INTRODUCTION: Fabry disease (FD) can be undiagnosed in the context of multiple sclerosis (MS) due to similar clinical and paraclinical features. Our study aimed to determine the prevalence (and the necessity of screening) of FD among patients with possible or definite MS. METHODS: In this prospective monocentric observational study, we included consecutive patients enrolled between May 2017 and May 2019 after the first clinical event suggestive of MS. All patients underwent FD screening using dried blood spots in a stepwise manner combining genetic and enzyme testing. Patients were followed until May 2022. RESULTS: We included 160 patients (73.1% female, mean age 33.9 years). The 2017 revised McDonald's criteria for definite MS were fulfilled by 74 (46.3%) patients at the time of study recruitment and 89 (55.6%) patients after 3-5 years of follow-up. None of the patients had a pathogenic GLA variant, and four (2.5%) had a variant of unknown significance (p.A143T, p.S126G, 2 × p.D313Y). In two of these patients, the intrathecal synthesis of oligoclonal bands was absent, and none had hyperproteinorachia or pleocytosis in cerebrospinal fluid. Detailed examination of FD organ manifestations revealed only discrete ocular and kidney involvement in two patients. CONCLUSION: The prevalence of FD in the population of suspected or definite MS patients does not appear to be high. Our results do not support routine FD screening in all patients with a possible diagnosis of MS, but there is an urgent need to search for red flags and include FD in the differential diagnosis of MS.

2nd Department of Internal Cardiovascular Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czechia

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czechia

Department of Radiology 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czechia

See more in PubMed

Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–173. doi: 10.1016/S1474-4422(17)30470-2. PubMed DOI

Ömerhoca S, Yazici Akkaş S, Kale Içen N. Multiple sclerosis: diagnosis and differential diagnosis. Arch Neuropsychiatry. 2018;55:S1. doi: 10.29399/npa.23418. PubMed DOI PMC

Solomon AJ, Klein EP, Bourdette D. “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78:1986–1991. doi: 10.1212/WNL.0b013e318259e1b2. PubMed DOI PMC

Jurašić MJ, Bašić Kes V, Zavoreo I. Multiple sclerosis and Fabry disease - diagnostic “mixup”.". Mult Scler Relat Disord. 2019;34:112–115. doi: 10.1016/j.msard.2019.06.008. PubMed DOI

Böttcher T, Rolfs A, Tanislav C, Bitsch A, Köhler W, Gaedeke J, Giese AK, Kolodny EH, Duning T. Fabry disease - underestimated in the differential diagnosis of multiple sclerosis? PLoS ONE. 2013 doi: 10.1371/JOURNAL.PONE.0071894. PubMed DOI PMC

Lidove O, Kaminsky P, Hachulla E, et al. Fabry disease “The New Great Imposter”: results of the French Observatoire in Internal Medicine Departments (FIMeD) Clin Genet. 2012;81:571–577. doi: 10.1111/j.1399-0004.2011.01718.x. PubMed DOI

Saip S, Uluduz D, Erkol G. Fabry disease mimicking multiple sclerosis. Clin Neurol Neurosurg. 2007;109:361–363. doi: 10.1016/j.clineuro.2006.12.006. PubMed DOI

Invernizzi P, Bonometti MA, Turri E, Benedetti MD, Salviati A. A case of Fabry disease with central nervous system (CNS) demyelinating lesions: a double trouble? Mult Scler. 2008;14:1003–1006. doi: 10.1177/1352458508092355. PubMed DOI

Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–677. doi: 10.1007/s00439-017-1779-6. PubMed DOI PMC

Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:1–49. doi: 10.1186/1750-1172-5-30. PubMed DOI PMC

Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–254. doi: 10.1001/jama.281.3.249. PubMed DOI

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;79:31–40. doi: 10.1086/504601. PubMed DOI PMC

Tomek A, Petra R, Schwabová JP, et al. Nationwide screening for Fabry disease in unselected stroke patients. PLoS One. 2021;16:e0260601. doi: 10.1371/journal.pone.0260601. PubMed DOI PMC

Domingues RB, Fernandes GBP, de Moura Leite FBV, Tilbery CP, Thomaz RB, Silva GS, Mangueira CLP, Soares CAS. The cerebrospinal fluid in multiple sclerosis: far beyond the bands. Einstein (Sao Paulo) 2017;15:100–104. doi: 10.1590/S1679-45082017RW3706. PubMed DOI PMC

Tang MY, Hong YH, Zhou LX, Ni J. Fabry disease with aseptic meningitis: a case series and literature review of an underestimated clinical presentation. Curr Med Sci. 2022;42:274–279. doi: 10.1007/s11596-022-2578-4. PubMed DOI

