Grünert Sarah C, Baumgartner Matthias R, Bouchereau Juliette, Burlina Alberto, Clayton Peter T, de Las Heras Javier, Dionisi-Vici Carlo, Gemperle-Britschgi Corinne, Haase Claudia, Korman Stanley H, Krämer Johannes, Kühlwein Eva, Maier Esther M, Maiorana Arianna, Schiff Manuel, Schmid Carl Ulrich, Tangeraas Trine, Yamamoto Raina, Zschocke Johannes, Sass Jörn Oliver
Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Switzerland.
Genet Med. 2025 Sep;27(9):101484. doi: 10.1016/j.gim.2025.101484. Epub 2025 Jun 11.
Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in HMGCS2. Only 59 patients with this disorder have been reported so far.
We performed a comprehensive literature search to identify all published cases of HMGCS2D (n = 59). Additionally, the data of 16 patients with this disorder who are yet undescribed were collected. Clinical course, biochemical findings, and mutation data are highlighted and discussed. An overview on all HMGCS2 variants reported in patients is provided.
Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only 1 variant was identified to be common, (HMGCS2) NM_005518.4:c.634G>A p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established.
This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D, including a list of HMGCS2 variants identified in affected individuals.
酮体是一种重要的能量来源，对大脑的能量供应有很大贡献。线粒体3-羟基-3-甲基戊二酰辅酶A合酶缺乏症（HMGCS2D）是一种常染色体隐性酮生成障碍疾病，由HMGCS2基因的双等位基因变异引起。迄今为止，仅报道了59例该疾病患者。
我们进行了全面的文献检索，以确定所有已发表的HMGCS2D病例（n = 59）。此外，收集了16例尚未描述的该疾病患者的数据。重点突出并讨论了临床病程、生化检查结果和突变数据。提供了患者中报道的所有HMGCS2变异的概述。
68例患者（91%）出现急性代谢失代偿，大多在生命的第一年内，但在新生儿期之后。在几个家族中发现了无症状个体。6例患者（8%）死亡，主要在最初的代谢危机期间。存活患者的神经长期预后良好，几乎所有患者（98%）发育正常。仅发现1种变异（HMGCS2）NM_005518.4:c.634G>A p.(Gly212Arg)常见，在6个家族中发现。无法建立基因型与表型的相关性。
这项全面的数据分析提供了所有已发表的HMGCS2D患者的概述，包括在受影响个体中鉴定出的HMGCS2变异列表。
