• Loss-of-function mutations
• Newborn screening
• Early prevention
Major Phenotypic Features
• Age at onset: Between 3 and 24 months
• Hypoketotic hypoglycemia
• Hepatic encephalopathy
History and Physical Findings
A.N., a 6-month-old previously healthy girl, presents to the emergency department with vomiting and lethargy. Parents are healthy first cousins and have a healthy 2-year-old boy. A.N. was born in a country without newborn screening. When in the hospital, the patient had a seizure and physical examination showed hepatomegaly. Blood glucose was 32 mg/dL and ketone bodies were absent. Electrospray ionization tandem mass spectrometry (TMS) showed elevations of C10:1, C8, and C10 acylcarnitines, diagnostic for medium-chain acyl-CoA dehydrogenase deficiency (Fig. C-31). Consistent with her clinical history, physical features, and TMS results, DNA testing identified a homozygous Lys304Glu mutation in the ACADM gene, which encodes medium-chain acyl-CoA dehydrogenase. Her asymptomatic brother was tested and found to also be homozygous for the Lys304Glu mutation.
FIGURE C-31 Plasma acylcarnitine profiles obtained by flow injection electrospray ionization tandem mass spectrometry of butylated compounds. The peak heights, measured on the y-axis, indicate the amounts of various acylcarnitines containing either 6 carbons (C6), 8 carbons (C8), or 10 carbons with one unsaturated bond (C10:1), identified by their specific mass-to-charge ratio (m/z) measured in atomic mass units (amu) along the x-axis. A, Normal individual: the C6, C8, and C10:1 peaks are barely detectable. B, Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency patient: the C6, C8, and C10:1 peaks are markedly elevated, particularly the elevation of C8, which is characteristic of MCAD deficiency. See Sources & Acknowledgments.
Disease Etiology and Incidence
Disorders of fatty acid oxidation (FAODs) are a group of frequent inborn errors of metabolism with an estimated combined incidence of 1 in 9000. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (MIM 201450), the most common defect in the mitochondrial fatty acid oxidation pathway, is an autosomal recessive disorder caused by mutations in the ACADM gene, which encodes the MCAD enzyme. In white populations, the frequency of MCAD deficiency is about the same as that for phenylketonuria, approximately 1 in 14,000. However, the incidence of MCAD deficiency is lower, 1 in 23,000, among Asians and African-Americans.
MCAD deficiency is caused by homozygous or compound heterozygous mutations in ACADM. The point mutation c.985A>G, which causes an amino acid change from lysine to glutamate at residue 304 (Lys304Glu) of the mature MCAD protein, is found in approximately 70% of mutant alleles of clinically ascertained patients, but neonatal screening shows over 90 different loss-of-function mutations to date.
MCAD is one of the enzymes involved in mitochondrial fatty acid β-oxidation, which fuels hepatic ketogenesis, a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of increased energy demand. The disorder is associated with hypoketotic hypoglycemia and characteristic accumulations of dicarboxylic acids, medium-chain acylglycines, and acylcarnitines in plasma and urine.
Phenotype and Natural History
Children with MCAD deficiency are normal at birth and appear healthy but typically become ill during infancy when, for example, an intercurrent viral illness causes increased metabolic stress and decreased calorie intake. Although the disorder ordinarily presents between ages 3 and 24 months, a later presentation, even in adulthood, is possible. The combination of increased energy demand and reduced caloric supply precipitates acute symptoms of vomiting, drowsiness, or lethargy. Seizures may occur. Hepatomegaly and liver disease are often present during an acute episode, which can quickly progress to coma and death. At first presentation, 25% to 50% of the patients die during a metabolic crisis. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged period of fasting.
Biochemical studies reveal hypoketotic hypoglycemia. Elevation of octanoylcarnitine (C8:0) in peripheral blood by flow injection electrospray ionization TMS is considered to be diagnostic for MCAD deficiency (see Fig. C-31).
Metabolic decompensation can be fatal in patients in whom the diagnosis is not suspected. However, in patients in whom the diagnosis is suspected, decompensation can be prevented by avoiding fasting. If, however, a patient has increased energy demand and reduced oral intake because of an intercurrent illness or surgery, decompensation can be prevented or treated by the administration of intravenous glucose (10% dextrose plus electrolytes at 1.5 to 2 times maintenance) and carnitine (to promote efficient excretion of dicarboxylic acids). Prognosis is excellent when the diagnosis of MCAD deficiency is established and proper therapeutic measures are taken.
Given the frequency of the condition and the improved clinical outcome achieved by presymptomatic diagnosis and initiation of treatment, it became clear that FAODs, including MCAD deficiency, belonged on the list of disorders appropriate for newborn screening. As a result, acylcarnitine analysis by TMS of dried blood spots was added to many newborn screening programs starting in the mid-1990s. False-negative cases have been reported for MCAD deficiency, and are possible in all FAODs, because acylcarnitine profiles may be abnormal at birth but then give a false-negative normal result once the infant beings regular feeding. For this reason, enzyme measurement of MCAD activity in leukocytes or lymphocytes using phenylpropionyl-CoA as a substrate or molecular analysis of the ACADM gene, should be performed following a first positive newborn screen. Newborn screening for MCAD deficiency has been very successful because it has resulted in a 74% reduction in severe metabolic decompensation and/or death in these patients.
The mainstay in the treatment of MCAD deficiency is avoidance of fasting. In symptomatic patients, the most important aspect of treatment is reversal of catabolism and sustained anabolism by provision of simple carbohydrates by mouth (e.g., glucose tablets or sweetened, nondiet beverages) or intravenously if the patient is unable or unlikely to maintain or achieve anabolism through oral intake of food and fluids.
MCAD deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Given that a clear genotype-phenotype correlation does not exist for MCAD deficiency and that individuals may remain asymptomatic until late adulthood, apparently unaffected sibs of an affected child should be tested for MCAD deficiency.
Prenatal diagnosis for pregnancies at risk for MCAD deficiency and other FAODs is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis or chorionic villus sampling (CVS) (see Chapter 17). Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed. Prenatal diagnosis for pregnancies at increased risk is also possible by assay of MCAD enzymatic activity in CVS or amniocyte cultures. Amniocyte cultures can also be used for analysis of fatty acid oxidation as is done in fibroblast cultures. Preimplantation genetic diagnosis may be available for couples in whom the disease-causing mutations have been identified. Prenatal diagnosis, however, carries its own inherent risks and offers no advantage to timely postnatal measurement of plasma acylcarnitine and urine acylglycine levels. Prompt postnatal testing and consultation with a biochemical geneticist are indicated.
Questions for Small Group Discussion
1. What other FAODs are included in newborn screening programs?
2. What are the criteria for the inclusion of a disease in newborn screening programs?
3. Can individuals heterozygous for a mutation in ACADM be identified by newborn screening?
4. What are the false-positive and false-negative rates for MCAD deficiency by newborn screening?
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;33:521–526.
Matern D, Rinaldo P. Medium-chain acyl-coenzyme A dehydrogenase deficiency. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1424/.
Tein I. Disorders of fatty acid oxidation. Handb Clin Neurol. 2013;113:1675–1688.