Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) is a rare autosomal recessive inborn error of hepatic ketogenesis, caused by mutations in HMGCS2. As its clinical and laboratory manifestations resemble many other metabolic disorders, HMGCS2D definite diagnosis presents a challenge, frequently requiring molecular tests. Only 26 patients with HMGCS2 mutations have been previously described, and this study reports the first two unrelated Thai patients, a 9-month-old male and an 8-month-old female, with HMGCS2D. During acute episodes, steatorrhea and dyslipidemia occurred, both previously unreported. Increased serum levels of triglycerides, very low density lipoproteins (VLDL), and low density lipoproteins (LDL), along with a decreased serum level of HDL were found. Both patients had hypophosphatemic encephalopathy, and the female had metabolic acidosis without hypoglycemia. Trio whole-exome sequencing (WES) revealed that the male harbored two HMGCS2 mutations, a novel c.1480C>T (p.Arg494*) and a previously reported c.1502G>C (p.Arg501Pro), while the female was compound heterozygous for the c.1502G>C (p.Arg501Pro) and a previously reported mutation, c.520T>C (p.Phe174Leu). Interestingly, c.1502G>C (p.Arg501Pro) was not only found in both of our patients but also detected heterozygously in 9 out of 1081 unrelated individuals (allele frequency of 9/2162; 0.42%) in our in-house Thai exome database. Discovery of this common mutation suggests there could be about 14 babies with HMGCS2D within 800,000 newborns in Thailand annually. Therefore, awareness of HMGCS2D among medical personnel in Thailand should be raised.

线粒体3-羟基-3甲基戊二酰辅酶A合酶2缺乏症（HMGCS2D）是由HMGCS2突变引起的罕见的常染色体隐性先天性肝酮生成错误。由于HMGCS2D的临床和实验室表现与许多其他代谢异常相似，因此明确诊断提出了挑战，经常需要进行分子检测。只有26例HMGCS2患者先前已经描述了这种突变，该研究报告了头两名不相关的泰国患者，分别为9个月大的男性和8个月大的女性，患有HMGCS2D。在急性发作期间，发生脂肪泻和血脂异常，以前均未报道。发现甘油三酯，极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）的血清水平升高，以及HDL血清水平降低。两名患者均患有低磷酸盐血症性脑病，女性患有代谢性酸中毒而无低血糖。三重奏全外显子组测序（WES）显示该雄性携带两个HMGCS2突变，一种新的c.1480C> T（p.Arg494 *）和先前报道的c.1502G> C（p.Arg501Pro），而雌性则是c.1502G> C（p.Arg501Pro）的复合杂合子，先前报道的突变c.520T> C（p.Phe174Leu）。有趣的是，不仅在我们的两个患者中都发现了c.1502G> C（p.Arg501Pro），而且在我们内部泰国外显子组的1081个无关个体中（等位基因频率为9/2162； 0.42％）中有9个杂合了数据库。发现这种常见突变表明，在泰国，每年80万新生儿中大约有14名HMGCS2D婴儿。因此，应该提高泰国医务人员对HMGCS2D的认识。