# Prevalence of Fabry Disease in Patients on Dialysis in France

Florence Sens, Laure Guittard, Bertrand Knebelmann, Olivier Moranne, Gabriel Choukroun, Valérie de Précigout, Cécile Couchoud, Isabelle Deleruyelle, Léa Lancelot, Liên Tran Thi Phuong, et al.

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Florence Sens, Laure Guittard, Bertrand Knebelmann, Olivier Moranne, Gabriel Choukroun, et al. "Prevalence of Fabry Disease in Patients on Dialysis in France." International Journal of Molecular Sciences, 2024, 25 (18), pp.10104. 10.3390/ijms251810104. [hal-04719905]

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Article

Prevalence of Fabry Disease in Patients on Dialysis in France

Florence Sens <fnref n="1" />,<fnref n="2" />, Laure Guittard <fnref n="3" />,<fnref n="4" />, Bertrand Knebelmann <fnref n="5" /> ID, Olivier Moranne <fnref n="6" />, Gabriel Choukroun <fnref n="7" />,
Valérie de Précigout <fnref n="8" />, Cécile Couchoud <fnref n="9" /> ID, Isabelle Deleruyelle <fnref n="3" />, Léa Lancelot <fnref n="3" />, Liên Tran Thi Phuong <fnref n="10" />,
Thomas Ghafari <fnref n="11" />, FABRYDIAL Study Group †, Laurent Juillard <fnref n="1" />,<fnref n="2" />,‡ and Dominique P. Germain <fnref n="10" />,<fnref n="11" />,<fnref n="12" />,*,‡ ID

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**Citation:** Sens, F.; Guittard, L.; Knebelmann, B.; Moranne, O.; Choukroun, G.; de Précigout, V.; Couchoud, C.; Deleruyelle, I.; Lancelot, L.; Tran Thi Phuong, L.; et al. Prevalence of Fabry Disease in Patients on Dialysis in France. *Int. J. Mol. Sci.* **2024**, *25*, 10104. https://doi.org/10.3390/ijms251810104

Academic Editor: Maria Vittoria Cubellis

Received: 7 August 2024

Revised: 25 August 2024

Accepted: 26 August 2024

Published: 20 September 2024

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**Copyright:** © 2024 by the authors.
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4.0/).

**Abstract:** Numerous prevalence studies on Fabry disease (FD, OMIM #301500) have been conducted in dialysis populations across the world with variable and controversial results. The FABRYDIAL study aimed to estimate the prevalence of FD in patients aged 18 to 74 years on chronic dialysis in France. This cross-sectional study was conducted in patients undergoing dialysis. One hundred and twenty-four dialysis centers participated. Patients with proven causes of nephropathy unrelated to FD were excluded. Alpha-galactosidase A activity was assayed in men, and both α-galactosidase A and lyso-Gb₃ were assayed in women from dried blood spots. GLA gene sequencing was performed in case of abnormal values. If a variant was identified, a diagnosis validation committee was consulted for adjudication. Among the 6032 targeted patients, 3088 were included (73.6% of the eligible patients). Biochemical results were available for 2815 (1721 men and 1094 women). A genetic variant of GLA was identified in five patients: a benign c.937G>T/p.(Asp313Tyr) variant in two individuals, a likely benign c.427G>A/(p.Ala143Thr) variant, a likely benign c.416A>G/(p.Asn139Ser) variant, and a pathogenic c.1185dupG/p.Phe396Glyfs variant. Among the screened patients, the prevalence was 0.058% [0.010;0.328] in males, 0% [0.000;0.350] in females, and 0.035% [0.006;0.201] when both genders were pooled. Among all patients aged 18–74 years undergoing dialysis without a previously known cause of nephropathy unlinked to FD, the prevalence was 0.028% [0.006;0.121]. The prevalence of FD in a cohort of French dialysis patients was low. However, considering the prognostic impact of earlier diagnosis, signs of FD should be sought in patients with nephropathies of uncertain etiology.

**Keywords:** Fabry disease; dialysis; screening; prevalence; genetic variants

<footnote n="1">¹ Service de Néphrologie et d'Explorations Fonctionnelles, Hôpital Edouard Herriot, Hospices Civils de Lyon, F-69003 Lyon, France; florence.sens@chu-lyon.fr (F.S.); laurent.juillard@univ-lyon1.fr (L.J.)</footnote>

<footnote n="2">2 UMR Inserm 1060, Université Claude Bernard Lyon 1, F-69621 Villeurbanne, France</footnote>

<footnote n="3">3 Service Recherche et Epidémiologie Cliniques, Pôle Santé Publique, Hospices Civils de Lyon, F-69002 Lyon, France; laure.guittard@chu-lyon.fr (L.G.); isabelle.deleruyelle@chu-lyon.fr (I.D.); lea.lancelot@chu-lyon.fr (L.L.)</footnote>

