title: Phenotypic Variability and Newly Identified Mutations of the IVD Gene in Japanese Patients with Isovaleric Acidemia.
abstract: Isovaleric acidemia (IVA) is an autosomal recessive inborn error affecting leucine metabolism. It is caused by a deficiency in isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme that catalyzes the oxidation of isovaleryl-CoA to 3-methylcrotonyl-CoA. IVD is a FAD-containing enzyme, consisting of four identical subunits. Clinical features of IVA include poor feeding, vomiting, lethargy, developmental delay, metabolic acidosis, and a characteristic "sweaty foot" odor. IVA is one of the target disorders for newborn screening by tandem mass spectrometry (MS/MS). The human IVD gene is located on chromosome 15q. To date, over 50 disease-causing mutations have been reported worldwide. In this study, we searched for IVD mutations in five Japanese patients with IVA (neonatal type, two patients; chronic intermittent type, two patients; and mild biochemical type, one patient). The diagnosis of IVA was confirmed by urinary organic acid analysis using gas chromatography and mass spectrometry. All coding exons and the flanking introns in the IVD gene were amplified by PCR and were directly sequenced. We thus identified six hitherto unknown mutations (p.G94D, p.E116K, p.M167T, p.L243P, p.L246P, and c.696+1G>T) and four previously reported (p.R53P, p.R395C, p.Y403C, and p.E411K) pathogenic mutations. All patients were compound heterozygotes, and each mutation was identified in a single patient. Pathogenicity of newly identified mutations was validated using computational programs. Among them, the p.M167T is believed to influence FAD binding, as the position 167 is present in one of the FAD-binding sites. Our results have illustrated the heterogeneous mutation spectrum and clinical presentation of IVA in the Japanese patients.
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sakamoto
authors.forename: Natsuko
authors.initials: N
authors.lastname: Arai-Ichinoi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsubuchi
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Chinen
authors.forename: Hidenori
authors.initials: H
authors.lastname: Haruna
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Maruyama
authors.forename: Hidenori
authors.initials: H
authors.lastname: Sugawara
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002648:Child; D005091:Exons / Q000235:genetics; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns / Q000235:genetics; D050769:Isovaleryl-CoA Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D007930:Leucine / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D009812:Odorants; D010421:Pentanoic Acids / Q000097:blood*; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: D010421:Pentanoic Acids; D050769:Isovaleryl-CoA Dehydrogenase; D007930:Leucine; C038780:n-pentanoic acid