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Elevated Lyso-Gb3 Suggests the R118C GLA Mutation Is a Pathological Fabry Variant

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JIMD Reports, Volume 45

Part of the book series: JIMD Reports ((JIMD,volume 45))

Abstract

Background: Fabry disease (FD), an X-linked lysosomal storage disease, results from an α-galactosidase A deficiency and altered sphingolipid metabolism. An accumulation of globotriaosylsphingosine (lyso-Gb3) likely triggers the pathological cascade leading to disease phenotype. The pathogenic significance of several Fabry mutations including the R118C α-galactosidase (GLA) gene variant has been disputed. We describe three members of the same family with the R118C variant, each having documented clinical signs of FD, low residual enzyme levels, and an elevated lyso-Gb3 in one heterozygote.

Determining the clinical significance of each GLA gene variant remains an ongoing challenge, with potential for inadequate treatment if the diagnosis of FD is missed. Elevated lyso-Gb3 has been shown to be the most reliable noninvasive marker of clinically relevant GLA variants. While the R118C variant will likely lead to a milder phenotype, additional genetic, epigenetic, and environmental factors can ameliorate or exacerbate the expression and impact on the resultant phenotype and associated complications. Patients affected with this variant warrant closer review and better management of disease risk factors.

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Abbreviations

αGal:

Alpha-galactosidase A

FD:

Fabry disease

Gb3:

Globotriaosylceramide

GLA:

Gene encoding α-galactosidase

Lyso Gb3:

Globotriaosylsphingosine

References

  • Aerts JM, Groener JE, Kuiper S et al (2008) Elevated globotriaosylceramide is a hallmark of Fabry disease. Proc Natl Acad Sci U S A 105(8):2812–2817

    Article  CAS  Google Scholar 

  • Caetano F, Botelho A, Mota P, Silva J, Leitão Margues A (2014) Fabry disease presenting as apical left ventricular hypertrophy in a patient carrying the missense mutation R118C. Rev Port Cardiol 33(3):183.e1–183.e5

    Article  Google Scholar 

  • Desnick RJ, Allen KY, Desnick SJ, Raman MK, Bernlohr RW, Krivit W (1973) Fabry’s disease: enzymatic diagnosis of hemizygotes and heterozygotes. Alpha-galactosidase activities in plasma, serum, urine and leukocytes. J Lab Clin Med 81:157–171

    CAS  PubMed  Google Scholar 

  • Desnick RJ, Brady R, Barranger J et al (2003) Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 138:338–346

    Article  Google Scholar 

  • Desnick RJ, Doheny D, Chen B et al (2015) Fabry disease: the α-galactosidase A (GLA) c.427G>A (A143T) mutation, effect of the 5’-10C>T polymorphism. Mol Genet Metab 114:S11–S130

    Article  Google Scholar 

  • Ferreira S, Ortiz O, Germain DP et al (2015) The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies. Mol Genet Metab 114:248–258

    Article  CAS  Google Scholar 

  • Houge G, Tondel C, Kaarboe O, Hirth A, Bostad L, Svarstad E (2011) Fabry or not Fabry – a question of ascertainment. Eur J Hum Genet 19:1111

    Article  Google Scholar 

  • Linthorst GE, Bouwman MG, Wijburg FA, Aerts JM, Poorthuis BJ, Hollak CE (2010) Screening for Fabry disease in high-risk populations: a systematic review. J Med Genet 47:217–222

    Article  CAS  Google Scholar 

  • Liao H-C, Huang Y-H, Kao S-M et al (2013) Plasma globotriaosylsphingosine (lysoGb3) could be a biomarker for Fabry disease with a Chinese hotspot late-onset mutation (IVS4 + 919G>A). Clin Chim Acta 426:114–120

    Article  CAS  Google Scholar 

  • Lukas J, Giese A, Markoff A et al (2013) Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in Fabry disease. PLOS Genet 9(8):e1003632

