Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of radioactive substrates by cultured skin fibroblasts from the proband and asymptomatic family members was also determined and compared to that by normal fibroblasts and that by cells from a patient with glutaric aciduria type II. Feeding medium-chain triglycerides promptly induced vomiting and lethargy accompanied by a pronounced increase of urinary ethylmalonate. Significant increases of serum isovalerate and urinary isovalerylglycine were observed after leucine feeding, but urinary glutarate increased only slightly after lysine feeding. Thus, the results from clinical investigation remained equivocal as to whether pathways other than fatty acid oxidation were blocked in our patient. Oxidation of [1-(14)C]butyrate by cultured skin fibroblasts from the proband was reduced to 14% of control. In vitro oxidation of [2-(14)C]lysine and [2-(14)C]leucine was also reduced to 28 and 23% of control, respectively. Much more severe reduction in oxidation of these three substrates (3, 9, and 9%, respectively) was observed in glutaric aciduria type II cells. These results indicated that in the proband, degradative pathways of fatty acids, lysine, and leucine are blocked at the steps of butyryl-CoA, glutaryl-CoA, and isovaleryl-CoA dehydrogenases, respectively, as in the case of glutaric aciduria type II. Because activities of multiple acyl-CoA dehydrogenases are reduced, a deficiency of electron-transferring flavoprotein, which serves as a hydrogen-acceptor for these dehydrogenases, is postulated as the underlying mechanisms of these two diseases, but a genetic heterogeneity was indicated by significant differences in the residual activities in these two types of cells. The hypothesis of more than one mutant allele of an autosomal recessive gene was also suggested by the study on cells from asymptomatic members of the family.
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PMID:Ethylmalonic-adipic aciduria. In vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases. 50 Aug 26

Medium chain acyl-CoA dehydrogenase (MCAD) is a tetrameric flavoprotein essential for the beta-oxidation 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 (1p31). 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 high-carbohydrate, 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.
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PMID:Medium chain acyl-CoA dehydrogenase deficiency human genome epidemiology review. 1126 45

Trimethylaminuria (TMAU) is an autosomal recessive disease caused by excessive excretion into body fluids and breath of unoxidized trimethylamine (TMA) derived from the enterobacterial metabolism of dietary precursors. The condition is caused by deficiency of flavin-containing monooxygenase 3 (FMO3) which leads to impairment of hepatic TMA oxidation to the odorless trimethylamine N-oxide. Secondary TMAU is due to substrate overload in individuals with genetically determined reduced enzyme activity. Food protein-induced enterocolitis syndrome (FPIES) is characterized by recurrent episodes of emesis, diarrhea, dehydration, and lethargy after ingestion of offending foods. Its pathophysiology involves local non-IgE-mediated inflammation of the gastrointestinal tract, which leads to increased intestinal permeability. We report on an 8-month-old male who presented with typical episodes of FPIES associated with intense fish-like body odor. Further investigation in our patient revealed massive urinary TMA excretion during acute FPIES presentation and complete normalization between these episodes. The patient was found to be heterozygous for a novel, paternally inherited nonsense p.Tyr331X mutation and for two maternally inherited common polymorphisms, E158K and E308G, in the FMO3 gene. We propose that our patient was able to cope with the daily burden of TMA, but when challenged with substrate overload, he failed to oxidize TMA due to limited reserve enzyme capacity. We discuss the pathophysiology of TMAU and FPIES and suggest potential mechanisms for the clinical and biochemical findings. Our report illustrates the complex interplay of genetic and environmental factors in TMAU and sheds light on the pathophysiology of FPIES.
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PMID:Transient massive trimethylaminuria associated with food protein-induced enterocolitis syndrome. 2382 20