Abstract
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 analysis of the HMGCS2 gene. Seven related novel organic acids were identified in urine profiles. Five of them (3,5-dihydroxyhexanoic 1,5 lactone; trans-5-hydroxyhex-2-enoate; 4-hydroxy-6-methyl-2-pyrone; 5-hydroxy-3-ketohexanoate; 3,5-dihydroxyhexanoate) were identified by comparison with synthesized or commercial authentic compounds. We provisionally identified trans-3-hydroxyhex-4-enoate and 3-hydroxy-5-ketohexanoate by their mass spectral characteristics. These metabolites were found in samples taken during periods of decompensation and normalized when patients recovered. When cutoffs of adipic >200 and 4-hydroxy-6-methyl-2-pyrone >20 μmol/mmol creatinine were applied, all eight samples taken from five HMCS2-deficient patients during episodes of decompensation were flagged with a positive predictive value of 80 % (95 % confidence interval 35–100 %). Some ketotic patients had increased 4-hydroxy-6-methyl-2-pyrone. Molecular studies identified a total of 12 novel mutations, including a large deletion of HMGCS2 exon 1 in two families, highlighting the need to perform quantitative gene analyses. There are now 26 known HMGCS2 mutations, which are reviewed in the text. 4-Hydroxy-6-methyl-2-pyrone and related metabolites are markers for HMCS2 deficiency. Detection of these metabolites will streamline the biochemical diagnosis of this disorder.
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Abbreviations
- 4HMP:
-
4-hydroxy-6-methyl-2-pyrone
- HMCS2:
-
Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase protein
- MLPA:
-
Multiplex ligation-dependent probe amplification
References
Aledo R, Zschocke J, Pie J et al (2001) Genetic basis of mitochondrial HMG-CoA synthase deficiency. Hum Genet 109(1):19–23
Aledo R, Mir C, Dalton RN et al (2006) Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency. J Inherit Metab Dis 29(1):207–211
Bouchard L, Robert MF, Vinarov D et al (2001) Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients. Pediatr Res 49(3):326–331
Carpenter K, Bhattacharya K, Ellaway C, Zschocke J, Pitt JJ (2010) Improved sensitivity for HMG CoA synthase detection using key markers on organic acid screen [Abstract]. J Inherit Metab Dis 33(Supplement 1):S62
Carpenter K, Moore F, Bhattacharya K (2012) HMG CoA synthase deficiency - how common is it and how good are our markers? [Abstract]. Twin Res Hum Genet 15(4):578
Duran M (2003) Disorder of mitochondrial fatty acid oxidation and ketone body handling. In: Blau N, Duran M, Blaskovics ME, Gibson KM (eds) Physician’s guide to the laboratory diagnosis of metabolic diseases, 2nd edn. Springer, Berlin, pp 309–334
Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y (2014) Ketone body metabolism and its defects. J Inherit Metab Dis 37(4):541–551
Hogg SL, Pierre GM, Buck J, Thalange NMPC, Calvin J (2012) 4-hydroxy-6-methyl-2-pyrone and ketonuria in HMG-CoA synthase deficiency [Abstract]. J Inherit Metab Dis 35(Suppl 1):S60
Morris AA, Lascelles CV, Olpin SE, Lake BD, Leonard JV, Quant PA (1998) Hepatic mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme a synthase deficiency. Pediatr Res 44(3):392–396
Pitt JJ, Peter H, Mishra A et al (2009) Mitochondrial 3-hydroxy-3-methyl-glutaryl CoA synthase deficiency may be recognised by increased concentrations of 4-hydroxy-6-methyl-2-pyrone in urine organic acid analysis [Abstract]. Mol Genet Metab 98(1–2):51
Ramos M, Menao S, Arnedo M et al (2013) New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. Eur J Med Genet 56(8):411–415
Sass JO, Kuhlwein E, Klauwer D, Rohrbach M, Baumgartner MR (2013) Hemodiafiltration in mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMG-CoA synthase) deficiency [Abstract]. J Inherit Metab Dis 36(Suppl 2):S189
Shafqat N, Turnbull A, Zschocke J, Oppermann U, Yue WW (2010) Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. J Mol Biol 398(4):497–506
Thompson GN, Hsu BY, Pitt JJ, Treacy E, Stanley CA (1997) Fasting hypoketotic coma in a child with deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. N Engl J Med 337(17):1203–1207
Wolf NI, Rahman S, Clayton PT, Zschocke J (2003) Mitochondrial HMG-CoA synthase deficiency: identification of two further patients carrying two novel mutations. Eur J Pediatr 162(4):279–280
Zschocke J, Penzien JM, Bielen R et al (2002) The diagnosis of mitochondrial HMG-CoA synthase deficiency. J Pediatr 140(6):778–780
Acknowledgments
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 designing MLPA 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.
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All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki, 1975, as revised in 2000. Informed consent was obtained from all patients for study inclusion.
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Communicated by: K. Michael Gibson
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Pitt, J.J., Peters, H., Boneh, A. et al. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations. J Inherit Metab Dis 38, 459–466 (2015). https://doi.org/10.1007/s10545-014-9801-9
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DOI: https://doi.org/10.1007/s10545-014-9801-9