What is MCAD Deficiency?
Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency is an autosomal recessive fatty acid oxidation disorder that prevents the breakdown of medium-chain (4-10 carbon) fatty acids, leading to life-threatening episodes of hypoketotic hypoglycemia, metabolic decompensation, and sudden death, particularly during periods of fasting or illness. 1
Disease Mechanism and Genetics
- MCAD is a tetrameric flavoprotein enzyme essential for the beta-oxidation of medium-chain fatty acids in mitochondria 2
- The MCAD gene is located on chromosome 1 (1p31) 2
- A single prevalent mutation, G985A (causing K304E amino acid substitution), accounts for 90% of all disease-causing alleles 2, 3
- Among clinically diagnosed patients identified retrospectively, 81% are homozygous for K304E and 18% are compound heterozygotes 2
- The disorder is inherited in an autosomal recessive pattern and shows highest frequency in populations of Northern European descent due to a founder effect 1, 2
Clinical Presentation
MCAD deficiency can present at any age from birth to adulthood, but most commonly manifests in early childhood during metabolic stress 1
Acute Manifestations
- Hypoketotic hypoglycemia (the hallmark finding) 1
- Vomiting (frequently precedes sudden death by 12-24 hours) 4
- Lethargy, encephalopathy, and coma 2
- Hepatomegaly and liver disease 1
- Seizures, apnea, and respiratory arrest 2
- Cardiac arrest and sudden unexpected death 1, 2
Triggers for Metabolic Decompensation
- Prolonged fasting or inadequate caloric intake 1
- Intercurrent illness and infection 1, 2
- Any period when glucose availability is limited or energy needs exceed glucose supply 4
Long-Term Complications
- Developmental and behavioral disabilities 2
- Chronic muscle weakness 2
- Failure to thrive 2
- Cerebral palsy 2
- Attention deficit disorder 2
Diagnostic Approach
Diagnosis is almost exclusively a laboratory process, with acylcarnitine profile analysis serving as the key diagnostic test 1
Primary Diagnostic Tests
- Plasma acylcarnitine profile showing elevated octanoylcarnitine (C8) - this is the primary marker for MCAD deficiency 1, 4
- Plasma amino acid analysis 1
- Urine organic acid analysis to detect abnormal metabolites 1, 2
- Plasma carnitine levels (free and total) 1
Sample Collection Specifications
- Preferred sample type is plasma or serum for symptomatic patients 1
- Dried blood spots facilitate specimen transport and may increase sensitivity for long-chain FAO disorders 1
- All samples except dried filter paper specimens should be frozen immediately and shipped on dry ice 5
Confirmatory Testing
- DNA analysis for the G985A mutation provides definitive diagnosis in 75% of cases using a simple blood spot on a PKU card 6, 3
- Enzyme activity measurement in cultured skin fibroblasts for the remaining 25% of cases 6
Critical Clinical Pitfalls
Newborn Screening Does Not Eliminate Risk
Sudden death can still occur in MCAD deficiency despite detection by newborn screening, particularly in patients with markedly elevated C8 levels (≥6 μmol/L, with normal <0.8 μmol/L) 4
- Four documented cases of sudden death occurred despite newborn screening detection, with C8 levels ranging from 8.4 to 24.8 μmol/L 4
- Sudden death occurred in patients with various genotypes, not just those homozygous for the common G985A mutation 4
- Vomiting is a critical warning sign that frequently precedes sudden death by 12-24 hours and requires immediate emergency intervention 4
Incomplete Penetrance
- There appears to be a substantial number of asymptomatic individuals with MCAD deficiency 2
- Less than 10% of all patients with the gene defect are ever clinically diagnosed 6
- The relationship between enzyme deficiency and clinical disease expression remains incompletely understood 6