A novel likely pathogenic ACAT1 variant in a Mexican infant with beta-ketothiolase deficiency: Clinical and metabolic insights

Beta-ketothiolase deficiency is a rare autosomal recessive disorder caused by impaired mitochondrial acetoacetyl-CoA thiolase activity due to pathogenic variants in the ACAT1 gene. It is characterized by recurrent episodes of ketoacidosis triggered by catabolic stress, with variable clinical severity and risk of life-threatening metabolic decompensation. We report the case of a female infant born to consanguineous parents who presented with recurrent episodes of high–anion gap metabolic acidosis and progressive clinical deterioration. At 8 months of age, she developed respiratory distress and neurological impairment requiring prolonged hospitalization, including a 36-day stay in the pediatric intensive care unit complicated by pneumonia, ultimately requiring tracheostomy, as well as gastrostomy and fundoplication due to feeding difficulties. Following a brief discharge, she experienced rapid metabolic decompensation and was referred to our unit. Biochemical evaluation revealed elevated acylcarnitines, including C3DC-C4OH (0.46 μmol/L; reference ≤0.31), C4DC-C5OH (0.99 μmol/L; reference ≤0.58), and C5:1 (0.20 μmol/L; reference ≤0.05). Urine organic acid analysis demonstrated increased excretion of tiglyglycine, 2-methyl-3-hydroxybutyric acid, adipic acid, 3-hydroxybutyrate, and acetoacetate, consistent with impaired isoleucine catabolism. Clinically, the patient exhibited recurrent episodes of severe high–anion gap metabolic acidosis characterized by markedly reduced bicarbonate levels, elevated anion gap values, and compensatory respiratory alkalosis, reflecting ongoing metabolic instability. Molecular analysis identified a novel homozygous likely pathogenic ACAT1 variant (c.394G>C; p.Ala132Pro), establishing the diagnosis. Despite metabolic management including high-dose glucose infusion, protein restriction, and levocarnitine supplementation, the patient died following a gastroenteritis-triggered metabolic crisis. This case provides clinical and metabolic insights into beta-ketothiolase deficiency associated with a novel likely pathogenic ACAT1 variant. It highlights the importance of integrating biochemical and molecular findings for early diagnosis, as well as the critical role of preventing catabolic stress to avoid fatal metabolic decompensation. These findings support the expansion of neonatal screening strategies to improve outcomes in affected patients. • Novel likely pathogenic ACAT1 variant associated with beta-ketothiolase deficiency. • Recurrent high–anion gap metabolic acidosis indicates metabolic instability. • Biochemical and molecular integration is essential for diagnosis. • High risk of fatal decompensation during catabolic stress. • Early detection and expanded neonatal screening are critical.