<footnote n="4">4 Research on Healthcare Performance (RESHAPE), Inserm U1290, Université Claude Bernard Lyon, F-69373 Lyon, France</footnote>

<footnote n="5">5 Service de Néphrologie, Hôpital Necker, Assistance Publique Hôpitaux de Paris, Université de Paris, F-75015 Paris, France; bertrand.knebelmann@aphp.fr</footnote>

<footnote n="6">6 Service Néphrologie-Dialyse-Apherese, Hôpital Universitaire Caremeau, IDESP Université de Montpellier, F-30029 Nîmes, France; olivier.moranne@chu-nimes.fr</footnote>

<footnote n="7">7 Service de Néphrologie, Médecine Interne, Dialyse et Transplantation, CHU Amiens, F-80054 Amiens, France; choukroun.gabriel@chu-amiens.fr</footnote>

<footnote n="8">8 Service de Néphrologie, Hôpital Pellegrin, CHU Bordeaux, F-33076 Bordeaux, France; valerie.deprecigout@chu-bordeaux.fr</footnote>

<footnote n="9">9 Coordination Nationale Réseau Epidémiologique et Information en Néphrologie, Agence de la Biomédecine, F-93212 Saint-Denis-La-Plaine, France; cecile.couchoud@biomedecine.fr</footnote>

<footnote n="10">10 "Geneo" Referral Center for Fabry Disease and Lysosomal Diseases, MetabERN European Reference Network, F-92380 Garches, France; phuonglienvn282@gmail.com</footnote>

<footnote n="11">11 Division of Medical Genetics, APHP—Paris Saclay University, F-92380 Garches, France; thomas.ghafari@aphp.fr</footnote>

<footnote n="12">12 Division of Medical Genetics, University of Versailles, F-78180 Montigny, France</footnote>

<footnote>* Correspondence: dominique.germain@uvsq.fr; Tel.: +33-6-27-94-23-19</footnote>

<footnote>† Membership of the FABRYDIAL Study Group is provided in the Acknowledgments.</footnote>

<footnote>‡ These authors contributed equally to this work.</footnote>
# 1. Introduction

Fabry Disease (FD, OMIM #301500) is an X-linked lysosomal disease due to pathogenic variants in the GLA gene encoding for α-galactosidase A. It results in the accumulation of globotriaosylceramide (Gb₃) and its deacetylated derivative (lyso-Gb₃) in fluids and cellular lysosomes [1]. It is characterized by a wide phenotypic spectrum. In classic FD, patients typically exhibit neuropathic pain, angiokeratomas, hypohidrosis, gastrointestinal dysfunction, and *Cornea verticillata* from childhood or adolescence [1], but these early indicative signs are inconsistent [2,3]. Over the course of the disease, patients are susceptible to developing end-organ manifestations by the 4th or 5th decade of life, represented by heart failure and arrhythmias [4], end-stage-renal-disease (ESRD) [3,5,6], stroke [7], and premature death. Female patients are often symptomatic [8,9], although usually to a lesser extent than hemizygous males [10]. Since manifestations in adulthood are non-specific, FD is under-diagnosed. Screening for FD in high-risk groups is important for optimal management and family screening [3,10–12].

Many studies on the prevalence of FD in dialysis patients have been performed over the past twenty years [13–38]. Measured prevalence varied from 0 to 1.6% among males and 0 to 0.54% among females, with a systematic review suggesting a prevalence of 0.21% for males and 0.15% for females [39]. These differences could indicate a disparity in FD prevalence due to differences in healthcare system organization, leading to bias in patient selection. They may also be the consequence of methodological issues [40,41], such as an insufficient size of the populations screened [6–8,10,11,14,16–18], inaccurate screening tests [8,9,11–14,18,20,22], non-availability of confirmatory GLA variant analyses [16,17], and the absence of genotype/phenotype correlation to differentiate polymorphisms from pathogenic variants [39,42–44] since variants disclosed during a screening program may more likely be a mere coincidence and therefore benign than those disclosed in the course of a dedicated genetic outpatient clinic [45,46]. Therefore, the estimated prevalence of FD in many previous screening studies is questionable, and its generalizability to the population undergoing dialysis in France remains controversial.

The aim of the FABRYDIAL study was to estimate the prevalence of FD in a large cohort of French patients undergoing chronic dialysis aged 18 to 74 years. We also aimed to describe the phenotype of patients who harbor a GLA variant.

