Top

Published in:

Open Access 01-12-2020 | Fabry Disease | Research

Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients

Authors: Patrícia Varela, Gianna Mastroianni Kirsztajn, Fabiana L. Motta, Renan P. Martin, Lauro T. Turaça, Henrique L. F. Ferrer, Caio P. Gomes, Priscila Nicolicht, Maryana Mara Marins, Juliana G. Pessoa, Marion C. Braga, Vânia D’Almeida, Ana Maria Martins, João B. Pesquero

Published in: Orphanet Journal of Rare Diseases | Issue 1/2020

Abstract

Background

Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms.

Results

We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls.

Conclusion

The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease.

Available only for authorised users

Auray-Blais C, Ntwari A, Clarke JTR, Warnock DG, Oliveira JP, Young SP, Millington DS, Bichet DG, Sirrs S, West ML, Casey R, Hwu WL, Keutzer J, Zhang K, Gagnon, R. How well does urinary lyso-Gb3 function as a biomarker in Fabry disease? Clin Chim Acta 2010. https://doi.org/https://doi.org/10.1016/j.cca.2010.07.038.CrossRef

Boutin M, Gagnon R, Lavoie P, Auray-Blais C. LC-MS/MS analysis of plasma lyso-Gb3 in Fabry disease. Clin Chim Acta 2012. https://doi.org/https://doi.org/10.1016/j.cca.2012.09.026.CrossRef

El-Abassi R, Singhal D, England JD. Fabry's disease. J Neurol Sci 2014. https://doi.org/https://doi.org/10.1016/j.jns.2014.06.029.PubMedCrossRef

Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;22:5–30. https://doi.org/10.1186/1750-1172-5-30.CrossRef

Terryn W, Cochat P, Froissart R, Ortiz A, Pirson Y, Poppe B, Serra A, Van Biesen W, Vanholder R, Wanner C. Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European renal best practice. Nephrol Dial Transplant 2013. https://doi.org/https://doi.org/10.1093/ndt/gfs526.CrossRef

Oliveira JP, Ferreira S. Multiple phenotypic domains of Fabry disease and their relevance for establishing genotype– phenotype correlations. Appl Clin Genet. 2019. https://doi.org/. https://doi.org/10.2147/TACG.S146022.

Schiffmann R, Fuller M, Clarke LA, Aerts JM. Is it Fabry disease? Genet Med 2016. https://doi.org/https://doi.org/10.1038/gim.2016.55.PubMedCrossRef

Caudron E, Prognon P, Germain DP. Enzymatic diagnosis of Fabry disease using a fluorometric assay on dried blood spots: An alternative methodology Eur J Med Genet 2015. https://doi: https://doi.org/10.1016/ej.ejmg.2015.10.014.

Curiati MA, Aranda, CS, Kyosen SO, Varela P, Pereira VG, D’ Almeida V, Pesquero JB, Martins AM. The Challenge of Diagnosis and Indication for Treatment in Fabry Disease. J Inborn Errors Metab Screen 2017. https://doi.org/https://doi.org/10.1177/2326409816685735.CrossRef

10.

Stenson PD, Mort M, Ball EV, Howells K, Phillips AD, Thomas NS, Cooper DN. The human gene mutation database: 2008 update. Genome Med 2009. https://doi.org/https://doi.org/10.1186/gm13.PubMedPubMedCentralCrossRef

11.

Muller KB, Rodrigues MDB, Pereira VG, Martins AM, D’Almeida V. Reference values for lysosomal enzyme activities using dried blood spots samples – a Brazilian experience. Diagn Pathol 2010. https://doi.org/https://doi.org/10.1186/1746-1596-5-65.PubMedPubMedCentralCrossRef

12.

Varela P, Mastroianni Kirsztajn, G, Ferrer H, Aranda C, Wallbach K, Mata GF et al. Functional characterization and pharmacological evaluation of a novel GLA missense mutation found in a severely affected Fabry disease family. Nephron. 2019. https://doi.org/https://doi.org/10.1159/000503998.

13.

Desnick RJ, Chen R, Srinivasan R, Doheny DO, Bishop DF. The Fabry disease genotype-phenotype database (dbFGP): an international expert consortium. Mol.Genet.Metab. 2017. https://doi.org/https://doi.org/10.1016/j.ymgme.2016.11.082.CrossRef

14.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH et al. Analysis of protein-coding genetic variation in 60,706 humans. Nat.2016. https://doi.org/https://doi.org/10.1038/nature19057 .PubMedPubMedCentralCrossRef

15.

Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR. A global reference for human genetic variation. Nat. 2015. https://doi.org/https://doi.org/10.1038/nature15393.

16.

Naslavsky MS, Yamamoto GL, de Almeida TF, Ezquina SAM, Sunaga DY, Pho N, Bozoklian D, Sandberg TOM, Brito LA, Lazar M, Bernardo DV, Amaro E Jr, Duarte YAO, Lebrão ML, Passos-Bueno MR, Zatz M. Exomic variants of an elderly cohort of Brazilians in the ABraOM database. Hum Mutat 2017. https://doi.org/https://doi.org/10.1002/humu.23220.PubMedCrossRef

17.

