Conboy Erin, Vairo Filippo, Schultz Matthew, Agre Katherine, Ridsdale Ross, Deyle David, Oglesbee Devin, Gavrilov Dimitar, Klee Eric W, Lanpher Brendan
Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
JIMD Rep. 2018;40:63-69. doi: 10.1007/8904_2017_59. Epub 2017 Oct 14.
We report an 8-month-old infant with decreased consciousness after a febrile episode and reduced oral intake. He was profoundly acidotic but his lactate was normal. Serum triglycerides were markedly elevated and HDL cholesterol was very low. The urine organic acid analysis during the acute episode revealed a complex pattern of relative hypoketotic dicarboxylic aciduria, suggestive of a potential fatty acid oxidation disorder. MRI showed extensive brain abnormalities concerning for a primary energy deficiency. Whole exome sequencing revealed heterozygotic HMGCS2 variants. HMGCS2 encodes mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase-2 (HMGCS2), which catalyzes the irreversible and rate-limiting reaction of ketogenesis in the mitochondrial matrix. Autosomal recessive HMG-CoA synthase deficiency (HMGCS2D) is characterized by hypoketotic hypoglycemia, vomiting, lethargy, and hepatomegaly after periods of prolonged fasting or illness. A retrospective analysis of the urine organic acid analysis identified 4-hydrox-6-methyl-2-pyrone, a recently reported putative biomarker of HMGCS2D. There was also a relative elevation of plasma acetylcarnitine as previously reported in one case. Our patient highlights a unique presentation of HMGCS2D caused by novel variants in HMGCS2. This is the first report of HMGCS2D with a significantly elevated triglyceride level and decreased HDL cholesterol level at presentation. Given this, we suggest that HMGCS2D should be considered in the differential diagnosis when hypertriglyceridemia, or low HDL cholesterol levels are seen in a child who presents with acidosis, mild ketosis, and mental status changes after illness or prolonged fasting. Although HMGCS2D is a rare disorder with nonspecific symptoms, with the advent of next-generation sequencing, and the recognition of novel biochemical biomarkers, the incidence of this condition may become better understood.
我们报告了一名8个月大的婴儿，在发热发作后意识减退，经口摄入量减少。他存在严重酸中毒，但乳酸水平正常。血清甘油三酯显著升高，高密度脂蛋白胆固醇水平极低。急性发作期间的尿有机酸分析显示出相对低酮性二羧酸尿症的复杂模式，提示可能存在脂肪酸氧化障碍。磁共振成像（MRI）显示广泛的脑部异常，提示原发性能量缺乏。全外显子测序发现杂合的HMGCS2变异。HMGCS2编码线粒体3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）合酶-2（HMGCS2），其催化线粒体基质中酮体生成的不可逆限速反应。常染色体隐性HMG-CoA合酶缺乏症（HMGCS2D）的特征是在长期禁食或患病后出现低酮性低血糖、呕吐、嗜睡和肝肿大。对尿有机酸分析的回顾性分析发现了4-羟基-6-甲基-2-吡喃酮，这是最近报道的HMGCS2D的一种假定生物标志物。如先前在一例病例中所报道的，血浆乙酰肉碱也相对升高。我们的患者突出了由HMGCS2中的新型变异导致的HMGCS2D的独特表现。这是首次报道HMGCS2D在发病时甘油三酯水平显著升高且高密度脂蛋白胆固醇水平降低。鉴于此，我们建议当在患病或长期禁食后出现酸中毒、轻度酮症和精神状态改变的儿童中发现高甘油三酯血症或低高密度脂蛋白胆固醇水平时，应在鉴别诊断中考虑HMGCS2D。尽管HMGCS2D是一种具有非特异性症状的罕见疾病，但随着下一代测序技术的出现以及新型生化生物标志物的发现，这种疾病的发病率可能会得到更好的了解。