# 2. Results

## 2.1. *Patients*

Among the 6032 patients aged 18 to 74 years on chronic dialysis in the participating centers over the period considered, 714 were no longer treated at the centers when research staff visited for eligibility assessment, and 1121 met non-inclusion criteria, 89% of whom had a previously confirmed diagnosis of nephropathy unrelated to FD. A total of 3088 patients were included (73.6% of the 4197 eligible patients; 1888 men and 1200 women). Data from biochemical analyses were available for 2815 patients (1721 men and 1094 women); 97% (2719/2815) of samples were sent to the same laboratory (Figure 1). The median age was 63.5 years, and 61.1% of patients were men. In total, 97.7% of patients were treated with hemodialysis and 2.3% with peritoneal dialysis. The distribution of causal nephropathies was close to that of the French registry of dialysis patients when considering the exclusion criteria (Table 1).

<table><caption>**Table 1.** Characteristics of patients included in the FABRYDIAL study.</caption><thead><tr><th></th><th>Patients Included with Screening Results</th></tr></thead><tbody><tr><td>Sex (male), n (%)</td><td>n = 2815<br>1721 (61.1)</td></tr><tr><td>Age (years), median [IQR]</td><td>63.5 [54.2–69.5]</td></tr><tr><td>Diagnosis of ESRD, n (%)</td><td></td></tr><tr><td>Systemic hypertension</td><td>654 (23.3)</td></tr></tbody></table>
<table><caption>**Table 1.** *Cont.*</caption><thead><tr><th></th><th>Patients Included with Screening Results</th></tr></thead><tbody><tr><td>Diagnosis of ESRD, n (%)</td><td></td></tr><tr><td>Other vascular nephropathies</td><td>64 (2.3)</td></tr><tr><td>Type 2 diabetic nephropathy</td><td>768 (27.3)</td></tr><tr><td>Glomerulonephritis</td><td>375 (13.3)</td></tr><tr><td>Tubulo-interstitial impairment and toxicities</td><td>231 (8.2)</td></tr><tr><td>Non-renal urinary tract diseases</td><td>202 (7.2)</td></tr><tr><td>Hereditary diseases (except PKD)</td><td>37 (1.3)</td></tr><tr><td>Other causes</td><td>128 (4.5)</td></tr><tr><td>Unknown</td><td>356 (12.6)</td></tr><tr><td>Previous α-galactosidase A assay</td><td></td></tr><tr><td>Negative</td><td>96 (3.4)</td></tr><tr><td>Positive</td><td>95 (3.37)</td></tr><tr><td>Positive</td><td>1 (0.03)</td></tr><tr><td>Dialysis modality, n (%), (6 missing data)</td><td></td></tr><tr><td>Hemodialysis</td><td>2745 (97.7)</td></tr><tr><td>Peritoneal dialysis</td><td>64 (2.3)</td></tr><tr><td>Main home in the geographical areas of the study, n (%), (22 missing data)</td><td>2729 (97.7)</td></tr></tbody></table>

Abbreviations: ESRD: End-stage renal disease, IQR: Interquartile range, PKD: Polycystic kidney disease.

<figure><img src="image_6.png" /><figcaption>**Figure 1.** Flow diagram of the FABRYDIAL study.</figcaption></figure>
## 2.2. Biochemical Screenings and Genetic Analyses

GLA gene analysis was performed for 91 patients; a genetic variant was found in five of them (four males and one female) (Table 2).

<table><caption>**Table 2.** Clinical, biological, and genetic data from patients identified with a variant identified in GLA.</caption><thead><tr><th>Sex</th><th>Age</th><th>Familial History</th><th>Kidney Disease</th><th>Age at ESRD</th><th>Early Signs</th><th>Cardiac Dysfunction</th><th>Comorbidities</th><th>α-GalA Activity</th><th>Lyso-Gb3</th><th>Gene Variant</th><th>Final Diagnosis</th></tr></thead><tbody><tr><td>M</td><td>66</td><td>0</td><td>Sclerodermic renal crisis</td><td>61</td><td>No</td><td>Altered left ventricular ejection fraction HF</td><td>Hypertension, Atrial fibrillation, Depression</td><td>4.1 (previously 1.7 in 2016)</td><td>Previously 1.8 in 2016</td><td>c.416A>G (SNV)</td><td>Negative</td></tr><tr><td>F</td><td>68</td><td>0</td><td>Membrano-proliferative GN</td><td>26</td><td>Acroparesthesia (late onset), abdominal pains</td><td>No</td><td>None</td><td>0.99</td><td>1.2</td><td>c.937G>T (SNV)</td><td>Negative</td></tr><tr><td>M</td><td>47</td><td>0</td><td>Hepato-renal syndrome</td><td>45</td><td>No</td><td>Ventricular hypertrophy without HF</td><td>Ethyl cirrhosis</td><td>0.86</td><td>-</td><td>c.937G>T (SNV)</td><td>Negative</td></tr><tr><td>M</td><td>61</td><td>0</td><td>Calcineurin Inhibitors toxicity</td><td>60</td><td>No</td><td>No</td><td>Cobalt fibrosis, Bipulmonary transplantation</td><td>1.04</td><td>-</td><td>c.427G>A (SNV)</td><td>Negative</td></tr><tr><td>M</td><td>63</td><td>First-degree premature deaths (1, 42 and 59 y.o.)</td><td>Unknown</td><td>61</td><td>Hypohidrosis, heat intolerance, diarrhea, tinnitus, angiokeratoma, hypoacousia</td><td>Hypertrophic cardiomyopathy at 38 y.o. + HF</td><td>Atrial fibrillation</td><td>0.15</td><td>117.8</td><td>c.1185dupG (Frameshift mutation)</td><td>Fabry disease</td></tr></tbody></table>

