Analysis of the clinical phenotype and genotype features of 5 cases of beta-ketothiolase deficiency

Beta-Ketothiolase deficiency (BKTD) is a rare congenital inherited metabolic disorder associated with defects in the catabolism of isoleucine. This article introduces the clinical phenotypes and genetic variation characteristics of 5 pediatric patients with BKTD. We retrospectively analyzed the clinical manifestations, laboratory parameters and genetic testing data of 5 pediatric patients with BKTD treated at Beijing Children’s Hospital from April 2018 to October 2024. Among the 5 patients, 4 were male and 1 was female. Their ages of diagnose ranged from 6 months to 1 year and 10 months, with a median age of 9 months. The main clinical manifestations included lethargy, tachypnea, vomiting, respiratory failure, severe metabolic acidosis, and elevated ketone bodies in blood and urine after infection. The levels of 3-hydroxybutyrylcarnitine, 3-hydroxyisovalerylcarnitine, and tiglylcarnitine in the blood were elevated, reaching 2.3 to 18.1 times, 2.3 times, and 2.7 to 5.3 times the upper limits of normal, respectively. The levels of 2-methyl-3-hydroxybutyrate in urine were elevated in all 5 patients, reaching 5.3 to 80.5 times the upper limit of normal. Meanwhile, 3 patients had elevated levels of tiglylglycine and 2-methylacetoacetate in urine. Among the 5 patients, patients 1, 2, and 5 carried three previously unreported missense variations: c.439G > T (p.Val147Leu), c.193 A > T (p.Thr65Ser), and c.224 C > A (p.Ala75Asp). Patients 2 and 3 carried the splice site variation c.1163 + 5G > C and the frameshift variation c.552_555del, respectively, both of which were previously unreported. After clinical diagnosis of BKTD, the patients were given a low-protein, high-carbohydrate, low-fat diet, supplemented with L-carnitine, vitamins B1 and B2. The follow-up time ranged from 4 months to over 6 years. One patient still experienced 1 to 2 episodes of mild metabolic acidosis annually due to non-adherence to dietary management and infections, but none of the patients had severe metabolic crises. BKTD is a rare disease primarily caused by variations in the ACAT1 gene. The Onset triggers, symptoms, and lab results varied widely among patients. This study not only reported new genetic findings but also stressed the importance about recognizing BKTD in infants and toddlers with non-diabetic ketoacidosis. Early acute care and sustained follow-up secure better outcomes.