Molecular Basis of the Disease

MCAD is an intramitochondrial enzyme that is encoded by a nuclear gene. The normal function of MCAD is the initial dehydrogenation of acyl-CoAs with chain lengths of 4 to 12 carbons. Defective function leads to the accumulation of metabolites of the medium-chain fatty acids, mainly the dicarboxylic acids, acylglycine in urine, and acylcarnitine in plasma. At present, many states within the United States employ tandem mass spectrometry in their newborn screening program, which allows detection of the abnormal plasma acylcarnitine profile characteristic of MCAD deficiency. These metabolites are at their highest concentration in the blood in the first few days of life, making the newborn period the ideal time for detection. Accordingly, the specificity of this testing is 100%, as no false negatives have been reported. MCAD enzymatic activity also can be assayed in several different tissue types.

Because fatty acid oxidation fuels hepatic ketogenesis, the symptoms of the disorder appear after periods of prolonged fasting or intercurrent infections and include hypoketotic hypoglycemia, lethargy, seizures, coma, and, without treatment, death. Complications of the disease can include hepatomegaly, acute liver disease, and brain damage. The disease typically presents before 2 years of age but after the newborn period. However, individuals have been described who present with symptoms within the first few days of life as well as those who present as adults.

MCAD deficiency is an autosomal recessive disorder that is prevalent in individuals of northwestern European ancestry, with the highest overall frequency of 1 in 4,900 in

Table 8-3. Genotypes of 57 MCAD-Deficient Newborns Detected

Using MS/MS to Screen More Than 1.1 Million Newborns (Neo

Gen Screening, Pittsburgh, PA, USA)

Mutation Position and Type

Number of Patients Identified

985 A^G/985 A^G


985 A^G/199 T^C (exon 3)


985 A^G/deletion 343-348


985 A^G/other*


985 A^G/unidentified


799 G^A/254 G^A




Source: Reprinted with permission from Chace DH, Kalas TA,

Naylor EW. The application of tandem mass spectrometry to

neonatal screening for inherited disorders of intermediary metab

olism. Annual Review of Genomics and Human Genetics 3:17-45,

© 2002 by Annual Reviews,

*Other mutations:

244 insertion T (exon 4)

362 C^T (exon 5)

489 T^G (exon 7)

IVS 5+1 G^A

IVS 8+6 G^T

northern Germany. The incidence in the United States is somewhat lower and is estimated to be 1 in 15,700. The MCAD gene, ACADM,spans a 44kb region on chromosome 1p31 and contains 12 exons encoding a protein of 421 amino acids. A single founder mutation in exon 11, 985A^G, which results in the substitution of the acidic amino acid, glutamate, for the basic amino acid, lysine (K304E), represents 90% of all alleles in the northern European population. However, recent studies of the US population, attributable to the expansion of newborn screening for MCAD deficiency, indicate that this mutation accounts for 79% of the total mutant alleles in the US population (Table 8-3).23 The discrepancy between the two results is presumably due to the greater ethnic diversity of the US population.

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