Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
OMIM Link for MCAD Deficiency
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The acyl-CoA dehydrogenases are a family of enzymes involved in the first step of the mitochondrial β-oxidation of fatty acids. Medium chain acyl-CoA dehydrogenase (MCAD) is so called because of the size range of its fatty acyl-CoA substrates. MCAD acts on fatty acyl-CoA molecules that range in size from 12 to 4 carbons in length. The MCAD gene resides on chromosome 1p31 spanning 12 exons. At least 344 mutant MCAD genes have been identified. By far, the most prevalent mutation (89%) found in MCAD patients is a single nucleotide substitution at position 985. This substitution is a A for G change that converts amino acid 329 from a lysine to a glutamic acid (K29E). This mutation alters the α-helical domain of the C-terminal portion of the enzyme. In addition to the A985G substitution mutation several additional nucleotide substitution mutants, insert and deletion mutants have been identified in MCAD patients.
Deficiency in MCAD is the most common defect observed in the process of mitochondrial β-oxidation of fatty acids. In fact, MCAD deficiency is one of the most common inherited disorders of metabolism occurring with a frequency of approximately 1 in 10,000 live births. This disorder has been described in populations world-wide with the most occurring in individuals of northwestern European origin. The most common symptom of MCAD deficiency is episodic hypoketotic hypoglycemia brought on by fasting. Symptoms appear within the first 2 years of life. Clinical crisis is characterized by an infant presenting with episodes of vomiting and lethargy that my progress to seizures and ultimately coma. A prior upper respiratory or gastrointestinal viral infection will lead to reduced oral intake in these infants which can precipitate the acute crisis. The first episode in an infant may be fatal and the death ascribed to sudden infant death syndrome (SIDS). Autopsy results will often find marked fatty liver (hepatic steatosis) and cerebral edema. These findings are sometimes misdiagnosed as Reye syndrome especially in the circumstance where there is reported a prior infection. Because the capacity of the gluconeogenesis pathway is limited in newborn infants, they are highly susceptible to the lack of brain energy from the ketones that would normally be derived from fatty acid oxidation. For this reason, therapy for MCAD deficiency patients is the avoidance of fasting and IV glucose to treat acute episodes. The primary goal of treatment is to avoid fasting, provide adequate caloric intake and aggressive therapy during periods of infection. In addition to caloric intake, treatment with oral carnitine increases the removal of toxic intermediates that accumulate during periods of fasting and stress.
MCAD deficiency is a disease that satisfies the criteria for newborn screening and is in fact one of the diseases that is screened for in the US in all newborns. MCAD deficiency is a common inherited disorder with a frequency that approaches PKU. The disease can result in life threatening complications and relatively simple dietary intervention can avert the clinical phenotype of MCAD deficiency.
The defect in fatty acid oxidation leads to the presence, in the plasma and urine, of metabolic intermediates such as dicarboxylic acids. Characteristic and diagnostic of MCAD deficiency is the presence of octanoylcarnitine. Diagnosis can be made within 24 to 48h in specialized laboratories using tandem mass spectrometry (MS) of the blood for specific acylcarnitines. In MCAD deficiency the acylcarnitines that are found are highly diagnostic and specific for this disorder and include C6:0-, 4-cis-, and 5-cis-C8:1, C8:0, and 4-cis-C10:1 acylcarnitine species. The nomenclature C6:0, for example, refers to a fatty acid 6 carbons in length with no sites of unsaturation, whereas, C8:1 refers to a 8 carbon fatty acid with 1 site of unsaturation.
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Michael W. King, Ph.D / IU School of Medicine / miking at iupui.edu