Medium chain acyl-CoA dehydrogenase deficiency: Human genome epidemiology review

Abstract

Medium chain acyl-CoA dehydrogenase (MCAD) is a tetrameric flavoprotein essential for the poxidation of medium chain fatty acids. MCAD deficiency (MCADD) is an inherited error of fatty acid metabolism. The gene for MCAD is located on chromosome one (lp31). One variant of the MCAD gene, G985A, a point mutation causing a change from lysine to glutamate at position 304 (K304E) in the mature MCAD protein, has been found in 90% of the alleles in MCADD patients identified retrospectively. There is a high frequency of MCADD among people of Northern European descent, which is believed to be due to a founder effect. MCADD is inherited in an autosomal recessive manner. Of patients clinically diagnosed with MCADD, 81% who have been identified retrospectively are homozygous for K304E, and 18% are compound heterozygotes for K304E. Clinical data on the probability of clinical disease indicates that MCADD patients are at risk for the following outcomes: hypoglycemia, vomiting, lethargy, encephalopathy, respiratory arrest, hepatomegaly, seizures, apnea, cardiac arrest, coma, and sudden and unexpected death. Long-term outcomes include developmental and behavioral disability, chronic muscle weakness, failure to thrive, cerebral palsy, and attention deficit disorder (ADD). Differences in clinical disease specific to allelic variants have not been documented. Factors that may increase risk for disease onset or modify disease severity are age when the first episode occurred, fasting, and presence of infection. Acute attacks must be treated immediately with appropriate intravenous doses of glucose. For those diagnosed, long-term management of the disease includes preventing stress caused by fasting and maintaining a highcarbohydrate, reduced-fat diet, and carnitine supplementation. Hospitalization costs attributable to morbidity and mortality from MCADD are unknown; MCADD is not a diagnosis in the International Classification of Disease, 10th Revision (ICD-10) codebook.Furthermore, the penetrance of the MCAD genotypes is unknown; there appears to be a substantial number of asymptomatic MCADD individuals and some uncertainty regarding which individuals will manifest symptoms and which individuals will remain asymptomatic. Several technologies are available to detect MCADD. Diagnostic technologies include DNA-based tests for K304E mutations using the polymerase chain reaction (PCR), and the detection of abnormal metabolites in urine. Screening technologies include tandem mass spectrometry (MS/MS), which detects abnormal metabolites mostly in blood. State programs are beginning to offer screening in newborns for MCADD using MS/MS. In addition, a private company currently offers voluntary supplemental newborn screening for MCADD to birthing centers. Genetics in Medicine, 1999:1(7):332-339.

Reporting, Appraising, and Integrating Data on Genotype Prevalence and Gene-Disease Associations

“…Thus, sufficient information should be presented to assess whether controls would have become cases if they had developed the disease. In regard to genotype prevalence, many early studies were based on convenience samples, and not infrequently, little information was given on how the samples were selected (10,34,36,38).…”

Forensic Pathology and Newborn Screening for Inborn Errors of Metabolism: Implications for the Middle East

“…At autopsy, the body was that of a cachectic, pre-pubes- MCAD is the most common and fatal inherited disorder of fatty acid metabolism [8][9][10][11][12]. Typically, the presentation is sudden death in a child less than 1 year of age after a period of fasting, such as after a mild viral illness, or diarrhea.…”

PPARα siRNA-Treated Expression Profiles Uncover the Causal Sufficiency Network for Compound-Induced Liver Hypertrophy

“…For example, in the mouse study, PPARa activity was measured directly by the mRNA level in siRNA profiles, whereas in the rat study, it was measured indirectly by the mRNA levels of the PPARa target genes. Nevertheless, 11 of the 15 identified genes have comprehensive functional annotations, and eight of these 11 genes (73%) have been reported either to be associated with or to cause liver hypertrophy or hepatomegaly [30][31][32].…”

“…Acadm, also called mediumchain acyl-CoA dehydrogenase (MCAD), encodes an essential enzyme for fatty acid oxidation. MCAD deficiency in mice or humans can cause liver hypertrophy and hepatic steatosis [32,33]. Meanwhile, Pck1, also known as phosphoenolpyruvate carboxykinase (PEPCK), encodes a rate-limiting enzyme for gluconeogenesis.…”