β—ケトチオラーゼ欠損症

BACKGROUND AND OBJECTIVE: Congenital and developmental disorders should be detected early to avoid complications such as disability and death. The Philippine clinical practice guidelines (CPG) were developed to guide healthcare professionals on screening for congenital and developmental disorders among apparently healthy neonates and children. METHODS: Following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to CPG development recommended by the Department of Health (DOH), the steering committee, composed of clinical geneticists, developmental pediatricians, family and community medicine physicians, and ambulatory and community pediatricians, set the objectives of the CPG and formulated clinical questions in consultation with stakeholders. There were 15 priority guideline questions that covered various disorders including inborn errors of metabolism, critical congenital heart disease, developmental delay, learning disabilities, and autism. Evidence review experts systematically reviewed existing clinical practice guidelines, appraised, and summarized the evidence. A multisectoral panel formulated recommendations through a formal consensus based on the evidence summaries. The CPG was externally reviewed prior to publication. RESULTS: The CPG provides twenty (20) recommendations on fifteen (15) prioritized questions in the screening for certain congenital and developmental disorders. This CPG contains recommendations for the screening for critical congenital heart disease, thalassemia, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, developmental delay, and autism spectrum disorder. Recommendations against routine screening of cystic fibrosis, sickle cell disease, methionine adenosyltransferase deficiency, tyrosinemia, long chain 3-hydroxy acyl CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD), carnitine palmitoyl transferase types 1 and 2 (CPT1, CPT2) and glutaric aciduria type 2 (GA2), biotidinase deficiency, beta-ketothiolase deficiency, holocarboxylase synthetase deficiency, and isovaleric acidemia were made. CONCLUSION: The consensus panel recommended the screening of certain conditions, based on the available evidence, the burden of disease, the cost of the confirmatory testing, and its applicability to the population. Although this CPG intends to influence the direction of health policies for the general population, it should not be the sole basis for recreating or abolishing practices that aim to improve the health conditions of many Filipinos, particularly those part of the workforce.

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

INTRODUCTION AND IMPORTANCE: 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. CASE PRESENTATION: 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. CLINICAL DISCUSSION: 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. CONCLUSION: 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.