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Introduction

This inherited metabolic disorder is the most common form of Acyl-CoA dehydrogenase deficiencies. In the USA, it affects approximately 1 in 15,000 to 20,000 newborns of both genders equally, but the incidence is even higher in people from Northern Europe (up to 1 in 12,000 newborns). Inheritance is autosomal recessive and the defect in the Acyl-CoA dehydrogenase, C-4 to C-12 straight chain (ACADM) gene has been mapped to chromosome 1p31.1. Medium-chain fatty acids consist of aliphatic tails of 6 to 12 carbon atoms, and MCAD has a chain-length substrate specificity ranging from C4 to C12. About 80% of patients are homozygous for a single mutation while the remaining 20% are either single mutation carriers or compound heterozygotes. In many countries, standard neonatal screening now includes testing for MCADD, which then allows for proactive treatment during times of decreased fluid and caloric intake and/or increased energy demands and allows for favorable prognosis. Onset is usually in the first 2 years of life (typically between 3 and 15 months of age). However, in some rare cases, symptoms may not become apparent until later in childhood or even adulthood. An episode of decompensation is usually triggered by prolonged fasting and/or increased energy demands, such as during a minor illness (eg, gastrointestinal infection with vomiting/diarrhea), surgery, or any other forms of stress. Metabolic decompensation is more likely the younger the patient is (less reserves, higher metabolic rate) and happens once the hepatic glycogen supplies become depleted. In healthy people, fatty acids are metabolized to ketones, which then become a major energy source after the glycogen stores have been exhausted. However, MCADD results in accumulation of fatty acids and inadequate supply of ketones (such as ketone beta-hydroxybutyrate) and eventually severe hypoglycemia. Nevertheless, the presence of ketones does not eliminate the diagnosis of MCADD, since 29% of patients subsequently diagnosed with the disorder had ketones in their urine at the time of clinical onset. The accumulation of medium-chain organic acids, corresponding acyl-carnitines and acyl-CoAs—the biochemical hallmark of beta-oxidation defects—can lead to toxic effects on liver, muscles, and central nervous system. Metabolic decompensation has a mortality rate of up to 25%, and survivors carry a significant risk of long-term illness and developmental disability. The initial signs of metabolic decompensation include lethargy (in 84% of patients), vomiting (in 66%), encephalopathy (in 49%), respiratory arrest (in 48%), seizures (in 43%), cardiac arrest (in 36%), and even sudden death (in 18%). Additional findings include severe metabolic acidosis, hypoketotic hypoglycemia (not an early sign!), hyperammonemia, arrhythmias, muscle weakness and coma. Acute liver failure may present with hepatomegaly (in 44% of patients, secondary to accumulation of fat), pathologic liver function tests (often normal partial thromboplastin time and only mildly prolonged prothrombin time and elevated serum transaminases levels), and encephalopathy (secondary to hyperammonemia and accumulation of other toxic metabolites). Some of these patients were labeled as sudden infant death syndrome before autopsy revealed MCADD. Cardiac anomalies have been described in some MCADD patients and include ...

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