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

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.

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

“…In vitro studies indicate that 2MAA and 2M3HB exert neurotoxic effects (Leipnitz et al, ; Rosa et al, ). Therefore, accumulated isoleucine‐catabolic metabolites may contribute to neurological impairment in patients with T2 deficiency (Fukao et al, ; Paquay et al, ). Accordingly, T2 deficiency should be considered not only as a ketolytic defect but also as a defect in isoleucine catabolism with the potential for insidious cerebral toxicity.…”

“…This is an important topic for future research. Another unresolved issue is the therapeutic implications; the effectiveness of carnitine supplementation and protein, particularly isoleucine, restriction in preventing chronic neurological impairment remains to be determined (Fukao et al, ).…”

“…Death or permanent neurological abnormalities (e.g., gait disturbances, movement disorders, hypotonia, and mental retardation) are well documented potential complications. On the other hand, some patients remain asymptomatic (Abdelkreem et al, ; Fukao et al, , ). Of note, secondary carnitine deficiency is rare in T2 deficiency but if present, it may suppress β‐oxidation and modify the clinical manifestation of T2 deficiency from ketoacidotic to hypoketotic hypoglycemic events (Alijanpour et al, ).…”

“…Based on the T2 enzymatic activity detected on expression of variant cDNAs, patients with T2 deficiency can be divided into two categories: Those with "mild" variants, in whom at last one of the two variant alleles retains some residual T2 activity, and those with "severe" variants, in whom none of the two variant alleles has any residual T2 activity . Patients with mild variants can develop episodic ketoacidosis as severe and frequent as those with severe variants; however, the above mentioned isoleucine-catabolic intermediates, essentially TIG, tend to be more subtle in the former patients not only in stable states but also during acute ketoacidosis , Fukao et al, 2012 Fukao et al, 2014Fukao et al, , 2018. Of note, secondary carnitine deficiency is rare in T2 deficiency but if present, it may suppress β-oxidation and modify the clinical manifestation of T2 deficiency from ketoacidotic to hypoketotic hypoglycemic events (Alijanpour et al, 2019).…”

“…The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolism (Fukao et al, , ). Human tissues have, at least, five other thiolase isoenzymes: Cytosolic acetoacetyl‐CoA thiolase (CT, EC 2.3.1.9), mitochondrial 3‐ketoacyl‐CoA thiolase (T1, EC 2.3.1.16), the β subunit of the mitochondrial trifunctional enzyme that catalyzes 3‐ketoacyl‐CoA thiolase activity (TFE, EC 2.3.1.16), the peroxisomal 3‐ketoacyl‐CoA thiolase (AB‐thiolase, EC 2.3.1.16), and the peroxisomal thiolase type‐1 (SCP2‐thiolase; EC 2.3.1.176).…”