Desmet FO, Hamroun D, Lalande M, Collod-Beround G, Claustre M, Beround C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acid Res 2009. https://doi.org/https://doi.org/10.1093/nar/gkp215.PubMedPubMedCentralCrossRef

18.

Gelfman S, Wang Q, McSweeney KM, Ren Z, La Carpia F, Halvorsen M, Schoch K, Ratzon F, Heinzen EL, Boland MJ, Petrovski S, Goldstein DB. Annotating pathogenic non-coding variants in genic regions. Nat Commun 2017. https://doi.org/https://doi.org/10.1038/s41467-017-00141-2.

19.

Shin SH, Murray GJ, Kluepfel-Stahl S, Cooney AM, Quirk JM, Schiffmann R, Brady RO, Kaneski CR. Screening for pharmacological chaperones in Fabry disease. Biochem Biophys Res Commun. 2007. https://doi.org/10.1016/j.bbrc.2007.05.082 PubMedPubMedCentralCrossRef

20.

Wu X, Katz E., Della Valle MC, Mascioli K, Flanagan, et al. A pharmacogenetic approach to identify mutant forms of α-galactosidase A that respond to a pharmacological chaperone for Fabry disease. Human mutation, 2011. https://doi.org/10.1002/humu.21530. PubMedPubMedCentralCrossRef

21.

Shimotori M, Maruyama H, Nakamura G, Suyama T, Sakamoto F, Itoh M, et al. Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone. Hum Mutat. 2008. https://doi.org/10.1002/humu.9520 PubMedCrossRef

22.

Chamoles NA, Blanco M. Gaggioli. Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta. 2001;308(1–2):195–6. 11432396.PubMedCrossRef

23.

Okur I, Ezgu F, Biberoglu G. Screening for Fabry disease in patients undergoing dialysis for chronic renal failure in Turkey: identification of new case with novel mutation. Gene 15. 2013. doi: https://doi.org/10.1016/j.gene.2013.05.050.PubMedCrossRef

24.

Castilhos CD, Mezzalira J, Goldim MP, Daitx VV, Garcia Cda S, Andrade CV, Breier AC, Cé J, Mello AS, Coelho JC. Determination of the lysosomal hydrolase activity in blood collected on filter paper, an alternative to screen high risk populations. Gene. 2014. https://doi: https://doi.org/10.1016/j.gene.2013.11.101.PubMedCrossRef

25.

Fuller M, Lovejoy M, Brooks DA, Harkin ML, Hopwood JJ, Meikle PJ. Immunoquantification of alpha-galactosidase: evaluation for the diagnosis of Fabry disease. Clin Chen 2004. https://doi:https://doi.org/10.1373/clinchem.2004.037937.PubMedCrossRef

26.

Lukacs Z, Hartung R, Beck M, Mengel E. Direct comparison of enzyme measurements from dried blood and leukocytes from male and female Fabry disease patients. J. Inherit Metab Dis. 2007. https://doi::https://doi.org/10.1007/s10545-007-0679-7.

27.

Van der Tol L, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE, Hollak CE. A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet 2014. https://doi.org/https://doi.org/10.1136/jmedgenet-2013-101857.PubMedCrossRef

28.

Ferri L, Guido C, la Marca G, Malvagia S, Cavicchi C, Fiumara A, Barone R, Parini R, Antuzzi D, Feliciani C, Zampetti A, Manna R, Giglio S, Della Valle CM, Wu X, Valenzano KJ, Benjamin R, Donati MA, Guerrini R, Genuardi M, Morrone A. Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Clin Genet 2012. https://doi.org/https://doi.org/10.1111/j.1399-0004.2011.01689.x.PubMedCrossRef

29.

Tanislav C, Kaps M, Rolfs A, Bottcher T, Lackner K, Paschke E. Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: a pilot study. Eur J Neurol2011. https://doi.org/https://doi.org/10.1111/j.1468-1331.2010.03227.x.PubMedCrossRef

30.

Pisani A, Imbriaco M, Zizzo C, Albeggiani G, Colomba P, Alessandro R. A classical phenotype of Anderson-Fabry disease in a female patient with intronic mutations of the GLA gene: a case report. BMC Cardiovasc Disord 2012. https://doi.org/https://doi.org/10.1186/1471-2261-12-39.

31.

Oliveira JP, Ferreira S, Barceló J, Gaspar P, Carvalho F, Sá Miranda MC, Månsson JE. Effect of single-nucleotide polymorphisms of the 5′ untranslated region of the human α-galactosidase gene on enzyme activity, and their frequencies in Portuguese caucasians. J Inherit Metab Dis 2008. https://doi.org/https://doi.org/10.1007/s10545-008-0818-9.CrossRef

32.

