Beta-Ketothiolase Deficiency: A Comprehensive Review of Genetic Variants and Pathophysiology

Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive disorder caused by mutations in the ACAT1 gene, also known as mitochondrial acetoacetyl-coenzyme A thiolase (MAT) deficiency. This enzyme defect impairs the breakdown of ketone bodies and isoleucine, leading to significant metabolic disturbances. BKD is characterized by episodic ketoacidosis, developmental delays, muscle weakness, and potential neurological damage, typically manifesting in early childhood. To date, approximately 130 mutations have been reported in association with BKD. This review aims to elucidate the pathophysiological mechanisms underlying the disease and discusses the mutation spectrum of the ACAT1 gene, including its functional implications. Current management strategies emphasize dietary modifications, such as protein restriction and carnitine supplementation, along with vigilant monitoring to prevent metabolic crises and long-term complications. Advances in genetic research, especially the advent of gene therapies like clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, offer promising future treatment options. However, these innovative therapies require extensive research and clinical trials before they can be implemented for BKD patients. Until such advances are realized, genetic counseling remains the cornerstone of preventive care, particularly for families with a history of the disorder or known carrier status.