Phenotypic Variability and Newly Identified Mutations of the IVD Gene in Japanese Patients with Isovaleric Acidemia

Phenotypic Variability and Newly Identified Mutations of the IVD Gene in Japanese Patients with Isovaleric Acidemia

OSAMU SAKAMOTO,¹ NATSUKO ARAI-ICHINOI,¹ HIROSHI MITSUBUCHI,² YASUTSUGU CHINEN,³ HIDENORI HARUNA,⁴ HIDEHIKO MARUYAMA,⁵ HIDENORI SUGAWARA⁶ and SHIGEO KURE¹

¹Department of Pediatrics, Tohoku University School of Medicine, Sendai, Miyagi, Japan
²Department of Neonatology, Kumamoto University Hospital, Kumamoto, Kumamoto, Japan
³Department of Pediatrics, Faculty of Medicine, University of the Ryukyus, Nakagami-gun, Okinawa, Japan
⁴Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
⁵Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
⁶Yokohama City University Medical Center, Children's Medical Center, Yokohama, Kanagawa, Japan

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.

keywords —— isovaleric acidemia; isovaleryl-CoA dehydrogenase; IVD; newborn screening; tandem mass spectrometry

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Tohoku J. Exp. Med., 2015, 236, 103-106

Correspondence: Osamu Sakamoto, M.D., Ph.D., Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: osakamoto-thk@umin.ac.jp