Journal of Human Genetics https://doi.org/10.1038/s10038-018-0524-x REVIEW ARTICLE Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency Toshiyuki Fukao 1,2 ● Hideo Sasai 1 ● Yuka Aoyama 3 ● Hiroki Otsuka 1 ● Yasuhiko Ago 1 ● Hideki Matsumoto 1 ● Elsayed Abdelkreem 1,4 Received: 25 June 2018 / Revised: 18 September 2018 / Accepted: 3 October 2018 © The Author(s) under exclusive licence to The Japan Society of Human Genetics 2018 Abstract 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. Introduction Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2, EC 2.3.1.9) deficiency (OMIM #203750, *607809) was first described as an inborn error of isoleucine catabolism in 1971 [1–3]. Later this disorder was revealed to be a defect in mitochondrial acetoacetyl-CoA thiolase activity that affects both isoleucine catabolism and ketolysis [4]. Hence, this disorder is classified as an organic aciduria or as a defect in ketolysis. The disorder is clinically characterized by intermittent ketoacidotic episodes [5–7]. Our group has intensively studied T2 deficiency from both clinical and molecular perspectives [3, 8–45]. A cohort of 26 cases was previously reported in 2001 [25]. In 2017, four more cohorts of 26, 41, 32, and 10 cases from different areas and ethnicities were reported [41, 42, 46, 47]. This number of cases may be sufficient to understand the clinical manifes- tation of the disorder. Here, we review the clinical mani- festation of T2 deficiency, mainly in patients from the five reported cohorts and we discuss what remains to be solved. We will especially focus on newborn screening (NBS) and neurological manifestation of the disorder. T2 defi- ciency is included in newborn screening in some countries, although there are several reports of false-negative results [46, 48–51], including in Japanese cases [3, 15, 28]. Neurological manifestation/complication in T2 deficiency has been regarded as a sequela of severe metabolic acidosis; however, several patients have developed neurological problems without apparent severe metabolic acidosis [9, 13, 25, 26, 31, 32, 35, 38, 46, 47, 52]. Pathophysiology T2 catalyzes the interconversion of acetyl-CoA and acetoacetyl-CoA in mitochondria of both liver and * Toshiyuki Fukao toshi-gif@umin.net 1 Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 500-1194, Japan 2 Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan 3 Department of Biomedical Sciences, College of Life and Health Sciences, Education and Training Center of Medical Technology, Chubu University, Kasugai, Japan 4 Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt 1234567890();,: 1234567890();,: