Identification of a Novel Mutation in Patients with Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Yang, Bing; Ding, Jindong; Zhou, Changcheng; Dimachkie, Mazen M.; Sweetman, Lawrence; Dasouki, Majed; Wilkinson, Jeff; Roe, Charles R.

doi:10.1006/mgme.2000.2978

Cited by 15 publications

(8 citation statements)

References 10 publications

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“…The functional consequence can be expected to be similar to an adjacent point mutation (c.617G4T) substituting leucine for arginine at the same codon. This alteration was previously found in two unrelated clinically affected MCADD patients [Yang et al, 2000] and can therefore be assumed to be deleterious to MCAD protein function. 5) Protein alignments across species revealed that all novel missense mutations affect amino acid residues that are highly conserved in acyl-CoA-dehydrogenases of other eukaryotic organisms (data not shown).…”

Section: Spectrum Of Acadm Sequence Variationsmentioning

confidence: 60%

“…This study revealed two rare ACADM variations in a homozygous state (c.799G4A and c.616C4T) that were associated with acylcarnitine concentrations in the range of a ''mild'' biochemical phenotype (Table 6) similar to patients bearing the c.199T4C alteration (group 3). Both c.799G4A and c.617G4T (affecting the same amino acid position as c.616C4T) were previously reported to occur in symptomatic MCADD patients in a compound heterozygous state with 985A4G [Andresen et al, 1997;Yang et al, 2000]. Additionally, the variation c.799G4A showed two molecular defects in E. coli expression studies, namely decreased enzyme activity and hindered tetramer assembly, and is therefore considered to be severe [Andresen et al, 1997].…”

Section: Discussionmentioning

confidence: 92%

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Population spectrum ofACADMgenotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency

et al. 2005

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Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most frequent inherited defect of fatty acid oxidation, with a significant morbidity and mortality in undiagnosed patients. Adverse outcomes can effectively be prevented by avoiding metabolic stress and following simple dietary measures. Therefore, prospective newborn screening (NBS) is being proposed for this condition. However, technical validation of MCADD population screening and assessment of its overall benefit require broadening of the as-yet-scarce knowledge of the MCADD genetic heterogeneity unraveled by NBS and its phenotypic consequences. Here, we describe the entire spectrum of sequence variations occurring in newborns with MCADD in the population of Bavaria, Germany, in relation to the biochemical phenotype. Among 524,287 newborns, we identified 62 cases of MCADD, indicating a birth incidence of 1 in 8,456. In all of the 57 newborns available for analysis, two alterations within the MCADD gene (ACADM) were identified. The most prevalent alteration c.985A>G (Lys329Glu) occurred in 27 (47%) newborns in the homozygous and in 18 (32%) in the heterozygous state (63% of defective alleles). The mild folding variant c.199T>C (Tyr67His) was identified in nine individuals, six of them being compound heterozygous with c.985A>G (Lys329Glu). Neither of the prevalent alterations were found in the remaining nine newborns. A total of 18 sequence variations were identified; 13 of them were novel: eight missense mutations, one nonsense mutation, two splice variants, and two small deletions. The remaining five were previously reported in MCADD patients. The ACADM heterogeneity uncovered was larger as anticipated from previous c.985A>G (Lys329Glu) carrier screening data. In addition, we show that MCADD appears to occur as frequently in Turkish newborns as in the native German population. Our data validate that biochemical NBS for MCADD is a highly specific procedure for disease detection, with the identification of a significant share of milder biochemical phenotypes, such as c.199T>C (Tyr67His). These show statistically lower acylcarnitine markers, allowing us to distinguish subgroups within the spectrum of ACADM sequence variations that correlate to biochemical MCADD disease expression. Our data might provide technical and medical guidance for decision making in the worldwide efforts to introduce MCADD population screening.

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Section: Spectrum Of Acadm Sequence Variationsmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 92%

Population spectrum ofACADMgenotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency

et al. 2005

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“…Although at least one allele was found to harbor the 985A > G mutation in more than 90% of Caucasian patients [23,24], previous studies on the prevalence of this mutation failed to identify any mutant allele among Japanese newborns [24][25][26]. To our knowledge other than 985A > G, 49 sporadic mutations have been reported [17,[27][28][29][30][31][32][33][34][35][36][37][38][39], only two of which were definitely documented in non-Caucasian subjects [37,39]. None of these various mutations was observed in the three patients in this study, except 157C > T in one allele of patient 1, which had been identified in two symptomatic European patients [28].…”

Section: Discussionmentioning

confidence: 91%

Enzymatic diagnosis of medium-chain acyl-CoA dehydrogenase deficiency by detecting 2-octenoyl-CoA production using high-performance liquid chromatography: A practical confirmatory test for tandem mass spectrometry newborn screening in Japan

Tanaka

Sakura

Yofune

et al. 2005

Journal of Chromatography B

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“…A 30-year-old man presented with rhabdomyolysis, muscle weakness, and acute encephalopathy after exposure to cold without food intake [Ruitenbeek et al, 1995]. The third patient was 19 years old when she had an attack of alteration in consciousness, followed by one day of nausea, vomiting, and drowsiness in connection with severe dehydration [Yang et al, 2000].…”

Section: Medium-chain Acyl-coa Dehydrogenase (Mcad) Deficiencymentioning

confidence: 99%

Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship

et al. 2001

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Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype-phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype-phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders.

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Identification of a Novel Mutation in Patients with Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Cited by 15 publications

References 10 publications

Population spectrum ofACADMgenotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency

Population spectrum ofACADMgenotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency

Enzymatic diagnosis of medium-chain acyl-CoA dehydrogenase deficiency by detecting 2-octenoyl-CoA production using high-performance liquid chromatography: A practical confirmatory test for tandem mass spectrometry newborn screening in Japan

Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship

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