β—ケトチオラーゼ欠損症

OBJECTIVES: Ketone body metabolism defects are rare inherited disorders that may present with life-threatening metabolic crises in childhood. This study aimed to describe and compare clinical, biochemical, and genetic findings in patients with three ketone metabolism defects. METHODS: In this retrospective study, data from eight genetically confirmed patients were analyzed: 3 with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2), 4 with beta-ketothiolase deficiency (BKTD), and 1 with succinyl-CoA:3-oxoacid CoA transferase deficiency (SCOT). Patients were followed at the Pediatric Nutrition and Metabolism Department of Adana City Training and Research Hospital since October 2023. RESULTS: Eight patients (5 female, 3 male) were included; consanguinity was present in 7 families. Triggers included vaccination, infections, gastroenteritis, and dietary changes. All presented with severe metabolic acidosis requiring hemodialysis. Ketone levels were absent/very low in HMGCS2 deficiency and markedly elevated in BKTD and SCOT deficiency. Hypoglycemia occurred only in HMGCS2, while hyperglycemia was seen in BKTD and SCOT. Hepatomegaly was present in all HMGCS2, SCOT patients and in half of BKTD cases. Elevated 3-hydroxybutyrylcarnitine/3-hydroxyisobutyrylcarnitine (C4-OH) was found in all BKTD patients. One HMGCS2 patient had thrombocytopenia and coagulopathy. Genetic analysis identified homozygous pathogenic/likely pathogenic variants in HMGCS2, ACAT1, and OXCT1, including three novel variants. All patients remained clinically stable on dietary treatment. CONCLUSIONS: HMGCS2 deficiency, BKTD, and SCOT deficiency show overlapping features but can be distinguished by ketone levels, glucose patterns, and acylcarnitine profiles. Novel variants expand the mutational spectrum. Early diagnosis and management are crucial to prevent irreversible neurological damage.

BACKGROUND: Beta-ketothiolase deficiency (BKTD) is a rare autosomal recessive metabolic disorder affecting isoleucine catabolism and ketone body utilization, demonstrating marked clinical and biochemical heterogeneity. This study aims to characterize the longitudinal clinical, biochemical, and genetic features of a single-center BKTD cohort and evaluate phase-dependent dynamics in metabolic biomarkers during acute crises and stable follow-up periods. METHODS: Twenty patients from 11 families diagnosed with BKTD were included in this retrospective study. Longitudinal clinical findings, plasma acylcarnitines via LC-MS/MS, and urinary organic acids via GC-MS were comprehensively evaluated during both acute catabolic crises and stable follow-up intervals. ACAT1 variants and genotype-phenotype correlations were statistically analyzed. RESULTS: The median age at diagnosis was 9.5 months, and parental consanguinity was present in 81.8% of families. Clinical manifestations ranged from asymptomatic disease to severe metabolic crises, with neurological involvement in 10% of patients and mortality in 5%. The most frequent ACAT1 variant was c.158G > A, accounting for 42.1% of cases. Plasma C5OH was the most consistent biomarker, remaining elevated in 100% of acute and 97.1% of stable samples. Plasma C5:1 was elevated in 85.7% and 73.5% of acute and stable samples, respectively. In contrast, C4OH elevation was observed only during acute crises (28.6%) and was absent during stable follow-up. Urinary 2M3HB and TIG were elevated in all acute samples but showed reduced positivity rates during remission. CONCLUSION: BKTD exhibits significant phase-dependent metabolic variability driven by catabolic stress. Longitudinal multi-marker evaluation is essential, as single-time-point biochemical assessments during stable remission carry a distinct risk of false-negative results.

OBJECTIVE: Beta-ketothiolase deficiency (BKTD) is a rare genetic metabolic disorder caused by variants in the ACAT1 gene. It can induce severe metabolic acidosis, which may be life-threatening. This study reports two critically ill children with newly diagnosed BKTD and includes a literature review to comprehensively depict the clinical, biochemical, and genetic profiles of BKTD patients in China. METHODS: We retrospectively analyzed clinical, biochemical, and Sanger sequencing data of two newly diagnosed BKTD children from our hospital, and systematically reviewed 74 additional Chinese cases from the literature, totaling 76 patients. RESULTS: Both newly diagnosed cases presented with severe metabolic crises. Patient 1 was found to have a globally novel compound heterozygous variant of ACAT1 (c.1222G>A and c.414A>C). Patient 2, who presented with pre-existing developmental delay and growth failure, achieved normal growth and development following metabolic intervention. The retrospective cohort study indicated that 38.0% (19/50) of the patients had neurological involvement, but only a few had permanent sequelae. Regarding screening markers, the detection rate of 2-methyl-3-hydroxybutyric acid (2M3HB) was 100% (66/66), while that of 3-hydroxybutyrylcarnitine (C4OH acylcarnitine) was 96.3% (26/27). A total of 77 variants were identified in 70 sequenced patients, confirming that c.622C>T and c.1124A>G were the most frequent variant hotspots in the Chinese population, differing from those reported in other countries. CONCLUSION: Acute episodes of BKTD are often accompanied by neurological involvement, but this neurological involvement is mostly transient and reversible. Blood C4OH acylcarnitine can serve as an effective supplement to traditional screening methods. This study discovered new variations that expand the variant spectrum of ACAT1 and identified the ACAT1 gene variant hotspots in the Chinese population. Overall, this study comprehensively and systematically depicts the disease profile of BKTD patients in China, providing valuable baseline data for clinical diagnosis and genetic counseling in the country.

Beta-ketothiolase deficiency (BKTD), also called mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is a rare autosomal recessive inborn error of metabolism affecting isoleucine catabolism and ketone body utilization. Although recurrent ketoacidotic crises are the hallmark of the disease, neurological complications-particularly basal ganglia injury-are increasingly recognized. We report a 2-year-old girl with known BKTD who presented with severe euglycemic ketoacidosis and acute encephalopathy. Initial CT showed symmetric hypodensity confined to the bilateral globus pallidi. Follow-up CT during ongoing metabolic instability demonstrated interval progression to involve the bilateral putamina and cerebral peduncles. MRI, obtained after referral, revealed nonenhancing T2/FLAIR hyperintense, T1 hypointense globus pallidus lesions without diffusion restriction but with punctate SWI hypointensities consistent with microcystic cavitary degeneration and microhemorrhage. There were additional diffusion-restricting lesions in the bilateral cerebral peduncles, small nonrestricting white matter foci in the frontal and right parietal lobes, and generalized cerebral atrophy. A baseline MRI 17 months earlier had been normal. This case illustrates the evolution from acute pallidal injury to irreversible basal ganglia necrosis with microhemorrhage and concurrent acute/subacute tract involvement, and highlights how CT and MRI together can characterize the spectrum of BKTD-related brain injury.

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.