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Clinical, biochemical and genetic analyses in two Korean patients with medium-chain acyl-CoA dehydrogenase deficiency.

Woo HI, Park HD, Lee YW, Lee DH, Ki CS, Lee SY, Kim JW - Korean J Lab Med (2011)

Bottom Line: It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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 detected asymptomatic patients with MCADD 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.

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Related in: MedlinePlus

Diagram of protein structure near the c.461T>G (p.L154W) mutation. (A) Leu154 lies on the loop between the N-terminal α domain and β domain, shown in sky blue. (B) The novel Leu154Trp mutation produces side-chain clash with Glu152 (dotted pink line). Hydrogen bonds are shown by the dotted green lines.
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Figure 2: Diagram of protein structure near the c.461T>G (p.L154W) mutation. (A) Leu154 lies on the loop between the N-terminal α domain and β domain, shown in sky blue. (B) The novel Leu154Trp mutation produces side-chain clash with Glu152 (dotted pink line). Hydrogen bonds are shown by the dotted green lines.

Mentions: In Patient 1, sequence analysis of the ACADM gene revealed a known mutation, c.449_452delCTGA (p.Thr150-ArgfsX4), in exon 6 and a previously unrecognized mutation in the same exon, a T to G transversion at position 461 that would alter a leucine to tryptophan at amino acid position 154 (p.L154W) (Fig. 1). Sequencing analysis of Patient 1's parents showed that the mother was heterozygous for the c.449_452delCTGA mutation, and the father was heterozygous for the c.461T>G mutation. A control study conducted using the exon 6 targeted sequencing analyses in 340 alleles of 170 healthy subjects did not reveal any carriers of the c.461T>G mutation. The novel mutation is associated with major amino acid substitutions, and this mutation is likely to be the cause of the disorder. Using the SWISS-MODEL and Swiss-Pdb Viewer, the protein structure was analyzed: the novel mutation was predicted to cause no significant structural destruction, but it produced a side-chain clash that could result in backbone shifts in order to avoid clashes between amino acid side chains and its local backbone (Fig. 2).


Clinical, biochemical and genetic analyses in two Korean patients with medium-chain acyl-CoA dehydrogenase deficiency.

Woo HI, Park HD, Lee YW, Lee DH, Ki CS, Lee SY, Kim JW - Korean J Lab Med (2011)

Diagram of protein structure near the c.461T>G (p.L154W) mutation. (A) Leu154 lies on the loop between the N-terminal α domain and β domain, shown in sky blue. (B) The novel Leu154Trp mutation produces side-chain clash with Glu152 (dotted pink line). Hydrogen bonds are shown by the dotted green lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3111034&req=5

Figure 2: Diagram of protein structure near the c.461T>G (p.L154W) mutation. (A) Leu154 lies on the loop between the N-terminal α domain and β domain, shown in sky blue. (B) The novel Leu154Trp mutation produces side-chain clash with Glu152 (dotted pink line). Hydrogen bonds are shown by the dotted green lines.
Mentions: In Patient 1, sequence analysis of the ACADM gene revealed a known mutation, c.449_452delCTGA (p.Thr150-ArgfsX4), in exon 6 and a previously unrecognized mutation in the same exon, a T to G transversion at position 461 that would alter a leucine to tryptophan at amino acid position 154 (p.L154W) (Fig. 1). Sequencing analysis of Patient 1's parents showed that the mother was heterozygous for the c.449_452delCTGA mutation, and the father was heterozygous for the c.461T>G mutation. A control study conducted using the exon 6 targeted sequencing analyses in 340 alleles of 170 healthy subjects did not reveal any carriers of the c.461T>G mutation. The novel mutation is associated with major amino acid substitutions, and this mutation is likely to be the cause of the disorder. Using the SWISS-MODEL and Swiss-Pdb Viewer, the protein structure was analyzed: the novel mutation was predicted to cause no significant structural destruction, but it produced a side-chain clash that could result in backbone shifts in order to avoid clashes between amino acid side chains and its local backbone (Fig. 2).

Bottom Line: It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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 detected asymptomatic patients with MCADD 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.

Show MeSH
Related in: MedlinePlus