    Article  CAS  Google Scholar 

  • Mehta A, Clarke JTR, Giugliani R, Elliott P, Linhart A, Beck M, Sunder-Plassmann, on behalf of the FOS Investigators (2009) Natural course of Fabry disease: changing pattern of causes of death in FOS – Fabry Outcome Survey. J Med Genet 46:548–552

    Article  CAS  Google Scholar 

  • Mitobe S, Togawa T, Tsukimara T et al (2012) Mutant α galactosidase A with M296I dose not cause elevation of the plasma globotriaosylsphingosine level. Mol Genet Metab 104:623–626

    Article  Google Scholar 

  • Niemann M, Rolfs A, Störk S et al (2014) Gene mutations versus clinical relevant phenotypes. Lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 7:8–16

    Article  CAS  Google Scholar 

  • Nowak A, Mechtler TP, Desnick RJ, Kasper DC (2017) Plasma LysoGb3: a useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes. Mol Genet Metab 120:57–61

    Article  CAS  Google Scholar 

  • Rombach SM, Dekker N, Bouwman MG et al (2010) Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta 1802:741–748

    Article  CAS  Google Scholar 

  • Schiffmann R, Fuller M, Clarke LA, Aerts JM (2016) Is it Fabry’s disease? Genet Med 18(12):1181–1185

    Article  CAS  Google Scholar 

  • Smid BE, van der Tol L, Biegstraaten M et al (2015) Plasma globotriaosylsphingosine in relations to phenotypes of Fabry disease. J Med Genet 52:262–268

    Article  CAS  Google Scholar 

  • Talbot A, Nicholls K, Fletcher J, Fuller M (2017) A simple method for quantification of plasma globotriaosylsphingosine: utility for Fabry disease. Mol Genet Metab 122:121–125

    Article  CAS  Google Scholar 

  • von Scheidt W, Eng CM, Fitzmaurice TF et al (1991) An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med 324:395–399

    Article  Google Scholar 

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Acknowledgments

The authors thank Elizabeth Centra and Donna North for sample preparation and testing of all Fabry patients.

Author information

Authors and Affiliations

  1. Department of Nephrology, Royal Melbourne Hospital, Parkville, VIC, Australia

    Andrew Talbot & Kathy Nicholls

  2. Department of Medicine, University of Melbourne, Parkville, VIC, Australia

    Kathy Nicholls

Authors
  1. Andrew Talbot
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  2. Kathy Nicholls
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Corresponding author

Correspondence to Andrew Talbot .

Editor information

Editors and Affiliations

  1. Tulane University Medical School, New Orleans, LA, USA

    Eva Morava

  2. Division of Metabolism & Children’s Research Centre, University Children’s Hospital Zürich, Zürich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, MN, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Martina Huemer

Appendices

Take Home Message

The Fabry R118C GLA mutation may cause clinically significant disease with reduced α galactosidase level and requires ongoing patient follow-up.

Compliance with Ethics Guidelines

Details of Contributions of Individual Authors

Andrew Talbot was responsible for data interpretation and original manuscript preparation.

Kathy Nicholls was involved in data interpretation and original manuscript preparation.

Conflict of Interest

Nil direct.

Andrew Talbot has received research support, speaker honoraria, and travel assistance from Shire Corporation and Sanofi Corporation, speaker honoraria and travel assistance from Dainippon Sumitomo Pharma Co, and research support from Amicus Therapeutics and Protalix Biotherapeutics.

Kathy Nicholls has received research support, speaker honoraria, and travel assistance from Shire Corporation and Sanofi Corporation and research support from Amicus Therapeutics and Protalix Biotherapeutics.

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). Informed consent was obtained from all patients for data analysis of results included in the study.

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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)

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Talbot, A., Nicholls, K. (2018). Elevated Lyso-Gb3 Suggests the R118C GLA Mutation Is a Pathological Fabry Variant. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 45. JIMD Reports, vol 45. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_146

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  • DOI: https://doi.org/10.1007/8904_2018_146

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-58646-4

  • Online ISBN: 978-3-662-58647-1

  • eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)

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