Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10 years’ experience of a medical center in northern Vietnam
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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.
KeywordsMuch Recent Common Ancestor Urinary Organic Acid Newborn Screening Program Propionic Acidemia ACAT1 Mutation
The authors thank Ms. Naomi Sakaguchi (technician; Gifu University) for her invaluable technical assistance.
Compliance with ethical standards
Conflict of interest
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.
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.
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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