Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy
-
Yujuan Wang
Abstract
Objectives
Mitochondrial acetoacetyl-CoA thiolase (beta-ketothiolase, T2) is necessary for the catabolism of ketone bodies andisoleucine. T2 deficiency is an autosomal recessive metabolic disorder caused by variant in the ACAT1 gene. In this report, we describe two novel ACAT1 variant identified in a Chinese family.
Case presentation
The 9-month-old male proband was admitted to the pediatric intensive care unit for altered consciousness. At the time of admission, the patient had acidosis, drowsiness, and respiratory failure. Both urine organic acid analyses and LC–MS/MS suggested T2 deficiency. Novel compound heterozygous variant (c.871G>C and c.1016_1017del) in the ACAT1 gene were detected in the proband by WES and verified through direct sequencing. Family analysis demonstrated that the first variant was transmitted from his father and the second variant was from his mother, indicating autosomal recessive inheritance. This report is the first to describe the association of these variant with T2 deficiency based on genetic testing. Although these variant were identified in the patient’s elder sister and elder brother, they continue to be asymptomatic.
Conclusions
We identified two novel ACAT1 variants associated with T2 deficiency. The identification expands the spectrum of known variant linked to the disorder.
-
Research funding: None declared.
-
Author contributions: (I) Conception and design: Yujuan Wang and Qian Gao. (II) Administrative support: Youpeng Jin. (III) Provision of study materials or patients: Yujuan Wang, Qian Gao, and Youpeng Jin. (IV) Collection and assembly of data: Xiaowei Xin and Yi Yin. (V) Data analysis and interpretation: Yujuan Wang, Qian Gao, and Chun Zhao. (VI) Manuscript writing: All authors. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital) and with the Helsinki Declaration (as revised in 2013).
References
1. Fukao, T, Sasai, H, Aoyama, Y, Otsuka, H, Ago, Y, Matsumoto, H, et al.. Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency. J Hum Genet 2019;64:99–111. https://doi.org/10.1038/s10038-018-0524-x.Search in Google Scholar
2. Fukao, T, Yamaguchi, S, Kano, M, Orii, T, Fujiki, Y, Osumi, T, et al.. Molecular cloning and sequence of the complementary DNA encoding human mitochondrial acetoacetyl-coenzyme A thiolase and study of the variant enzymes in cultured fibroblasts from patients with 3-ketothiolase deficiency. J Clin Invest 1990;86:2086–92. https://doi.org/10.1172/jci114946.Search in Google Scholar
3. Daum, RS, Lamm, PH, Mamer, OA, Scriver, CR. A “new” disorder of isoleucine catabolism. Lancet 1971;2:1289–90. https://doi.org/10.1016/s0140-6736(71)90605-2.Search in Google Scholar
4. Fukao, T, Mitchell, G, Sass, JO, Hori, T, Orii, K, Aoyama, Y. Ketone body metabolism and its defects. J Inherit Metab Dis 2014;37:541–51. https://doi.org/10.1007/s10545-014-9704-9.Search in Google Scholar PubMed
5. Hori, T, Yamaguchi, S, Shinkaku, H, Horikawa, R, Shigematsu, Y, Takayanagi, M, et al.. Inborn errors of ketone body utilization. Pediatr Int 2015;57:41–8. https://doi.org/10.1111/ped.12585.Search in Google Scholar PubMed
6. Abdelkreem, E, Harijan, RK, Yamaguchi, S, Wierenga, RK, Fukao, T. Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Hum Mutat 2019;40:1641–63. https://doi.org/10.1002/humu.23831.Search in Google Scholar PubMed PubMed Central
7. Lin, Y, Yang, Z, Yang, C, Hu, H, He, H, Niu, T, et al.. C4OH is a potential newborn screening marker-a multicenter retrospective study of patients with beta-ketothiolase deficiency in China. Orphanet J Rare Dis 2021;16:224. https://doi.org/10.1186/s13023-021-01859-5.Search in Google Scholar PubMed PubMed Central
8. Nguyen, KN, Abdelkreem, E, Colombo, R, Hasegawa, Y, Can, NT, Bui, TP, 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 2017;40:395–401. https://doi.org/10.1007/s10545-017-0026-6.Search in Google Scholar PubMed
9. Su, L, Li, X, Lin, R, Sheng, H, Feng, Z, Liu, L. Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene. Metab Brain Dis 2017;32:2063–71. https://doi.org/10.1007/s11011-017-0097-y.Search in Google Scholar PubMed
