Clinical, Biochemical and Genetic Analyses in Two Korean Patients with Medium-chain Acyl-CoA Dehydrogenase Deficiency
1
조회
0
다운로드
2
인용
0
참고문헌
키워드
초록
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive hereditary metabolic disorder of mitochondrial fatty acid β-oxidation. It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness. The most frequently isolated mutation in the acyl-CoA dehydrogenase, medium-chain (ACADM) gene of Caucasian patients with MCADD is c.985A>G, but ethnic variations exist in the frequency of this mutation. Here, we describe 2 Korean pediatric cases of MCADD, which was detected during newborn screening by tandem mass spectrometry and confirmed by molecular analysis. The levels of medium-chain acylcarnitines, including octanoylcarnitine (C8), hexanoylcarnitine (C6), and decanoylcarnitine (C10), were typically elevated. Molecular studies revealed that Patient 1 was a compound heterozygote for c.449_452delCTGA (p.Thr150ArgfsX4) and c.461T>G (p.L154W) mutations, and Patient 2 was a compound heterozygote for c.449_452delCTGA (p.Thr150ArgfsX4) and c.1189T>A (p.Y397N) mutations. We also detected asymptomatic MCADD in some patients by using a newborn screening test and confirmed it by ACADM mutation analysis. This report presents evidence of the biochemical and molecular features of MCADD in Korean patients and, to the best of our knowledge, this is the first report of the c.461T>G mutation in the ACADM gene.
Abstract
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive hereditary metabolic disorder of mitochondrial fatty acid β-oxidation. It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness. The most frequently isolated mutation in the acyl-CoA dehydrogenase, medium-chain (ACADM) gene of Caucasian patients with MCADD is c.985A>G, but ethnic variations exist in the frequency of this mutation. Here, we describe 2 Korean pediatric cases of MCADD, which was detected during newborn screening by tandem mass spectrometry and confirmed by molecular analysis. The levels of medium-chain acylcarnitines, including octanoylcarnitine (C8), hexanoylcarnitine (C6), and decanoylcarnitine (C10), were typically elevated. Molecular studies revealed that Patient 1 was a compound heterozygote for c.449_452delCTGA (p.Thr150ArgfsX4) and c.461T>G (p.L154W) mutations, and Patient 2 was a compound heterozygote for c.449_452delCTGA (p.Thr150ArgfsX4) and c.1189T>A (p.Y397N) mutations. We also detected asymptomatic MCADD in some patients by using a newborn screening test and confirmed it by ACADM mutation analysis. This report presents evidence of the biochemical and molecular features of MCADD in Korean patients and, to the best of our knowledge, this is the first report of the c.461T>G mutation in the ACADM gene.
참고문헌 (24)
- Iafolla AK, "Medium-chain acyl-coenzyme A dehydrogenase deficiency: clinical course in 120 affected children", J Pediatr, 124, pp.409~415 (1994)
- Andresen BS, "Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS", MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency, 2001, pp.68, 1408~1418
- Andresen BS, "The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype", Hum Mol Genet, 6, pp.695~707 (1997)
- Sander S, "Neonatal screening for medium chain acyl-CoA deficiency: high incidence in Lower Saxony (northern Germany)", Eur J Pediatr, 160, pp.318~319 (2001)
- Maier EM, "Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency", Hum Mutat, 25, pp.443~452 (2005)
- Grosse SD, "The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update", Genet Med, 8, pp.205~212 (2006)
- Shigematsu Y, "Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan", J Chromatogr B Analyt Technol Biomed Life Sci, 776, pp.39~48 (2002)
- Yoon HR, "Screening of newborns and high-risk group of children for inborn metabolic disorders using tandem mass spectrometry in South Korea: a three-year report", Clin Chim Acta, 354, pp.167~180 (2005)
- Purevsuren J, "A novel molecular aspect of Japanese patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD): c.449-452delCTGA is a common mutation in Japanese patients with MCADD", Mol Genet Metab, 96, pp.77~79 (2009)
- Ensenauer R, "Genotypic differences of MCAD deficiency in the Asian population: novel genotype and clinical symptoms preceding newborn screening notification", Genet Med, 7, pp.339~343 (2005)
- Yokoi K, "Acylcarnitine profiles during carnitine loading and fasting tests in a Japanese patient with medium-chain acyl-CoA dehydrogenase deficiency", Tohoku J Exp Med, 213, pp.351~359 (2007)
- Tajima G, "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", J Chromatogr B Analyt Technol Biomed Life Sci, 823, pp.122~130 (2005)
- Matsubara Y, "Molecular cloning and nucleotide sequence of cDNA encoding the entire precursor of rat liver medium chain acyl coenzyme A dehydrogenase", J Biol Chem, 262, pp.10104~10108 (1987)
- Waddell L, "Medium-chain acyl-CoA dehydrogenase deficiency: genotype- biochemical phenotype correlations", Mol Genet Metab, 87, pp.32~39 (2006)
- Van Hove JL, "Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: diagnosis by acylcarnitine analysis in blood", Am J Hum Genet, 52, pp.958~966 (1993)
- Zschocke J, "Molecular and functional characterisation of mild MCAD deficiency", Hum Genet, 108, pp.404~408 (2001)
- Nagao M, "Frequency of 985A-to-G mutation in medium-chain acyl-CoA dehydrogenase gene among patients with sudden infant death syndrome, Reye syndrome, severe motor and intellectual disabilities and healthy newborns in Japan", Acta Paediatr Jpn, 38, pp.304~307 (1996)
- Tanaka K, "A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain Acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration", Pediatr Res, 41, pp.201~209 (1997)
- Zytkovicz TH, "Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program", Clin Chem, 47, pp.1945~1955 (2001)
- Hsu HW, "Spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by newborn screening", Pediatrics, 121, pp.1108~1114 (2008)
- Flanagan SE, "Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations", Genet Test Mol Biomarkers, 14, pp.533~537 (2010)
- Ng PC, "Accounting for human polymorphisms predicted to affect protein function", Genome Res, 12, pp.436~446 (2002)
- Arnold GL, "Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State", Mol Genet Metab, 99, pp.263~268 (2010)
- Andresen BS, "A rare disease-associated mutation in the medium-chain acyl- CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl- CoA dehydrogenase (SCAD)", Am J Hum Genet, 53, pp.730~739 (1993)
