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

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

Journal: Genetics in medicine : official journal of the American College of Medical Genetics 2025;27(9):101484

PMID: 40515583

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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.

Address: Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany. Electronic address: [email protected].; Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Switzerland.; Reference Center for Inherited Metabolic Diseases, Hôpital Necker-Enfants Malades, APHP and Université Paris Cité, Paris, France.; Division of Inherited Metabolic Diseases, University Hospital Padua, Padua, Italy.; Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.; Division of Paediatric Metabolism, CIBERER, MetabERN, Cruces University Hospital, University of the Basque Country (UPV/EHU), Biobizkaia Health Research Institute, Bilbao, Spain.; Division of Metabolic Diseases and Hepatology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.; Division of Metabolism, University Children's Hospital Zurich, Zurich, Switzerland.; Klinik für Kinder- und Jugendmedizin, Erfurt, Germany.; Wilf Children's Hospital, Shaare Zedek Medical Center, Jerusalem, Israel.; Division of Pediatric Neurology, Metabolics and Social Pediatrics, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm University, Ulm, Germany.; University Children's Hospital Zurich - Eleonore Foundation, Zürich, Switzerland.; Department of Inborn Errors of Metabolism, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany.; Reference Center for Inherited Metabolic Diseases, Hôpital Necker-Enfants Malades, APHP and Université Paris Cité, Paris, France; Inserm UMRS_1163, Institut Imagine, Paris, France.; Praxis für Kinder- und Jugendmedizin, Miltenberg, Germany.; Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.; MVZ Dr Eberhard Partner Dortmund ÜBAG, Dortmund, Germany.; Institute for Human Genetics, Medical University Innsbruck, Innsbruck, Austria.; Research Group Inborn Errors of Metabolism, Department of Natural Sciences and Institute for Functional Gene Analytics (IFGA), Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany. Electronic address: [email protected].

DOI: 10.1016/j.gim.2025.101484

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MeSH Terms: Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Hydroxymethylglutaryl-CoA Synthase, Ketone Bodies, Mitochondria, Mitochondrial Diseases, Mutation