Abbreviations: α-GalA: α-galactosidase A, ESRD: End-stage renal disease, F: Female, GN: Glomerulonephritis, HF: Heart failure, Lyso-GB3: Lyso-globotriaosylceramide, M: Male, SNV: Single nucleotide variant, y.o.: years old.

Review and adjudication of the five patients identified with a GLA variant were conducted by the multidisciplinary DVC (Table 2).

### 2.2.1. Patient 1: No FD

The patient was a 66-year-old man with systemic hypertension, atrial fibrillation, and cardiac failure. At the age of 61, he presented with a sclerodermic renal crisis confirmed by biopsy, and dialysis was initiated. In 2016, he had benefited from an α-GalA assay that was lowered to 1.7 µmol/L/h (ref. ≥ 2.6), lyso-Gb3 was 1.8 ng/mL (ref. < 1.8), GLA sequencing found a missense variant c.416A>G (p.Asn139Ser), initially suspected to be associated with a late-onset cardiac variant [47]. However, the pathogenicity of this variant was subsequently challenged [48]. The screening was redone in 2017–2018: α-GalA was normal (4.11 µmol/L/h). The p.Asn139Ser variant was found 27 times in ExAC and 34 times in the gnomAD exome database. Both SIFT and Polyphen2 predicted a benign variant. The normal α-Gal A value on DBS in this male patient ruled out FD, while the history was not suggestive. We suggest that the p.Asn139Ser variant is a likely benign GLA variant not associated with FD [48].

### 2.2.2. Patient 2: No FD

This 68-year-old woman began dialysis at the age of 26, one year after membrane-proliferative glomerulonephritis was diagnosed by renal biopsy. She reported fatigue, acroparesthesias (attributed to beta-2-microglobulin amyloidosis), abdominal pain, and constipation. α-GalA was moderately lowered (0.99 µmol/L/h), lyso-Gb3 was within normal values (1.18 ng/mL), GLA gene sequencing identified a heterozygous benign variant c.937G>T (p.Asp313Tyr) [42,49]. The diagnosis of Fabry disease was not confirmed.
### 2.2.3. Patient 3: No FD

This 47-year-old man was followed for chronic kidney disease since he was 40 and began dialysis at the age of 45 in the context of hepato-renal syndrome due to ethylic cirrhosis. Since 2016, he also had concentric hypertrophic cardiomyopathy (interventricular septum thickness: 14 mm). No renal biopsy had been performed. α-GalA was mildly lowered but with a significantly elevated residual level (0.86 µmol/L/h). GLA gene sequencing identified a non-pathogenic hemizygous variant c.937G>T (p.Asp313Tyr) [42,49,50]. FD diagnosis was not confirmed.

### 2.2.4. Patient 4: No FD

This 61-year-old man presented with cobalt pulmonary fibrosis and required a bipulmonary transplant at the age of 59, the consequences of which were marked by six months in intensive care units and dialysis at the age of 60. No renal biopsy had been performed. α-GalA was only slightly lowered (1.04 µmol/L/h). GLA gene sequencing identified a hemizygous variant c.427G>A (p.Ala143Thr) of unknown significance, which has been extensively discussed in the literature with several lines of evidence in favor of a likely benign variant [42-44,50-53]. FD diagnosis was not confirmed.