Lidove O, Chauveheid MP, Caillaud C, et al. Aseptic meningitis and ischaemic stroke in Fabry disease. Int J Clin Pract. 2009;63:1663–1667. doi: 10.1111/j.1742-1241.2009.02115.x. PubMed DOI

Rost NS, Cloonan L, Kanakis AS, et al. Determinants of white matter hyperintensity burden in patients with Fabry disease. Neurology. 2016;86:1880. doi: 10.1212/WNL.0000000000002673. PubMed DOI PMC

Link H, Huang YM. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J Neuroimmunol. 2006;180:17–28. doi: 10.1016/j.jneuroim.2006.07.006. PubMed DOI

Dutra-Clarke M, Tapia D, Curtin E, et al. Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy. Mol Genet Metab Rep. 2021;26:100700. doi: 10.1016/j.ymgmr.2020.100700. PubMed DOI PMC

Ford H. Clinical presentation and diagnosis of multiple sclerosis. Clin Med. 2020;20:380. doi: 10.7861/clinmed.2020-0292. PubMed DOI PMC

Wattjes MP, Ciccarelli O, Reich DS, et al. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol. 2021;20:653–670. doi: 10.1016/S1474-4422(21)00095-8. PubMed DOI

Cocozza S, Russo C, Pontillo G, Pisani A, Brunetti A. Neuroimaging in Fabry disease: current knowledge and future directions. Insights Imaging. 2018;9:1077. doi: 10.1007/s13244-018-0664-8. PubMed DOI PMC

Reková P, Dostálová G, Kemlink D, et al. Detailed phenotype of GLA variants identified by the nationwide neurological screening of stroke patients in the Czech Republic. J Clin Med. 2021 doi: 10.3390/JCM10163543. PubMed DOI PMC

Živná M, Dostálová G, Barešová V et al (2022) AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis? bioRxiv 2022.09.27.509714. 10.1101/2022.09.27.509714

Eng CM, Niehaus DJ, Enriquez AL, Burgert TS, Ludman MD, Desnick RJ. Fabry disease: twenty-three mutations including sense and antisense CPG alterations and identification of a deletional hot-spot in the α-galactosidase A gene. Hum Mol Genet. 1994;3:1795–1799. doi: 10.1093/hmg/3.10.1795. PubMed DOI

Kiesling JL (2014) Missouri’s full population pilot screening for Fabry disease and the implications for families. https://www.aphl.org/conferences/proceedings/Documents/2014/NBS/29Kiesling.pdf. Accessed 26 Dec 2022

Terryn W, Vanholder R, Hemelsoet D, et al. Questioning the pathogenic role of the GLA p.Ala143Thr “Mutation” in Fabry disease: implications for screening studies and ERT. JIMD Rep. 2013;8:101–108. doi: 10.1007/8904_2012_167. PubMed DOI PMC

Genome Aggregation Database. https://gnomad.broadinstitute.org/. Accessed 26 Dec 2022

Duro G, Zizzo C, Cammarata G, et al. Mutations in the GLA gene and LysoGb3: is it really Anderson-Fabry disease? Int J Mol Sci. 2018 doi: 10.3390/IJMS19123726. PubMed DOI PMC

Effraimidis G, Rasmussen ÅK, Bundgaard H, Sørensen SS, Feldt-Rasmussen U. Is the alpha-galactosidase A variant p.Asp313Tyr (p. D313Y) pathogenic for Fabry disease? A systematic review. J Inherit Metab Dis. 2020;43:922–933. doi: 10.1002/jimd.12240. PubMed DOI

Hasholt L, Ballegaard M, Bundgaard H, et al. The D313Y variant in the GLA gene - no evidence of a pathogenic role in Fabry disease. Scand J Clin Lab Invest. 2017;77:617–621. doi: 10.1080/00365513.2017.1390782. PubMed DOI

Palaiodimou L, Stefanou MI, Bakola E, et al. D313Y variant in Fabry disease: a systematic review and meta-analysis. Neurology. 2022;99:e2188–e2200. doi: 10.1212/WNL.0000000000201102. PubMed DOI

Haile Y, Deng X, Ortiz-Sandoval C, et al. Rab32 connects ER stress to mitochondrial defects in multiple sclerosis. J Neuroinflammation. 2017;14:1–13. doi: 10.1186/s12974-016-0788-z. PubMed DOI PMC

Russo C, Cocozza S, Riccio E, et al. Prevalence of GLA gene mutations and polymorphisms in patients with multiple sclerosis: a cross-sectional study. J Neurol Sci. 2020 doi: 10.1016/J.JNS.2020.116782. PubMed DOI

Briones-Buixassa L, Milà R, Ma Aragonès J, Bufill E, Olaya B, Arrufat FX. Stress and multiple sclerosis: a systematic review considering potential moderating and mediating factors and methods of assessing stress. Health Psychol Open. 2015 doi: 10.1177/2055102915612271. PubMed DOI PMC