Beta-ketothiolase deficiency: two novel ACAT1 variants and a retrospective study of 76 cases in China.
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.