Journal article

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations

James J Pitt, Heidi Peters, Avihu Boneh, Joy Yaplito-Lee, Stefanie Wieser, Katrin Hinderhofer, David Johnson, Johannes Zschocke



Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase (HMCS2) deficiency results in episodes of hypoglycemia and increases in fatty acid metabolites. Metabolite abnormalities described to date in HMCS2 deficiency are nonspecific and overlap with other inborn errors of metabolism, making the biochemical diagnosis of HMCS2 deficiency difficult. Urinary organic acid profiles from periods of metabolic decompensation were studied in detail in HMCS2-deficient patients from four families. An additional six unrelated patients were identified from clinical presentation and/or qualitative identification of abnormal organic acids. The diagnosis was confirmed by sequencing and deletion/duplication analy..

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Funding Acknowledgements

We thank Ms. Avantika Mishra, Ms. Mary Eggington, and Mr. Michiel van Werkhoven for expert technical assistance; Dr. Alison Cozens for clinical input into patient management; and PD Dr. Martina Witsch-Baumgartner for molecular diagnostic work in three patients. We also thank Drs. Kevin Carpenter, Carolyn Ellaway, and Kaustuv Bhattacharya (Westmead Children's Hospital, Sydney, Australia); Mr. Lawrence Greed, Dr. Barry Lewis, and Dr. Shanti Balasubramaniam (Princess Margaret Hospital for Children, Perth, Australia); Dr. Clodagh Loughrey (Belfast Health and Social Care Trust, Belfast, UK); Drs. Lara Abulhoul and James Leonard (Institute of Child Health, London, UK); and Dr. Martin Lindner (Univ. Children's Hospital, Heidelberg, Germany) for referring patients for genetic studies, agreeing to the publication of mutations, and providing clinical details. We also thank Drs. Anders Nygren and Jan Shouten (MRC Holland, Amsterdam, The Netherlands) for designingMLPA probes for the HMGCS2 gene and the reviewer of this manuscript for pointing out the possible involvement of L-3-hydroxybuyrate in ketone formation. A preliminary report of sections of this work was presented previously in abstract form (Pitt et al. 2009). This work was supported by the Victorian Government's Operational Infrastructure Support Program.