Gervas-Arruga J, Cebolla J, Irun P, Perez-Lopez J, Plaza L, Roche J et al. Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase a (GLA) gene. BMC Genet 2015. https://doi: https://doi.org/10.1186/s12863-015.0267-z.

33.

Vieitez I, Souto-Rodriguez O, Fernandez-Mosquera L, San Millan B, Teijeira S, Fernandez-Martin J et al. Fabry disease in the Spanish population: observational study with detection of 77 patients. Orphanet of rare diseases 2018. https://doi:https://doi.org/10.1186/s13023-018-0792-8.

34.

Ferreira S, Ortiz A, Germain DP, Viana-Baptista M, Caldeira-Gomes A, Camprecios M, Fenollar-Cortés M, Gallegos-Villalobos Á, Garcia D, García-Robles JA, Egido J, Gutiérrez-Rivas E, Herrero JA, Mas S, Oancea R, Péres P, Salazar-Martín LM, Solera-Garcia J, Alves H, Garman SC, Oliveira JP. The alpha-galactosidase a p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies. Mol Genet Metab. 2015 Feb;114(2):248–58.PubMedCrossRef

35.

Froissart R, Guffon N, Vanier MT, Desnick RJ, Maire I. Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma. Mol Genet Metab. 2003 Nov;80(3):307–314.Pubmed PMID:1468097.

36.

Benjamin ER, Della Valle MC, Wu X, Katz E, Pruthi F, Bond S, Bronfin B, Williams H, Yu J, Bichet DG, Germain DP, Giugliani R, Hughes D, Schiffmann R, Wilcox WR, Desnick RJ, Kirk J, Barth J, Barlow C, Valenzano KJ, Castelli J, Lockhart DJ. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat. Genet. Med. 2017. https://doi.org/https://doi.org/10.1038/gim.2016.122.PubMedPubMedCentralCrossRef

37.

Yasuda M, Shabbeer J, Benson SD, Maire I, Burnett RM, Desnick RJ. Fabry disease: characterization of alpha-galactosidase a double mutations and the D313Y plasma enzyme pseudodeficiency allele. Hum Mutat 2003. https://doi.org/https://doi.org/10.1002/humu.10275.PubMedCrossRef

38.

Hasholt L, Ballegaard M, Bundgaard H, Christiansen M, Law I, Lund AM et al. The D313Y variant in the GLA gene - no evidence of a pathogenic role in Fabry disease. Scand J Clin Lab Invest. 2017. Htpps://doi: https://doi.org/10.1080/00365513.2017.1390782.PubMedCrossRef

39.

Niemann M, Rolfs A, Giese A, Mascher H, Breunig F, Ertl G, Wanner C, Weidemann F. Lyso-Gb3 indicates that the alpha-Galactosidase a mutation D313Y is not clinically relevant for Fabry disease. JIMD Rep 2013. https://doi: https://doi.org/10.1007/8904_2012_154.

40.

Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ. High incidence of later-onset fabry disease revealed by newborn screening Am J Hum Genet 2006. https://doi: https://doi.org/10.1086/504601.PubMedCrossRef

41.

Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ. Nature and frequency of mutations in the alpha-galactosidase a gene that cause Fabry disease. Am J Hum Genet. 1993;53(6):1186–97.PubMedPubMedCentral

42.

Lukas J, Giese AK, Markoff A, Grittner U, Kolodny E, Mascher H, Lackner KJ, Meyer W, Wree P, Saviouk V, Rolfs A. Functional characterization of alpha-galactosidase a mutation as a basis for a new classification system in fabry disease. PLoS Genet 2013. https://doi.org/https://doi.org/10.1371/journal.pgen.1003632.PubMedPubMedCentralCrossRef

43.

Lukas J, Scalia S, Eichler S, Pockrandt AM, Dehn N, Cozma C et al. Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Diseas. Hum Mut. 2015. https://doi.org/10.1002/humu.22910.PubMedCrossRef

Title: Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients
Authors: Patrícia Varela
Gianna Mastroianni Kirsztajn
Fabiana L. Motta
Renan P. Martin
Lauro T. Turaça
Henrique L. F. Ferrer
Caio P. Gomes
Priscila Nicolicht
Maryana Mara Marins
Juliana G. Pessoa
Marion C. Braga
Vânia D’Almeida
Ana Maria Martins
João B. Pesquero
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Fabry Disease
Published in: Orphanet Journal of Rare Diseases / Issue 1/2020
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-019-1274-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients

Abstract

Background

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2020

Childhood Langerhans cell histiocytosis with severe lung involvement: a nationwide cohort study

Epidemiological and advanced therapeutic approaches to treatment of uveitis in pediatric rheumatic diseases: a systematic review and meta-analysis

Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a six month phase II randomized study with 24 months of follow-up

Quality of life data for individuals affected by spinal muscular atrophy: a baseline dataset from the Cure SMA Community Update Survey

Diabetes management in Wolcott-Rallison syndrome: analysis from the German/Austrian DPV database

Factors associated with refractory autoimmune necrotizing myopathy with anti-signal recognition particle antibodies