Abstract
Currently, six inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature are known. The “Primary 3-methylglutaconic aciduria,” 3-methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted “Secondary 3-methylglutaconic acidurias” (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, “not otherwise specified (NOS) 3-MGA-uria”), the origin of 3-methylglutaconic aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-methylglutaconic aciduria. After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3-methylglutaconic aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-methylglutaconic aciduria and also provides a simple test to discriminate between primary and secondary 3-methylglutaconic aciduria in regular patient care.
Competing interests: None declared
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Barth PG, Wanders RJ, Vreken P (1999) X-linked cardioskeletal myopathy and neutropenia (Barth syndrome)-MIM 302060. J Pediatr 135:273–276
Christodoulou J, McInnes RR, Jay V et al (1994) Barth syndrome: clinical observations and genetic linkage studies. Am J Med Genet 50:255–264
Duran M, Beemer FA, Tibosch AS, Bruinvis L, Ketting D, Wadman SK (1982) Inherited 3-methylglutaconic aciduria in two brothers–another defect of leucine metabolism. J Pediatr 101:551–554
Engelke UF, Kremer B, Kluijtmans LA et al (2006) NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism. NMR Biomed 19:271–278
Ensenauer R, Muller CB, Schwab KO, Gibson KM, Brandis M, Lehnert W (2000) 3-Methylglutaconyl-CoA hydratase deficiency: a new patient with speech retardation as the leading sign. J Inherit Metab Dis 23:341–344
Haan EA, Scholem RD, Pitt JJ, Wraith JE, Brown GK (1987) Episodes of severe metabolic acidosis in a patient with 3-methylglutaconic aciduria. Eur J Pediatr 146:484–488
Kelley RI, Kratz L (1995) 3-Methylglutaconic acidemia in Smith–Lemli–Opitz syndrome. Pediatr Res 37:671–674
Kelley RI, Cheatham JP, Clark BJ et al (1991) X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria. J Pediatr 119:738–747
Pei W, Kratz LE, Bernardini I et al (2010) A model of Costeff syndrome reveals metabolic and protective functions of mitochondrial OPA3. Development 137:2587–2596
Roullet JB, Merkens LS, Pappu AS et al (2012) No evidence for mevalonate shunting in moderately affected children with Smith–Lemli–Opitz syndrome. J Inherit Metab Dis 35:859–869
Ruesch S, Krahenbuhl S, Kleinle S et al (1996) Combined 3-methylglutaconic and 3-hydroxy-3-methylglutaric aciduria with endocardial fibroelastosis and dilatative cardiomyopathy in male and female siblings with partial deficiency of complex II/III in fibroblasts. Enzyme Protein 49:321–329
Wortmann SB, Rodenburg RJ, Jonckheere A et al (2009) Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy. Brain 132:136–146
Wortmann SB, Kluijtmans LA, Engelke UF, Wevers RA, Morava E (2012) The 3-methylglutaconic acidurias: what’s new? J Inherit Metab Dis 35:13–22
Wortmann SB, Duran M, Anikster Y et al (2013a) Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. J Inherit Metab Dis 36:923–928
Wortmann SB, Kluijtmans LA, Rodenburg RJ et al (2013b) 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. J Inherit Metab Dis 36:913–923
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Jerry Vockley, M.D., Ph.D.
Appendices
Disclosures
None declared.
Compliance with Ethics Guidelines
Conflict of Interest
Saskia B. Wortmann, Leo A.J. Kluijtmans, Silvia Sequeira, Ron A. Wevers, and Eva Morava declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Oral informed consent was obtained from all patients for being included in the study.
Details of the Contributions of Individual Authors
Saskia B. Wortmann and Eva Morava planned the study. Saskia B. Wortmann, Silvia Sequeira, and Eva Morava conducted the study in patients. Leo A.J. Kluijtmans and Ron A. Wevers conducted the biochemical measurements. All authors interpreted and discussed the results. Saskia B. Wortmann wrote the manuscript which was read and corrected by all authors.
Rights and permissions
Copyright information
© 2014 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Wortmann, S.B., Kluijtmans, L.A.J., Sequeira, S., Wevers, R.A., Morava, E. (2014). Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports Volume 16. JIMD Reports, vol 16. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_309
Download citation
DOI: https://doi.org/10.1007/8904_2014_309
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-44586-0
Online ISBN: 978-3-662-44587-7
eBook Packages: MedicineMedicine (R0)