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Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency


Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency (OMIM #203750, *607809) is an inborn error of metabolism that affects isoleucine catabolism and ketone body metabolism. This disorder is clinically characterized by intermittent ketoacidotic crises under ketogenic stresses. In addition to a previous 26-case series, four series of T2-deficient patients were recently reported from different regions. In these series, most T2-deficient patients developed their first ketoacidotic crises between the ages of 6 months and 3 years. Most patients experienced less than three metabolic crises. Newborn screening (NBS) for T2 deficiency is performed in some countries but some T2-deficient patients have been missed by NBS. Therefore, T2 deficiency should be considered in patients with severe metabolic acidosis, even in regions where NBS for T2 deficiency is performed. Neurological manifestations, especially extrapyramidal manifestations, can occur as sequelae to severe metabolic acidosis; however, this can also occur in patients without any apparent metabolic crisis or before the onset of metabolic crisis.

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We thank Professor emeritus Tadao Orii (Gifu University) and Professor emeritus Seiji Yamaguchi (Shimane University) for their mentorship, Professor Grant Mitchell and Professor Oliver Sass for long-term collaborations and for discussions on defective ketone body metabolism. We also thank Ms Naomi Sakaguchi for her dedicated assistance with laboratory work. This research was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant Numbers 16K09962, 15K01693], by AMED under Grant Number JP17ek0109276, and by Health and Labour Sciences Research Grants (H29-nanchitou(nan)-ippan-051) for Research on rare and intractable diseases. We thank Jeremy Allen, PhD, from Edanz Group ( for editing a draft of this manuscript.


This research was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant Numbers 16K09962, 15K01693], by AMED under Grant Number JP17ek0109276, and by Health and Labour Sciences Research Grants [H29-nanchitou(nan)-ippan-051] for Research on rare and intractable diseases.

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Correspondence to Toshiyuki Fukao.

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Fukao, T., Sasai, H., Aoyama, Y. et al. Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency. J Hum Genet 64, 99–111 (2019).

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