title: Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency.
abstract: Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase (T2) deficiency) is an inherited disease of isoleucine catabolism and ketone body utilization caused by ACAT1 mutations. We identified ten Indian patients who manifested with ketoacidotic episodes of variable severity. The patients showed increased urinary excretion of isoleucine-catabolic intermediates: 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate, and tiglylglycine. Six patients had a favorable outcome, one died, and three developed neurodevelopmental sequela. Mutational analysis revealed a common (p.Met193Arg) and four novel (p.Ile323Thr, p.Ala215Asn, c.1012_1015dup, and c.730+1G>A) ACAT1 mutations. Transient expression analyses of wild-type and mutant cDNA were performed at 30, 37, and 40°C. A p.Ile323Thr mutant T2 was detected with relative enzyme activity and protein amount of 20% and 25%, respectively, compared with wild type at 37°C; it was more prevalent at 30°C but ablated at 40°C. These findings showed that p.Ile323Thr had a significant residual T2 activity with temperature-sensitive instability. Neither residual enzymatic activity nor mutant T2 protein was identified in p.Met193Arg, p.Ala215Asn, and c.1012_1015dup mutations using supernatants; however, these mutant T2 proteins were detected in insoluble pellets by immunoblot analysis. Expression analyses confirmed pathogenicity of these mutations. T2 deficiency has a likely high incidence in India and p.Met193Arg may be a common mutation in the Indian population.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.|Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt.
authors.forename: Elsayed
authors.initials: E
authors.lastname: Abdelkreem
authors.affiliation: Department of Clinical Genetics and Metabolic Medicine, Rainbow Hospital for Women and Children, Hyderabad, India.
authors.forename: Radha Rama Devi
authors.initials: RRD
authors.lastname: Akella
authors.affiliation: MILS International India, Mumbai, India.
authors.forename: Usha
authors.initials: U
authors.lastname: Dave
authors.affiliation: Department of Pediatrics, Jupiter Life Line Hospital, Thane, Maharashtra, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Sane
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Otsuka
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Sasai
authors.affiliation: Education and Training Center of Medical Technology, Chubu University, Aichi, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Aoyama
authors.affiliation: Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Nakama
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt.
authors.forename: Shaimaa
authors.initials: S
authors.lastname: Mahmoud
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abd El Aal
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan. toshi-gif@umin.net.|Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan. toshi-gif@umin.net.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukao
keywords: ACAT1; Beta-ketothiolase deficiency; Expression analysis; Ketoacidosis; Mutations; T2 deficiency