Medium Chain Acyl-CoA Dehydrogenase Deficiency in Pennsylvania: Neonatal Screening Shows High Incidence and Unexpected Mutation Frequencies

Ziadeh, Rana; Hoffman, Eric P.; Finegold, David N.; Hoop, R. C.; Brackett, Jeffrey C.; Strauss, Arnold W.; Naylor, Edwin W.

doi:10.1203/00006450-199505000-00021

Cited by 154 publications

(82 citation statements)

References 12 publications

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“…Despite this limitation, Ziadeh and colleagues' 1995 populationbased study of U.S. newborns demonstrated a frequency of homozygosity (1120,408) that is similar to those estimated in some northern European countries. 5 Ziadeh and colleagues studied the first 80,371 newborns from a supplemental newborn screening program in Pennsylvania and eastern Ohio for more than 35 metabolic disorders.5 Despite the heterogeneity of the population, which included high proportions of Eastern Table 1 Frequency by country of homozygosity and heterozygosity for K304E which is consistent with data from retrospective studies (because data are still pending, this study is not listed in Table 1). …”

supporting

confidence: 75%

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

Wang

Fernhoff

Harnnon

et al. 1999

Genetics in Medicine

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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.

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supporting

confidence: 75%

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

Wang

Fernhoff

Harnnon

et al. 1999

Genetics in Medicine

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“…This is of importance also since acyl-CoA dehydrogenases have been recognized to be the source of medically relevant genetic defects (Gregersen, 1985, Roe andCoates, 1995). In particular the K304E-MCADH mutation (Kieweg et al, 1997) is among the rnost common found in humans (Ziadeh et al, 1995). During our studies of various mutants of human MCADH, and specifically of the one above, we have observed differences in the electrophoretic migration behavior between native MCADH and recombinant proteins expressed heterologously (Bross et al, 1995).…”

Section: Introductionmentioning

confidence: 89%

Medium-Chain Acyl CoA Dehydrogenase: Evidence for Phosphorylation

Macheroux¹,

Sanner²,

Büttner³

et al. 1997

Biological Chemistry

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Mature medium chain acyl-CoA dehydrogenase isolated from pig kidney (pkMCADH) and originating from mitochondria carries a phosphate group as demonstrated by 31 P-NMR-spectroscopy and chemical analysis. Two broad resonances at -6.3 and -8 ppm are observed and are assigned to the pyrophosphate group of the cofactor FAD. A third, narrow resonance at 4.65 ppm indicates the presence of a phosphomonoester residue. Chemical analysis of intact pkMCADH shows the presence of 3 ± 0.3 phosphates, those of FAD and of an additional covalently attached phosphate. With recombinant, human wild type MCADH expressed in and purified from E. coli only the two FAD phosphates (2 ± 0.35) are found. Similarly, pkMCADH which has been converted to the apoenzyme and reconstituted to holoenzyme also contains 2 ± 0.4 phosphates. The covalently bound phosphate can be hydrolyzed by phosphatase and subsequently removed by dialysis. The phosphate group has no detectable effect on the catalytic activity of the MCADH measured with artificial and natural electron acceptors such as pig electron transferring flavoprotein. However, phosphorylation has a marked effect on protein solubility which is ffi5-fold lower for the dephosphorylated protein.

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“…In these cohorts, the c.985A>G mutation in the ACADM gene accounted for about 90% of disease-causing alleles (Gregersen et al 1991;Yokota et al 1991;Derks et al 2006). In addition to this most common mutation in Europe, in screening cohorts other mutations, especially c.199T>C, are frequently found (Ziadeh et al 1995;Andresen et al 2001;Maier et al 2005;Waddell et al 2006;Hsu et al 2008). There is ongoing discussion, whether patients with this potentially mild mutation would ever show any clinical phenotype (Andresen et al 2001) or might not require treatment at all (Sturm et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening

et al. 2015

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Background: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is included in many newborn screening programmes worldwide. In addition to the prevalent mutation c.985A>G in the ACADM gene, potentially mild mutations like c.199T>C are frequently found in screening cohorts. There is ongoing discussion whether this mutation is associated with a clinical phenotype.Methods: In 37 MCADD patients detected by newborn screening, biochemical phenotype (octanoylcarnitine (C8), ratios of C8 to acetylcarnitine (C2), decanoylcarnitine (C10) and dodecanoylcarnitine (C12) at screening and confirmation) and clinical phenotype (inpatient emergency treatment, metabolic decompensations, clinical assessments, psychometric tests) were assessed in relation to genotype.

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Medium Chain Acyl-CoA Dehydrogenase Deficiency in Pennsylvania: Neonatal Screening Shows High Incidence and Unexpected Mutation Frequencies

Cited by 154 publications

References 12 publications

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

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

Medium-Chain Acyl CoA Dehydrogenase: Evidence for Phosphorylation

Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening

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