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.

Beta ketothiolase deficiency is a hereditary metabolic disorder caused by the pathogenic variants of the ACAT gene, which encodes for the mitochondrial enzyme acetoacetyl-CoA thiolase. Patients with a deficiency of the enzyme experience recurrent episodes of metabolic ketoacidosis. Knowledge of the clinical course of this entity, together with the available diagnostic tests, allows for its early diagnosis and prompt intervention to avoid complications or death of the infant. In this study, we present a case of a 9-month-old girl that attended the emergency room and diagnosis was made at the first episode of metabolic ketoacidosis.

Beta-ketothiolase deficiency (BKTD) is a rare inborn error of metabolism that impairs both isoleucine catabolism and ketone body utilization. The disorder may present with acute metabolic crises, often precipitated by infections or fasting, and can lead to life-threatening complications if not promptly diagnosed and managed. We report the case of a previously healthy 2.8-year-old man who developed vomiting, diarrhea, and fever, followed by progressive loss of consciousness. Neurological examination revealed generalized muscle rigidity, limb spasticity, and asymmetrical pupils. Laboratory investigations showed severe metabolic acidosis, hyperammonemia, and acute kidney injury. Neuroimaging findings included bilateral basal ganglia involvement and cerebellar abnormalities. Metabolic workup demonstrated elevated urinary organic acids, confirming BKTD, which was subsequently validated through genetic analysis identifying an ACAT1 gene mutation. This case underscores the importance of considering metabolic disorders in critically ill pediatric patients presenting with acute neurological symptoms and metabolic deterioration. Early recognition of BKT deficiency is crucial, as targeted metabolic management - including dietary intervention and comprehensive supportive care - can mitigate acute crises and prevent long-term neurological sequelae. Early metabolic evaluation in children with unexplained neurological decline remains essential. Prompt diagnosis and timely initiation of appropriate management strategies significantly improve outcomes in patients with BKTD.

Acetoacetyl-CoA thiolase deficiency, also known as Beta-ketothiolase deficiency (BKTD), is an autosomal recessive organic aciduria included in the Italian newborn screening (NBS) panel. It is caused by mutations in the ACAT1 gene, which encodes the mitochondrial acetyl-CoA acetyltransferase. Its deficiency impairs the degradation of isoleucine and acetoacetyl-CoA, leading to the accumulation of toxic metabolites. We describe three cases of BKTD. The first newborn showed increase in C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. Urinary organic acids (uOAs) revealed marked excretion of 2-methyl-3-hydroxybutyrate. Tiglylglycine was absent. Genetic testing identified the compound heterozygosity for two pathogenic ACAT1 variants. The second patient showed increased levels of C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. uOAs revealed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous VUS in ACAT1 was identified. The third case showed elevation of C4DC/C5OH, C3DC/C4OH in the NBS, with a slight increase in C5:1. uOAs showed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous missense VUS was identified in the ACAT1 gene. BKTD exhibited variable NBS biochemical phenotypes across the three cases. While C5OH and C5:1, the primary markers, were not consistently elevated in all our cases, C4OH strongly increased in all three. Our findings support the use of C4OH in a combined marker strategy to improve BKTD NBS.

Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency (OMIM #203750, *607809) is an autosomal recessive disorder of isoleucine catabolism and ketone body utilization. It is caused by mutations in the ACAT1 gene and characterized by intermittent ketoacidosis episodes triggered by ketogenic stresses, with no clinical symptoms between the episodes. Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis. T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia. This study presents data from twelve patients with T2 deficiency, diagnosed between 7 months and 22 months of age at two tertiary care centers in Palestine. The clinical, biochemical, molecular genetic data, and neurological outcomes are reviewed. We report on twelve patients (6 females and 6 males) from eight families in four different regions of the West Bank and Gaza Strip. All patients were offspring of consanguineous marriages. Ketoacidotic episodes were the predominant manifestations in all patients, and each episode was triggered by either acute gastroenteritis or upper respiratory infections. One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward. The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine. Ten of the twelve patients had favorable outcomes, while two unfortunately passed away at the time of the study. Molecular genetic analysis of the ACAT1 gene was conducted on nine patients from six families, revealing four different variants, two of which were novel. Additionally, a founder mutation was identified in six patients from three families. The study underscores the critical role of genetic research in unraveling the complexities of beta-ketothiolase deficiency and related disorders. By identifying haplotype blocks, founder mutations, and novel pathogenic variants, researchers can significantly improve diagnostic precision, enhance genetic counseling, and lay the groundwork for developing targeted therapies. We identified two novel variants and a founder mutation, thereby broadening the genetic spectrum of this rare disease.