Abstract
Beta-ketothiolase (T2) deficiency is an inherited disease of isoleucine and ketone body metabolism caused by mutations in the ACAT1 gene. Between 2005 and 2016, a total of 41 patients with T2 deficiency were identified at a medical center in northern Vietnam, with an estimated incidence of one in 190,000 newborns. Most patients manifested ketoacidotic episodes of varying severity between 6 and 18 months of age. Remarkably, 28% of patients showed high blood glucose levels (up to 23.3 mmol/L). Ketoacidotic episodes recurred in 43% of patients. The age of onset, frequency of episodes, and identified genotype did not affect patient outcomes that were generally favorable, with the exception of seven cases (five died and two had neurological sequelae). Custom-tailored acute and follow-up management was critical for a positive clinical outcome. Two null mutations, c.622C>T (p.Arg208*) and c.1006-1G>C (p.Val336fs), accounted for 66% and 19% of all identified ACAT1 mutant alleles, respectively. Most patients showed characteristic biochemical abnormalities. A newborn screening program could be expected to have a high yield in Vietnam. Investigation findings of haplotypes linked to the most common ACAT1 mutation (c.622C>T) are consistent with an ancient common founder of mutation-bearing chromosomes belonging to the Kinh ethnic population. The direct management and long-term follow-up of a large number of T2-deficient patients enabled us to study the natural history of this rare disease.
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Abdelkreem E, Otsuka H, Sasai H et al (2016) Beta-ketothiolase deficiency: resolving challenges in diagnosis. J Inborn Errors Metab Screen 4:1–9
Akella RR, Aoyama Y, Mori C, Lingappa L, Cariappa R, Fukao T (2014) Metabolic encephalopathy in beta-ketothiolase deficiency: the first report from India. Brain Dev 36:537–540
Aramaki S, Lehotay D, Sweetman L, Nyhan WL, Winter SC, Middleton B (1991) Urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate and tiglylglycine after isoleucine loading in the diagnosis of 2-methylacetoacetyl-CoA thiolase deficiency. J Inherit Metab Dis 14:63–74
Bonnefont JP, Specola NB, Vassault A et al (1990) The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr 150:80–85
Buhaş D, Bernard G, Fukao T, Décarie JC, Chouinard S, Mitchell GA (2013) A treatable new cause of chorea: beta-ketothiolase deficiency. Mov Disord 28:1054–1056
Daum RS, Lamm PH, Mamer OA, Scriver CR (1971) A “new” disorder of isoleucine catabolism. Lancet 2:1289–1290
den Dunnen JT, Dalgleish R, Maglott DR et al (2016) HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat 37:564–569
Erdol S, Ture M, Yakut T et al (2016) A Turkish patient with succinyl-CoA:3-oxoacid CoA transferase deficiency mimicking diabetic ketoacidosis. J Inborn Errors Metab Screen 4:1–5
Fu X, Iga M, Kimura M, Yamaguchi S (2000) Simplified screening for organic acidemia using GC/MS and dried urine filter paper: a study on neonatal mass screening. Early Hum Dev 58:41–55
Fukao T, Scriver CR, Kondo N, T2 Collaborative Working Group (2001) The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. Mol Genet Metab 72:109–114
Fukao T, Matsuo N, Zhang GX et al (2003) Single base substitutions at the initiator codon in the mitochondrial acetoacetyl-CoA thiolase (ACAT1/T2) gene result in production of varying amounts of wild-type T2 polypeptide. Hum Mutat 21:587–592
Fukao T, Nguyen HT, Nguyen NT et al (2010) A common mutation, R208X, identified in Vietnamese patients with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab 100:37–41
Fukao T, Maruyama S, Ohura T et al (2012) Three Japanese patients with beta-ketothiolase deficiency who share a mutation, c.431A > C (H144P) in ACAT1: subtle abnormality in urinary organic acid analysis and blood acylcarnitine analysis using tandem mass spectrometry. JIMD Rep 3:107–115
Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y (2014) Ketone body metabolism and its defects. J Inherit Metab Dis 37:541–551
Hori T, Yamaguchi S, Shinkaku H et al (2015) Inborn errors of ketone body utilization. Pediatr Int 5:41–48
Leipnitz G, Seminotti B, Amaral AU, Fernandes CG, Dutra-Filho CS, Wajner M (2010) Evidence that 2-methylacetoacetate induces oxidative stress in rat brain. Metab Brain Dis 25:261–267
Nguyễn KV (2012) Vietnam: a long history, 8th edn. The Gioi, Hanoi
O’Neill ML, Kuo F, Saigal G (2014) MRI of pallidal involvement in beta-ketothiolase deficiency. J Neuroimaging 24:414–417
Ozand PT, Rashed M, Gascon GG et al (1994) 3-Ketothiolase deficiency: a review and four new patients with neurologic symptoms. Brain Dev 16:38–45
Rannala B, Reeve JP (2001) High-resolution multipoint linkage-disequilibrium mapping in the context of a human genome sequence. Am J Hum Genet 69:159–178
Reich DE, Goldstein DB (1999) Estimating the age of mutations using variation at linked markers. In: Goldstein GB, Schlötterer C (eds) Microsatellites: evolution and applications. Oxford University Press, Oxford, pp 129–138
Risch N, de Leon D, Ozelius L et al (1995) Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 9:152–159
Sarafoglou K, Matern D, Redlinger-Grosse K et al (2011) Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. Pediatrics 128:e246–e250
Søvik O (1993) Mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency: an inborn error of isoleucine and ketone body metabolism. J Inherit Metab Dis 16:46–54
Taylor KW (1983) The birth of Vietnam. University of California Press, Berkeley
Wen P, Chen Z, Wang G et al (2016) Analysis of clinical phenotype and ACAT1 gene mutation in a family affected with beta-ketothiolase deficiency. Chin J Med Genet 33:286–291
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The authors thank Ms. Naomi Sakaguchi (technician; Gifu University) for her invaluable technical assistance.
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Toshiyuki Fukao and Yuka Aoyama received Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [Nos. 16 K09962 and 15 K01693, respectively]. Roberto Colombo received a Grant-in-Aid for Scientific Research from Regione Lombardia, Italy (Innovative Research Project 1137–2010).
Khanh Ngoc Nguyen, Elsayed Abdelkreem, Yuki Hasegawa, Ngoc Thi Bich Can, Thao Phuong Bui, Hai Thanh Le, Mai Thi Chi Tran, Hoan Thi Nguyen, Hung Thanh Trinh, Hideo Sasai, Seiji Yamaguchi, and Dung Chi Vu declare that they have no conflicts of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients (or their parents) included in the study.
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This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant nos. 16 K09962 and 15 K01693) and, in part, by Regione Lombardia, Italy (Innovative Research Project 1137–2010).
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Communicated by: Jerry Vockley
Khanh Ngoc Nguyen, Elsayed Abdelkreem, Toshiyuki Fukao and Dung Chi Vu contributed equally to this work.
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Nguyen, K.N., Abdelkreem, E., Colombo, R. et al. Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10 years’ experience of a medical center in northern Vietnam. J Inherit Metab Dis 40, 395–401 (2017). https://doi.org/10.1007/s10545-017-0026-6
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DOI: https://doi.org/10.1007/s10545-017-0026-6