. Heidelberg: Springer Medizin Verlag

Tajima G, Sakura N, Yofune H, Nishimura Y, Ono H, Hasegawa Y, Hata I, Kimura M, Yamaguchi S, Shigematsu Y, Kobayashi M.
Enzymatic diagnosis of medium-chain acyl-CoA dehydrogenase deficiency by detecting 2-octenoyl-CoA production using high-performance liquid chromatography: a practical confirmatory test for tandem mass spectrometry newborn screening in Japan.
J Chromatogr B Analyt Technol Biomed Life Sci. 2005;823(2):122-30. PubMed abstract

Tanaka K, Gregersen N, Ribes A, Kim J, Kølvraa S, Winter V, Eiberg H, Martinez G, Deufel T, Leifert B, Santer R, François B, Pronicka E, László A, Kmoch S, Kremensky I, Kalaydjicva L, Ozalp I, Ito M.
A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain Acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration.
Pediatr Res. 1997;41(2):201-9. PubMed abstract

Waddell L, Wiley V, Carpenter K, Bennetts B, Angel L, Andresen BS, Wilcken B.
Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations.
Mol Genet Metab. 2006;87(1):32-9. PubMed abstract

Walter JH.
L-carnitine in inborn errors of metabolism: what is the evidence?.
J Inherit Metab Dis. 2003;26(2-3):181-8. PubMed abstract

Wilcken B.
Fatty acid oxidation disorders: outcome and long-term prognosis.
J Inherit Metab Dis. 2010;. PubMed abstract

Wilcken B, Haas M, Joy P, Wiley V, Bowling F, Carpenter K, Christodoulou J, Cowley D, Ellaway C, Fletcher J, Kirk EP, Lewis B, McGill J, Peters H, Pitt J, Ranieri E, Yaplito-Lee J, Boneh A.
Expanded newborn screening: outcome in screened and unscreened patients at age 6 years.
Pediatrics. 2009;124(2):e241-8. PubMed abstract

Yusupov R, Finegold DN, Naylor EW, Sahai I, Waisbren S, Levy HL.
Sudden death in medium chain acyl-coenzyme a dehydrogenase deficiency (MCADD) despite newborn screening.
Mol Genet Metab. 2010;101(1):33-9. PubMed abstract

Zytkovicz TH, Fitzgerald EF, Marsden D, Larson CA, Shih VE, Johnson DM, Strauss AW, Comeau AM, Eaton RB, Grady GF.
Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program.
Clin Chem. 2001;47(11):1945-55. PubMed abstract