### 2.2.5. Patient 5: Confirmed FD

A 63-year-old man was diagnosed with chronic kidney disease at age 54, and hemodialysis was initiated at age 61. No renal biopsy had been performed, and his nephropathy was of undetermined origin. Family history disclosed a medical history of cardio-renal disease in his mother and heart failure in two brothers who died at ages 42 and 59. The patient had no children. His medical records reported concentric hypertrophic cardiomyopathy of unknown cause: interventricular septum thickness: 14 mm). According to his nephrologist, the patient had no early signs suggestive of FD. However, careful clinical examination by a senior geneticist (DPG) disclosed chronic fatigue, hypohidrosis, heat intolerance, chronic diarrhea, hypoacousia, and tinnitus signs that can be found in association with FD. Additionally, hypohidrosis and angiokeratoma in the periumbilical and genital areas, which are symptoms highly suggestive of FD, were also evident. α-GalA activity was dramatically decreased (0.1 µmol/L/h), and lyso-Gb₃ was highly elevated (117.8 ng/mL). A class 5 pathogenic frameshift variant (c.1185dupG; p.Phe396Glyfs) was detected in the GLA gene, thereby definitely confirming the diagnosis of classic FD. The patient was initiated on enzyme replacement therapy (agalsidase beta), on which he remained for 5 years before passing away.

## 2.3. Prevalence of Fabry Disease in Dialysis Patients

FD was diagnosed in only one male and no female patients. Among the patients included in the FABRYDIAL study and screened (2815 patients), the prevalence of FD was 0.058% [0.010;0.328] in males, 0% [0.000;0.350] in females, and 0.035% [0.006;0.201] regardless of gender. Among eligible included patients (3088 patients), the prevalence was 0.053% [0.011;0.307] in males, 0% [0.000;0.319] in females, and 0.032% [0.007;0.188] regardless of gender. We considered that (i) all eligible patients (n = 4197) had the same prevalence as the 2815 included patients, i.e., 0.035%, (ii) the 1121 patients with an exclusion criteria linked to their nephropathy had a prevalence of 0%, and (iii) the 714 patients who were no longer present in the dialysis center at the time of the study had to be excluded from the prevalence calculation because we could not form a hypothesis. The prevalence among the target population (i.e., patients aged 18 to 74 years undergoing chronic dialysis without a previously known cause of nephropathy unlinked to FD) is therefore (0.035 × 4197 + 0 × 1121)/(4197 + 1121), i.e., 0.028% [0.006;0.121]; an estimation by sex was not possible because the gender of non-included patients was unknown for regulatory reasons.
### 3. Discussion

The FABRYDIAL study aimed to estimate the prevalence of FD in patients aged 18 to 74 years undergoing chronic dialysis in France. A total of 124 dialysis centers participated in the study, and 3088 patients were included. Biological samples were available for 2815 patients, namely the α-Gal A activity in men and both α-Gal A and lyso-Gb₃ in women. Among the cases with first-tier abnormal result(s) in whom GLA gene sequencing was performed, five patients were found to have a GLA genetic variant. After analysis by the DVC, only one male was considered to have FD. Among the patients included in the study and screened (2815 patients), the prevalence of FD was 0.058% [0.010;0.328] in males, 0% [0.000;0.350] in females, and 0.035% [0.006;0.201] in whatever the gender. Among all the patients aged 18 to 74 years undergoing chronic dialysis, the prevalence was estimated at 0.016%.

Many studies have been conducted to estimate the prevalence of FD in ESRD patients (Table 3) [6–24], but most have limitations [39–41]. Many lacked power (<1000 patients) [6–8,10,11,14,16–18,37], and most excluded women [6,7,10,15–17,19,24] or screened them only for α-GalA activity [8,9,11–14,18,20–22], possibly leading to false negatives [3,16,40]. The present study offers an approach that is both economically viable and scientifically valid, using a sensitive biological screening in women and a diagnostic algorithm consistent with recent data [30,53,54]. Another limitation of previously published studies is the frequent lack of distinction between benign and pathogenic variants of GLA [41–45,50,51], which can lead to overestimating the prevalence by up to 50% [25]. Finally, in countries in which there is no free access to dialysis, FD prevalence could be biased.

