Advertisement

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

  • Andrew TalbotEmail author
  • Kathy Nicholls
Research Report
Part of the JIMD Reports book series (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.

Keywords

Fabry disease Lyso-Gb3 Pathological variant 

Abbreviations

αGal

Alpha-galactosidase A

FD

Fabry disease

Gb3

Globotriaosylceramide

GLA

Gene encoding α-galactosidase

Lyso Gb3

Globotriaosylsphingosine

Notes

Acknowledgments

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

References

  1. 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):2812–2817CrossRefGoogle Scholar
  2. 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.e5CrossRefGoogle Scholar
  3. 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 81:157–171PubMedGoogle Scholar
  4. 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 138:338–346CrossRefGoogle Scholar
  5. 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–S130CrossRefGoogle Scholar
  6. 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 114:248–258CrossRefGoogle Scholar
  7. 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 19:1111CrossRefGoogle Scholar
  8. 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 47:217–222CrossRefGoogle Scholar
  9. 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 426:114–120CrossRefGoogle Scholar
  10. 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):e1003632CrossRefGoogle Scholar
  11. 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 46:548–552CrossRefGoogle Scholar
  12. 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 104:623–626CrossRefGoogle Scholar
  13. Niemann M, Rolfs A, Störk S et al (2014) Gene mutations versus clinical relevant phenotypes. Lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 7:8–16CrossRefGoogle Scholar
  14. 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 120:57–61CrossRefGoogle Scholar
  15. Rombach SM, Dekker N, Bouwman MG et al (2010) Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta 1802:741–748CrossRefGoogle Scholar
  16. Schiffmann R, Fuller M, Clarke LA, Aerts JM (2016) Is it Fabry’s disease? Genet Med 18(12):1181–1185CrossRefGoogle Scholar
  17. Smid BE, van der Tol L, Biegstraaten M et al (2015) Plasma globotriaosylsphingosine in relations to phenotypes of Fabry disease. J Med Genet 52:262–268CrossRefGoogle Scholar
  18. Talbot A, Nicholls K, Fletcher J, Fuller M (2017) A simple method for quantification of plasma globotriaosylsphingosine: utility for Fabry disease. Mol Genet Metab 122:121–125CrossRefGoogle Scholar
  19. 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 324:395–399CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of NephrologyRoyal Melbourne HospitalParkvilleAustralia
  2. 2.Department of MedicineUniversity of MelbourneParkvilleAustralia

Personalised recommendations