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Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.

Sarah C Grünert·Matthias R Baumgartner·Juliette Bouchereau·Alberto Burlina·Peter T Clayton·Javier de Las Heras·Carlo Dionisi-Vici·Corinne Gemperle-Britschgi·Claudia Haase·Stanley H Korman·Johannes Krämer·Eva Kühlwein·Esther M Maier·Arianna Maiorana·Manuel Schiff·Carl Ulrich Schmid·Trine Tangeraas·Raina Yamamoto·Johannes Zschocke·Jörn Oliver Sass
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Abstract

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D, including a list of HMGCS2 variants identified in affected individuals.

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ChildChild, PreschoolFemaleHumansInfantInfant, NewbornMaleHydroxymethylglutaryl-CoA SynthaseKetone BodiesMitochondriaMitochondrial DiseasesMutationHMGCS2KetogenesisKetone body metabolismKetone body synthesisMitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiencyJournal ArticleMeta-AnalysisResearch Support, Non-U.S. Gov't

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Sarah C Grünert, Matthias R Baumgartner, Juliette Bouchereau, Alberto Burlina, Peter T Clayton, Javier de Las Heras, Carlo Dionisi-Vici, Corinne Gemperle-Britschgi, Claudia Haase, Stanley H Korman, Johannes Krämer, Eva Kühlwein, Esther M Maier, Arianna Maiorana, Manuel Schiff, Carl Ulrich Schmid, Trine Tangeraas, Raina Yamamoto, Johannes Zschocke, Jörn Oliver Sass. 2025-06-11. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.. https://doi.org/10.1016/j.gim.2025.101484

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