<table><caption>**Table 3.** Summary of previously published screening studies for Fabry disease in dialysis patients.</caption><thead><tr><th>Author/Year</th><th>Country</th><th>Population</th><th>No of Patients</th><th>Male (%)</th><th>Screening Male</th><th>Screening Female</th><th>No Fabry Male/Female</th><th>Frequency (%) Male/Female</th></tr></thead><tbody><tr><td>Nakao/2003 [14]</td><td>Japan</td><td>He</td><td>514</td><td>100</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>None</td><td>6/NA</td><td>1.17/NA</td></tr><tr><td>Linthorst/ 2003 [15]</td><td>The Netherlands</td><td>He/PD</td><td>508</td><td>100</td><td>WBC α-GAL > Gn</td><td>None</td><td>1/NA</td><td>0.22/NA</td></tr><tr><td>Bekri/2004 [16]</td><td>France</td><td>He</td><td>106</td><td>56</td><td>WBC α-GAL > Gn</td><td>WBC α-GAL > Gn</td><td>1/0</td><td>1.69/0.00</td></tr><tr><td>Kotanko/2004 [17]</td><td>Austria</td><td>He/PD</td><td>2480</td><td>61</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>4/0</td><td>0.26/0.00</td></tr><tr><td>Ichinose/2005 [18]</td><td>Japan</td><td>He/PD</td><td>450</td><td>100</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>None</td><td>1/NA</td><td>0.22/NA</td></tr><tr><td>Tanaka/2005 [19]</td><td>Japan</td><td>He</td><td>696</td><td>58</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>4/1</td><td>1.00/0.34</td></tr><tr><td>Merta/2007 [20]</td><td>Czech</td><td>He</td><td>3370</td><td>45</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>AGAL blood spot > AGAL leuco > Gn</td><td>4/3</td><td>0.26/0.16</td></tr><tr><td>Terryn/2008 [21]</td><td>Belgium</td><td>He</td><td>1284</td><td>18</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>½</td><td>0.42/0.19</td></tr><tr><td>De Schoen-makere/2008 [22]</td><td>Belgium</td><td>Gr</td><td>673</td><td>41</td><td>Plasma α-GAL > Gn</td><td>Plasma α-GAL > Gn</td><td>1/0</td><td>0.36/0.00</td></tr><tr><td>Kleinert/2009 [23]</td><td>Austria</td><td>Gr</td><td>1306</td><td>100</td><td>Plasma α-GAL > Gn</td><td>None</td><td>2/NA</td><td>0.15/NA</td></tr></tbody></table>
<table><caption>**Table 3. Cont.**</caption><thead><tr><th>Author/Year</th><th>Country</th><th>Population</th><th>No of Patients</th><th>Male (%)</th><th>Screening Male</th><th>Screening Female</th><th>No Fabry Male/ Female</th><th>Frequency (%) Male/ Female</th></tr></thead><tbody><tr><td>Andrade/ 2008 [24]</td><td>Canada</td><td>CKD/PD/He/Gr</td><td>141/59/159/138</td><td>100</td><td>Plasma α-GAL > WBC α-GAL</td><td>None</td><td>0/NA</td><td>0.00/NA</td></tr><tr><td>Porsch/2009 [25]</td><td>Brazil</td><td>He</td><td>558</td><td>100</td><td>Plasma α-GAL</td><td>None</td><td>2/NA</td><td>0.36/NA</td></tr><tr><td>Gaspar/2010 [26]</td><td>Spain</td><td>He</td><td>911</td><td>60</td><td>Plasma α-GAL > Gn</td><td>Plasma α-GAL > Gn</td><td>4/4</td><td>0.55/0.54</td></tr><tr><td>Maruyama/ 2013 [27]</td><td>Japan</td><td>He/PD</td><td>1453</td><td>100</td><td>Plasma α-GAL + Lyso-Gb3 > Gn</td><td>None</td><td>4/NA</td><td>0.28/NA</td></tr><tr><td>Saito/2015 [28]</td><td>Japan</td><td>He/PD</td><td>8547</td><td>63</td><td>Plasma α-GAL > WBC α-GAL > Gn</td><td>Plasma α-GAL > WBC α-GAL leuco > Gn</td><td>2/0</td><td>0.04/0.00</td></tr><tr><td>Sodre/2017 [29]</td><td>Brazil</td><td>He</td><td>36,442 (Qnaire) --&gt; 8087 (Bio)</td><td>60</td><td>Questionnaire → Plasma α-GAL + Gn</td><td>Questionnaire --&gt; Plasma α-GAL + Gn</td><td>26/45</td><td>0.11/0.31</td></tr><tr><td>Moiseev/2019 [30]</td><td>Russia</td><td>He</td><td>5572</td><td>64</td><td>Plasma α-GAL > Gn + Gb3</td><td>Plasma α-GAL --&gt; Gn + GB3</td><td>19/1</td><td>0.53/0.05</td></tr><tr><td>Yalin/2019 [31]</td><td>Turkey</td><td>He/Gr</td><td>5477 (1652 He/3822 Gr)</td><td>63</td><td>Plasma α-GAL > Gn</td><td>Gn</td><td>17 (2 He/15 Gr)</td><td>0.31 (0.12He; 0.39Gr)</td></tr><tr><td>Frabasil/2019 [32]</td><td>Argentina</td><td>He/PD</td><td>9604</td><td>100</td><td>α-GAL > Gn</td><td>None</td><td>22/NA</td><td>0.23/NA</td></tr><tr><td>Jahan/2020 [33]</td><td>Australia</td><td></td><td>526</td><td></td><td>DBS α-GAL > Gn</td><td>DBS α-GAL > Gn</td><td>0/0</td><td>0.00/0.00</td></tr><tr><td>Alhemyadi/ 2020 [34]</td><td>Saudi Arabia</td><td></td><td>619</td><td></td><td>DBS α-GAL > WBC α-GAL > Gn</td><td>DBS α-GAL > WBC α-GAL > Gn</td><td>0/3</td><td>0.00/0.48</td></tr><tr><td>Nagata/2022 [35]</td><td>Japan</td><td>He/PD</td><td>2122 Including 1703</td><td></td><td>Plasma α-GAL > WBC α-GAL > Gn</td><td>None</td><td>1/NA</td><td>0.06/NA</td></tr><tr><td>Vigneau/2022 [36]</td><td>Western France</td><td>CKD stage 5D/T</td><td>819 including 242 CKD stage 5D</td><td>100</td><td>DBS α-GAL</td><td>NA</td><td>0/NA</td><td>0.00/NA</td></tr><tr><td>Mallett/2022 [37]</td><td>Australia</td><td>CKD stage 1-5D/T</td><td>2992</td><td>58</td><td>DBS α-GAL + Lyso-Gb3 > Gn</td><td>DBS α-GAL + Lyso-Gb3 > Gn</td><td>5/1</td><td>0.3/0.08</td></tr><tr><td>Cho/2024 [38]</td><td>South Korea</td><td>CKD stage 1-5</td><td>897 including 279 CKD stage 5D</td><td>45</td><td>α-GAL + Lyso-Gb3 > Gn</td><td>α-GAL + Lyso-Gb3 > Gn</td><td>0/1</td><td>0.00/0.2</td></tr><tr><td>Present study</td><td>France</td><td>He/PD</td><td>2815</td><td>61</td><td>α-GAL > Gn</td><td>α-GAL + Lyso-Gb3 > Gn</td><td>1/0</td><td>0.06/0.00</td></tr></tbody></table>