10. Fukao, T, Scriver, CR, Kondo, N, t2 Collaborative Working G. 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 Metabol 2001;72:109–14. https://doi.org/10.1006/mgme.2000.3113.Search in Google Scholar PubMed
11. Stéphanie, P, Agnès, B, Samia, P, Jean-François, B, Pascale, L, Dries, D, et al.. Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis. J Inherit Metab Dis 2017;40:415–22. https://doi.org/10.1007/s10545-017-0021-y.Search in Google Scholar PubMed
© 2022 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review Article
- Effects and dose-response relationships of exercise intervention on weight loss in overweight and obese children: a meta-regression and system review
- Original Articles
- Diabetic ketoacidosis in children with new-onset type 1 diabetes mellitus: demographics, risk factors and outcome: an 11 year review in Hong Kong
- Incidence tendency, etiological classification and outcome of congenital hypothyroidism in Guangzhou, China: an 11-year retrospective population-based study
- Metabolically healthy obesity in a paediatric obesity clinic
- Universal salt iodization potentially contributes to health equity: socio-economic status of children does not affect iodine status
- Association between clinical variations and copy number variations in cases with Turner syndrome
- The mediating function of obesity on endocrine-disrupting chemicals and insulin resistance in children
- Relationship between prolactin level and puberty in girls with early breast development
- Pattern of presentation of paediatric endocrine disorders in a Nigerian tertiary institution: an 11-year survey
- Case Reports
- Novel non-stop variant of the NR0B1 gene in two siblings with adrenal hypoplasia congenita
- Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy
- Craniosynostosis in a patient with Fanconi–Bickel syndrome: a case report
- Severe loss of adipose tissue in a Vietnamese lipodystrophy patient caused by LMNA p.G465D mutation: a first clinical characterization and two-year follow-up
- The response to growth hormone treatment in a child with short stature, growth hormone deficiency and autosomal dominant cutis laxa type 3 – case report
- Novel homozygous inactivating mutation in the luteinizing hormone receptor gene (LHCGR) associated with 46, XY DSD in a Moroccan family
Articles in the same Issue
- Frontmatter
- Review Article
- Effects and dose-response relationships of exercise intervention on weight loss in overweight and obese children: a meta-regression and system review
- Original Articles
- Diabetic ketoacidosis in children with new-onset type 1 diabetes mellitus: demographics, risk factors and outcome: an 11 year review in Hong Kong
- Incidence tendency, etiological classification and outcome of congenital hypothyroidism in Guangzhou, China: an 11-year retrospective population-based study
- Metabolically healthy obesity in a paediatric obesity clinic
- Universal salt iodization potentially contributes to health equity: socio-economic status of children does not affect iodine status
- Association between clinical variations and copy number variations in cases with Turner syndrome
- The mediating function of obesity on endocrine-disrupting chemicals and insulin resistance in children
- Relationship between prolactin level and puberty in girls with early breast development
- Pattern of presentation of paediatric endocrine disorders in a Nigerian tertiary institution: an 11-year survey
- Case Reports
- Novel non-stop variant of the NR0B1 gene in two siblings with adrenal hypoplasia congenita
- Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy
- Craniosynostosis in a patient with Fanconi–Bickel syndrome: a case report
- Severe loss of adipose tissue in a Vietnamese lipodystrophy patient caused by LMNA p.G465D mutation: a first clinical characterization and two-year follow-up
- The response to growth hormone treatment in a child with short stature, growth hormone deficiency and autosomal dominant cutis laxa type 3 – case report
- Novel homozygous inactivating mutation in the luteinizing hormone receptor gene (LHCGR) associated with 46, XY DSD in a Moroccan family
