2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways

Abstract

Background: 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetylcoenzyme A thiolase T2/ "beta-ketothiolase") is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1. Methods: We performed a systematic literature search for all available clinical descriptions of patients with MATD. Two hundred forty-four patients were identified and included in this analysis. Clinical course and biochemical data are presented and discussed. Results: For 89.6% of patients at least one acute metabolic decompensation was reported. Age at first symptoms ranged from 2 days to 8 years (median 12 months). More than 82% of patients presented in the first 2 years of life, while manifestation in the neonatal period was the exception (3.4%). 77.0% (157 of 204 patients) of patients showed normal psychomotor development without neurologic abnormalities. Conclusion: This comprehensive data analysis provides a systematic overview on all cases with MATD identified in the literature. It demonstrates that MATD is a rather benign disorder with often favourable outcome, when compared with many other organic acidurias.

C4OH is a Potential Screening Marker - A Multicenter Retrospective Study of Patients with Beta-Ketothiolase Deficiency in China

“…Fukao et al reported a 6year-old Japanese boy who was initially diagnosed with BKTD based on metabolic pro les, however, enzyme activity assays and mutation analysis nally con rmed the patient had HSD10MD [21]. Grunert et al recently described two patients who may actually have HSD10MD but were misdiagnosed as BKTD in earlier reports [1]. Thus the diagnosis of BKTD cannot be based solely on metabolite data.…”

“…Beta-ketothiolase de ciency (BKTD, OMIM #203750) is an autosomal recessive disorder caused by a defect in mitochondrial acetoacetyl-CoA thiolase (T2, EC 2.3.1.9), affecting both isoleucine catabolism and ketolysis [1][2][3].…”

“…Since the rst description of BKTD in 1971, approximately 250 patients have been detected worldwide [1]. While several retrospective studies investigating BTKD patients in various ethnic backgrounds have been reported [7][8][9][10], scant information is available regarding the incidence, NBS, and mutational spectrum in China.…”

Cardiac Complications of Propionic and Other Inherited Organic Acidemias

“…2-methylacetoacetyl-CoA thiolase (MAT; also known as β-ketothiolase, acetoacetyl-CoA thiolase, T2) deficiency results from pathogenic variants in ACAT1 , and is an organic aciduria involving defects in ketone body metabolism (ketolysis) and BCAA catabolism ( 90 ). MAT is involved in two metabolic pathways: (1) isoleucine catabolism, where it cleaves 2-methylacetoacetyl-CoA to propionyl-CoA and acetyl-CoA; (2) utilization of ketone bodies (ketolysis), cleaving acetoacetyl-CoA to acetyl-CoA ( 91 ). MAT deficiency was first described by Daum et al ( 92 ) as β-ketothiolase deficiency in a 6-year-old boy with severe metabolic acidosis and significant concentrations of the organic acids α-methyl-β-hydroxybutyric acid and α-methylacetoacetate in urine.…”

“…It can present clinically similar to ketotic hypoglycaemia and succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency (see next Section ), thus enzymatic diagnosis to confirm MAT deficiency is important ( 90 ). In total, 244 patients have been identified and reported thus far ( 91 ) but only one case had cardiac complications, an 8-year-old girl who died due to HF secondary to severe DCM ( 93 ).…”