Background and aim It is unclear which patients with Fabry disease (FD) are at risk for progression of white matter lesions (WMLs) and brain infarctions and whether enzyme replacement therapy (ERT) changes this risk. The aim of this study was to determine the effect of ERT and clinical characteristics on progression of WMLs and infarctions on MRI in patients with FD.
Methods MRIs were assessed for WMLs (Fazekas scale), infarctions and basilar artery diameter (BAD). The effect of clinical characteristics (renal and cardiac involvement, cardiovascular risk factors, cardiac complications, BAD) and ERT on WML and infarction progression was evaluated using mixed models.
Results One hundred forty-nine patients were included (median age: 39 years, 38% men, 79% classical phenotype). Median follow-up time was 7 years (range: 0–13 years) with a median number of MRIs per patient of 5 (range: 1–14), resulting in a total of 852 scans. Variables independently associated with WML and infarction progression were age, male sex and a classical phenotype. Progression of WMLs and infarctions was not affected by adding ERT to the model, neither for the whole group, nor for early treated patients. Progression was highly variable among patients which could not be explained by other known variables such as hypertension, cholesterol, atrial fibrillation and changes in kidney function, left ventricular mass or BAD.
Conclusion Progression of WMLs and cerebral infarctions in FD is mainly related to age, sex and phenotype. Additional effects of established cardiovascular risk factors, organ involvement and treatment with ERT are probably small to negligible.
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Contributors SK: study design, acquisition, analysis and interpretation of data, first draft of manuscript. MGFL: acquisition and interpretation of data, critical revision of manuscript. MRL: acquisition and interpretation of data, critical revision of manuscript. CEMH: study concept, study design, interpretation of data, study supervision, critical revision of manuscript. MES: acquisition and interpretation of data, critical revision of manuscript. IvS: interpretation of data, study supervision, critical revision of manuscript. LV: critical revision of manuscript. MGD: statistical support, critical revision of manuscript. ML: interpretation of data, study supervision, critical revision of manuscript.
Funding Study funded by the Academic Medical Center (innovation grant 2014).
Competing interests SK, MGFL, MRL, LV and MGD report no competing interests. MES is involved in premarketing studies with Idorsia. Financial arrangements are made through AMC Research BV. No fees, travel support or grants are obtained from Pharmaceutical Industry. CEMH and Mirjam Langeveld are involved in premarketing studies with Genzyme, Protalix and Idorsia. Financial arrangements are made through AMC Research BV. No fees, travel support or grants are obtained from Pharmaceutical Industry. IvS chairs a steering committee for CSL Behring and received departmental honoraria for serving on scientific advisory boards for CSL Behring and Baxter. All lecturing and consulting fees for INS were donated to the Stichting Klinische Neurologie, a local foundation that supports research in the field of neurological disorders.
Patient consent for publication Not required.
Ethics approval Patient records were de-identified prior to analysis. The Medical Ethics Review Committee of the AMC confirmed that the Medical Research Involving Human Subjects Act (WMO) does not apply to this study (W19-417 # 19.484). This study was conducted in accordance with the Declaration of Helsinki of 2013.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The datasets generated and analysed during the current study are not publicly available. Because of the rarity of the disease, even anonymised data can be linked to a specific individual. In case of a specific scientific question, requests to make part of the dataset available will be reviewed and seriously considered.