Abbreviations: α-GalA: α-galactosidase A, CKD: Chronic Kidney Disease, He: hemodialysis, Lyso-Gb3: Lyso-globotriaosylceramide, PD: peritoneal dialysis.

According to a meta-analysis, the prevalence of FD in dialysis is around 0.21% in men and 0.15% in women [25], much higher than the prevalence measured in the present study. When limiting the scope to studies in European populations of at least 1000 patients, all were carried out prior to 2008, and the prevalence they measured varied from 0.26% to 0.42% in men [3,12,14]. More recently published studies unrelated to Europe have observed similar results, except for the Japanese J-FAST study [28] and the Australian aCQuiRE study [38], which both measured a prevalence of 0.02% [28,38], close to that found in the present study.

Among the hypotheses that may explain the low prevalence found in the present study was the fact that a previously known diagnosis of FD would have been an exclusion criterion. However, investigators had to request the inclusion of patients for whom FD was confirmed, and an analysis of the data of the National Dialysis Registry (Registre Epidémiologie et Information en Néphrologie, REIN [55]) did not identify any patients with previously diagnosed FD among the screened patients, suggesting that no patient
with a known diagnosis of FD was excluded. The low prevalence could also be due to a lack of sensitivity, as measuring α-GalA on dried blood carries a risk of false negatives [16]; however, in our study, the α-GalA threshold was set high, so this risk was negligible in men. In women, the risk of having both α-GalA and lyso-Gb₃ in the normal ranges along with ESRD due to FD is also likely negligible [3,30,42,43]. However, cases of later-onset Fabry disease with high residual enzyme activity in heterozygote females in association with a coincident kidney disease leading to ESRD could have been missed. Alternatively, the prevalence in this study could reflect reality more accurately than in previous studies. Our approach aggregated phenotypic, biological, and genetic data, thereby avoiding over-diagnosing FD. As an example, thorough phenotype-genotype correlation allowed us to consider a patient with a likely benign variant (p.Asn139Ser), initially suspected to be associated with the later-onset cardiac phenotype of FD, as non-FD.

In the only diagnosed case of FD in this study, suggestive early signs and family history had been overlooked prior to the study. However, after examination, the FD-expert physician (DPG) identified a suggestive familial and personal history. The diagnosis led to the initiation of specific therapy and family screening [56]. This case emphasizes the importance of searching for a suggestive family history [56,57] and the need for nephrologists to be trained in recognizing the physical signs of FD, in particular when the etiology of the nephropathy is unknown.

