MCAD: Medium Chain acyl CoA Dehydrogenase - Information for Clinicians
Charles R. Roe, MD

Medium chain acyl CoA dehydrogenase (MCAD) deficiency is an autosomal recessive disorder of beta-oxidation of fatty acids, which occurs in approximately 1 in 20,000 live births. MCAD generally presents clinically between the second month and second year of life, although presentation as early as two days old and as late as 6 years old has been noted (**be aware that asymptomatic and symptomatic adults are now also being diagnosed, some after having their own MCAD children diagnosed or after an episode). MCAD deficiency occurs primarily in Caucasians of northern European background. Parental consanguinity and recurrence in siblings is observed.

The enzymatic deficiency is of the medium chain acyl CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydrogenases that carry out the initial dehyrdogenation step in the beta-oxidation cycle. MCAD deficiency impairs oxidation of dietary and endogenous fatty acids of medium chain length (6-12 carbon).

Clinical presentation is often triggered by a seemingly innocuous illness (like otitis media). The initiating event is probably due to prolonged fasting, which may lead to vomiting, lethargy, coma, cardiopulmonary arrest, or sudden unexplained death. Symptoms often precede the onset of profound hypoglycemia and are probably related to high free fatty acid levels. Hypoglycemia occurs from an inability to meet gluconeogenic requirements during fasting despite activation of an alternate pathway of substrate production, proteolysis. Physical examination of the acutely ill child is remarkable for mild to moderate hepatomegaly. Some patients may also have demonstrable muscle weakness.

Initial laboratory examination of blood may reveal hypoglycemia, mild metabolic acidosis, mild lactic acidosis, hyperammonemia, elevated BUN, and high uric acid levels. Liver function studies are also usually elevated. Examination of the urine often shows inappropriately low or absent ketones.

Biochemical testing of blood and urine for carnitine, acylcarnitines, acylglycines, and organic acids is diagnostic for this disorder. Low serum and urine carnitines are consistently found in the untreated patient. A generalized dicarboxylic aciduria is noted characterized by elevation of suberylglycine and hexanoylglycine. Plasma or blood spot acylcarnitine profiles show elevations of medium chain length fatty acid derived acylcarnitines, especially octanoylcarnitine.

Without prior indication of metabolic disease, 20-25 percent of patients with this disease will die with their first episode of illness. Cerebral edema, and fatty liver, heart and kidneys are noted at autopsy, often leading to a misdiagnosis of Reye's syndrome or Sudden Infant Death Syndrome(SIDS). This disorder accounts for about one of 100 SIDS deaths. All siblings of patients with MCAD should be tested for the disorder, even if they have been asymptomatic, because of the variability of age of initial presentation and the high risk of sudden death in unrecognized patients.

Analysis of fibroblasts from individuals tested for the activity of medium chain acyl CoA dehydrogenase clearly reveal the affected individuals while heterozygous carriers for the disease usually have intermediate levels of activity, but are otherwise clinically and bio-chemically unaffected.

Detection of mutations in the DNA of chromosome 1 in affected individuals allows for confirmation of biochemical testing and accurate detection of asymptomatic carriers in other family members. DNA analysis of postmortem tissue is possible when plasma and urine samples are not available, and has been diagnostic in fixed tissue over 20 years old.

Fundamental to the medical management of MCAD is to avoid fasting, particularly during periods of high metabolic stress, such as illness. Overnight fasts should last no longer than twelve hours, and infants should continue to receive nighttime or late evening feedings to reduce this period even further. High carbohydrate intake should be encouraged during illness, with initiation of intravenous glucose supplementation if the child is unsuccessful in keeping down fluids, or unable to take adequate oral feedings. The preventative efficiency of a low fat diet versus a normal fat diet is unclear, but high intake of long and medium chain fatty acids should be avoided.

Supplementation with oral L-carnitine at 100 mg/kg/day has been associated with a reduction in the frequency and severity of episodes in many patients. We recommend that the dose be increased to 200 mg/kg/day during acute illness. The continued need for carnitine supplementation post puberty is uncertain, and has not been adequately studied. The addition of 1 - 3 tablespoons of food grade cornstarch mixed in liquid at bedtime to some infants has also helped to decrease the frequency of morning hypoglycemia.

It is imperative that, on arrival in an emergency room while lethargic, 10% glucose is started immediately following blood chemistry sampling. The standard of emergency practice with the lethargic child is to use only normal saline. Several deaths have occurred because of this with MCAD deficient patients. The 2-3 hour delay, while waiting for results of chemistries, and receiving only saline deprives the child of the glucose that is critically needed. Several lawsuits are currently pending because of this. It is recommended that parents have written instructions in their wallets to present to emergency personnel to prevent this catastrophe.

Prenatal diagnosis is possible through amniocyte culture. In vitro probe of the beta-oxidation pathway or enzyme assay, and DNA analysis for the G985 mutation in amniocytes or chorionic villi can also be helpful in the diagnosis of affected and carrier fetuses in pregnancies at risk where both parents carry that mutation. Most families choose to test the infant postnatally during the neonatal periods since prophylactic treatment of MCAD, pending test results, is safe. Prenatal supplementation of the mother of a potentially affected fetus with L-carnitine to improve fetal carnitine stores may be an effective prenatal treatment, ensuring adequate carnitine availability in the newborn period.

References:

1. Roe, C.R, Millington, DS, Malthy, DA, Kinnebrew, P. Recognition of Medium Chain Acyl CoA Dehydrogenese Deficiency in Asymptomatic Siblings of Children Dying of Sudden Infant Death or Reye Like Syndromes. Journal of Pediatrics 1986; 108: 13.
2. Ding, J-H, Roe, CR, lafolla, AK, et al. Diagnosis of Medium Chain Acyl-CoA Dehydrogenase Deficiency in Children Dying Suddenly Without Explanation by Mutation Analysis in Post-mortem Fixed Tissue. New England Journal of Medicine 1991; 325(1): 61- 62.
3. Roe, C.R. and Ding, J.H.: Mitochondrial Fatty Acid Oxidation Disorders. In: The Metabolic and Molecular Bases of Inherited Diseases, 8th edition, Chpt. 101, McGraw-Hill, (In press, 2000).
4. Nada, MA, Chace, D, Spracher, H., Roe, CR: Investigation of beta oxidation intermediates in normal and MCAD-deficient fibroblasts using tandem mass spectrometry. Biochem. Molec. Med. 54: 59-66 (1995).
5. Nada, MA, Vianey-Saban, C, Roe, CR, et al: Prenatal diagnosis of mitochondrial fatty acid oxidation defects. Prenatal Diag., in press, 1995. 6. Iafolla, A.K., Thompson, R.J., Roe, C.R. Medium Chain Acyl Coenzyme A Dehydrogenase Deficiency Clinical Course in 120 Affected Children. Journal of Pediatrics 124 (3):409-415, 1994.