MCADD - Ongoing Assessment

Page Contents

• Overview
• Screening
• Diagnostic Criteria
• Pearls And Alerts
• History And Examination
• Clinical Classification
• Comorbid Conditions
• Resources

Overview

Children with MCAD deficiency will need chronic health care checks with their Medical Home provider, as well as periodic visits with the metabolic geneticist. Medical Home visits should include a review of MCADD and intercurrent problems, as well as developmental and educational screening. In addition, there should be a low threshold for evaluating these patients and providing interventions whenever they become ill. Although fasting tolerance improves with age, prolonged fasting in an affected individual can lead to coma and death at any age. Telephone medicine should never replace prompt evaluation. Special attention should be given to clinical symptoms of decreased oral intake, vomiting, diarrhea, fever, and level of alertness.[Walter: 2009] Home glucose monitors should not be encouraged as hypoglycemia is generally a late finding and normal glucose levels may instill a false sense of security.[Leonard: 2009]

Screening

MCADD is currently included in the expanded newborn screening panel of most states in the United States. If a child is identified as having MCADD, siblings and parents can be screened either by acylcarnitine profile or by mutation analyses looking for the mutation that was identified in the presenting child.

Diagnostic Criteria

The essential features of diagnosis include:

• Positive findings on expanded newborn screening
• Nonketotic hypoglycemia
• Elevations of C8, C6, C10, C10:1 acylcarnitines
• Elevations on urinary dicarboxylic acids, hexanoylglycine, suberylglycine and cis-4-decenoic acid
• DNA testing identifying the common A985G mutation (if clinical and biochemical findings consistent with diagnosis and no mutation is identified, then sequencing of the entire coding sequence or fatty acid oxidation studies in fibroblasts may be necessary to confirm the diagnosis)

Pearls And Alerts

There should be a low threshold for evaluating these patients and providing interventions when they become ill. Although fasting tolerance improves with age, prolonged fasting in an affected individual can lead to coma and death at any age.

Hypoglycemia occurs after the onset of clinical symptoms and is an unreliable marker for early decompensation or encephalopathy. Therefore, the use of home glucose monitoring is not encouraged. [Leonard: 2009]

History And Examination

Clinical Classification

There are two types of MCAD deficiency. Both are treated in essentially in the same way (see Treatment section). Also see the MCADD table ( 55 KB) .

Children with classic MCAD deficiency:

• if undiagnosed, have up to 25% mortality with the first metabolic crisis;
• have hepatomegaly accompanied by hypoketotic hypoglycemia, hyperuricemia, elevated LFTs, mild hyperammonemia, elevated anion gap;
• may have developmental regression, aphasia, ADHD, chronic muscle weakness;
• may have family members without symptoms or with varying degrees of the disorder suggesting environmental factors may also play a role in the natural history of the disorder; and
• are most commonly homozygous for the K304E (985A>G) mutation

Children with "mild" MCAD deficiency:

• have milder abnormalities on acylcarnitine profile;
• should be considered at risk for developing clinical symptoms;
• are either compound heterozygotes for K304E and another mutation or homozygous for other mutations. [Albers: 2001] [Zschocke: 2001]

Adults with MCAD deficiency

• may be underdiagnosed secondary to a lack of clinical suspicion
• may present with encephalopathy, rhabdomyolysis or cardiac failure after prolonged fasting (such as that seen with pre- and post-surgical fasting, prolonged labor, illness), strenuous exercise, or binge drinking [Lang: 2009] [Schatz: 2010]
• may have a mortality rate as high as 50% in acutely presenting adults [Lang: 2009]

Comorbid Conditions

Prior to identification by expanded newborn screening, up to 25% of undiagnosed patients died during the first decompensation. [Stanley: 2006] More recent data, that includes information about all ages, suggests that mortality approaches 29% in undiagnosed patients. [Lang: 2009] 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 undertook a natural history study in the Netherlands. They 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] An Australian study comparing cases diagnosed through newborn screening with those identified clinically, found that the risk of intellectual impairment or other morbidity is small. [Wilcken: 2009] The sample sizes in this study were, however, smaller than those in the report by Iafolla et al.

Resources

Authors

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

Albers S, Levy HL, Irons M, Strauss AW, Marsden D.
Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency.
J Inherit Metab Dis. 2001;24(3):417-8. 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

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

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

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

Stanley CA.
Hypoglycemia in the neonate.
Pediatr Endocrinol Rev. 2006;4 Suppl 1:76-81. PubMed abstract

Walter JH.
Tolerance to fast: rational and practical evaluation in children with hypoketonaemia.
J Inherit Metab Dis. 2009;32(2):214-7. 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

Zschocke J, Schulze A, Lindner M, Fiesel S, Olgemöller K, Hoffmann GF, Penzien J, Ruiter JP, Wanders RJ, Mayatepek E.
Molecular and functional characterisation of mild MCAD deficiency.
Hum Genet. 2001;108(5):404-8. PubMed abstract