MCAD deficiency, the most common of the disorders of fatty acid oxidation, occurs in approximately 1 in 15,000 births, varying from 1 in 6,500 to 1 in 17,000 in different populations. This disorder is seen almost exclusively in whites, especially those with Northwestern European heritage, among whom the carrier rate may be as frequent as 1 in 40 for the most common mutation, K304E. Most patients present between ages 5 and 24 months with vomiting, lethargy, and hypotonia that occur after a decreased carbohydrate intake associated with an intercurrent illness or fasting. Mild hepatomegaly and seizures may occur. Hypoglycemia, mildly elevated blood ammonia, and increased liver enzyme levels usually are noted. Any acidosis usually is mild. Urine and plasma ketones may be either absent or present in trace amounts, which has led to the term hypoketotic hypoglycemia for this group of disorders. However, some patients may make ketone bodies when severely stressed. The amount of ketones produced in these patients, as determined by plasma beta-hydroxybutyrate levels, is inappropriately low for the degree of hypoglycemia and the marked elevation of
plasma free fatty acids. The pathophysiologic reason for the hypoglycemia is understood incompletely but is believed to result from failure of the normal increase in gluconeogenesis with fasting, which usually occurs in response to increased acetyl-CoA and ketone body production.

Clinical presentation varies widely. Some patients have been identified in the newborn period due to a history of early hypoglycemia, whereas others were asymptomatic and were detected only by family studies or state-mandated newborn screening. Ill, affected patients may have a rapidly deteriorating course with an episode that progresses to coma and death from cardiorespiratory collapse or cerebral edema. The accumulation of acyl-CoA compounds, especially those with chain lengths of three carbons or more, frequently is associated with encephalopathy and may result in cerebral edema. Mortality has been reported to be highest (59%) at between ages 15 and 26 months. Approximately 25% of patients die with their first episode, which frequently is unrecognized as being a result of a disorder of fatty acid oxidation until the disorder is diagnosed in a second child in the family. Many of the deaths have been attributed to Reye syndrome or to sudden infant death syndrome. Autopsy findings include fatty infiltration of the liver, the pattern of which may be macrovesicular or microvesicular. Mitochondrial changes in the liver on electron microscopy differ from those seen in Reye syndrome. Condensed mitochondria, with increased matrix density and intracristal widening, or enlarged and abnormally shaped mitochondria, with an increase in the number of cristae and crystalloids in the matrix, may be seen.

With episodes, affected individuals accumulate metabolites of medium-chain length (C6 to C12), especially octanoic acid and 4-decanoic acid. Owing to the excessive accumulation of fatty acyl-CoA intermediates of medium-chain length in the mitochondria, alternative pathways of microsomal (omega and omega₁) oxidation and peroxisomal beta-oxidation become involved and lead to excessive production of (omega₁)-hydroxy acids and medium-chain dicarboxylic acids, such as adipic, suberic, and sebacic acids. Organic acid analysis using gas or liquid chromatography–mass spectrometry may detect these metabolites in the blood or urine of patients during episodes. Acyl-CoA compounds may be conjugated with glycine or with carnitine. Abnormal metabolites of medium-chain length may be detected as urinary acyl-glycine conjugates (stable isotope dilution gas chromatography–mass spectrometry) or by plasma or dried blood filter-paper sample acyl-carnitine profiles (fast atom bombardment with tandem mass spectrometry). The latter two tests are more sophisticated and sensitive than are routine organic acid measurements. Their use is indicated particularly in the evaluation of all patients suspected of having a defect in fatty acid oxidation. Between episodes, asymptomatic affected patients may have normal routine organic acid studies. However, urine acyl-glycine or dried blood filter-paper or plasma acyl-carnitine profiles usually are abnormal. Frequently, affected patients have abnormal plasma and urinary carnitine levels, with lowered total and elevated esterified fractions. Such patients should not be subjected to a provocative fast because of the possibility of inducing a fatal acute episode. The use of acyl-carnitine profiles from dried blood filter-paper samples has not only allowed identification of asymptomatic affected children, but also has led to retrospective diagnosis in children who have died, including several affected newborns. Those infants identified by newborn screening tests should have the diagnosis confirmed by repeat testing at a separate standard laboratory. Confirmation of deficient activity of MCAD may be shown in cultured skin fibroblasts by finding disease-specific labeled metabolites using tandem or electrospray mass spectrometry assay after feeding with carbon 14– or deuterium-labeled palmitate or linoleate.