Beta-ketothiolase deficiency

Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase deficiency, 3-oxothiolase deficiency, or T2 deficiency (OMIM #203750), is a rare inherited disorder of isoleucine catabolism and ketone body metabolism. It is caused by mutations in the ACAT1 gene, which encodes mitochondrial acetoacetyl-CoA thiolase (T2). This enzyme plays a critical role in the breakdown of the amino acid isoleucine and in the utilization of ketone bodies for energy. When the enzyme is deficient, the body cannot properly process these metabolic pathways, leading to the accumulation of toxic organic acids in the blood and urine. The disease primarily affects the metabolic and neurological systems. Patients typically present in infancy or early childhood with episodic ketoacidotic crises, which can be triggered by illness, fasting, or increased protein intake. During these episodes, affected individuals may experience severe metabolic acidosis, vomiting, dehydration, lethargy, and, if untreated, coma. Between episodes, many patients are clinically well. Laboratory findings characteristically include elevated urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine. Some patients may develop developmental delay or neurological complications, particularly if crises are frequent or poorly managed. Treatment focuses on prevention and management of ketoacidotic episodes. This includes avoidance of prolonged fasting, moderate protein restriction (particularly limiting isoleucine intake), and aggressive management of intercurrent illnesses with intravenous glucose and fluids to prevent catabolism. Carnitine supplementation may be used to help clear accumulated organic acids. With early diagnosis, often through newborn screening using tandem mass spectrometry, and appropriate dietary and emergency management, the long-term prognosis is generally favorable, and many patients lead relatively normal lives.

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