This study has several limitations, including the absence of participation of all French dialysis centers, the restriction to dialyzed patients rather than to all ESRD patients, a high rate (26.4%) of non-included eligible patients, and the lack of data related to such patients, especially regarding their gender. More importantly, diagnosis in female Fabry patients may have been missed since a recent large retrospective study conducted on 827 patients (374 males and 453 females), all with a causative variant in the GLA gene, showed that while 100% of male patients had an α-GalA activity lower than the reference value, regardless of the phenotype, more than 70% of female patients had normal enzyme activity, both with the classic variant and with late-onset variants. Those female patients would, therefore, escape diagnosis if the enzymatic test alone was used [58]. Similarly, 42% of females with a pathogenic variant in GLA had normal plasma lyso-Gb3 values with a significant difference between subjects with the classic variant compared to patients with a later-onset form of the disease [45,58]. In the case of classic Fabry disease, 83% of female patients had pathological values of plasma LysoGb3, meaning that using this test for diagnosis, up to 17% of female patients could, in theory, have been missed [58]. However, previous studies in female patients with Fabry disease have shown a strong correlation between low alpha-galactosidase activity (in association with a highly skewed X inactivation profile) and progression to end-stage renal disease, thereby highly reducing the risk of a false negative in our study population [8,9].

The strengths of the present study advocate for the scientific relevance of its results. The screening was conducted in a country where the national healthcare system covers the costs of dialysis, reducing patient selection bias. It relied on data from a nationwide dialysis database (REIN) [55,59]. Patients' screening was limited to patients dialyzed on a single date, according to the strict definition of prevalence. The protocol requested the inclusion of previously diagnosed FD patients in order to measure the prevalence of FD and not of "undiagnosed-FD". The diagnostic sensitivity was enhanced thanks to a systematic dosage of lyso-Gb₃ in addition to the α-Gal assay in women. Finally, the DVC reduced the risk of over-diagnosis of FD through the exclusion of non-pathogenic GLA variants [41–45,50,51].

In conclusion, the FABRYDIAL study aimed at estimating the prevalence of FD in patients aged 18 to 74 years undergoing chronic dialysis in France. Among the 2815 patients with available biological data, one patient was diagnosed with FD, leading to an estimated prevalence of 0.036% [0.006;0.201], 0.058% in men [0.01;0.328], and 0% in women [0;0.35]. When considering patients who were not included due to a previously known cause of nephropathy unlinked to FD, the prevalence in this population was lower, 0.028% [0.006;0.121]. The only FD-diagnosed patient presented with a highly suggestive history
and typical signs that should have evoked FD prior to initiating dialysis [60]. Nephrologists should be aware of FD and look for its early signs when caring for patients with nephropathy of uncertain etiology since earlier diagnosis and treatment of FD are associated with better outcomes [1,10,60–69].

**4. Patients and Methods**

**4.1. Context**

A standardized screening approach was proposed to dialysis centers, targeting patients aged 18 to 74 years undergoing chronic dialysis in order to identify and confirm FD patients. Patients were not eligible if the cause of their nephropathy was known and unrelated to FD, which was restricted to the following causes: polycystic kidney disease, type 1 diabetes or biopsy-proven IgA nephropathy, and membranous glomerulonephritis or ANCA-associated vasculitis. All patients confirmed non-objection before participation.

**4.2. Study Design and Ethics Statement**

This cross-sectional study targeted patients undergoing chronic dialysis in five geographical areas of France (Ile-de-France, Rhône-Alpes, Aquitaine, Picardie, and Gard). All dialysis centers were invited to participate in the study by local study coordinators; a total of 124 centers were included. The study received approval from the French National Data Protection Agency (Reference Methodology MR-003—Commission Nationale Informatique et Libertés, number 17-002). It was classified as non-interventional by the Review Board of the Regional Ethics Committee (2 December 2015). All eligible patients were offered to participate in the study. They were given a written explanatory document, and their non-objection was recorded. The study was in agreement with the Helsinki Declaration of 1975, as revised in 2013.

**4.3. Subjects**

Patients aged 18 to 74 years from all participating centers undergoing chronic dialysis during the week of 20 November 2017, were evaluated for eligibility. Eligibility criteria included a previous or scheduled FD screening test and a non-objection to participate in the study. Non-eligibility criteria included proven nephropathy unrelated to FD (same criteria as those of the FD screening campaign), the absence of health insurance coverage, or guardianship or tutelage. Reasons for non-inclusion of eligible patients could not be collected for regulatory reasons.

Data collection was facilitated by extracting data from the National Dialysis Registry (REIN [38]). All of the extracted data were systematically checked in the patient medical files.

**4.4. Biochemical Methods**

**4.4.1. Blood Spot Tests**

In the setting of routine care, two dried blood spots (DBS) were collected from patients on a filter paper (Whatman number 903 paper, Whatman, Middlesex, UK). The cards were air-dried, kept at room temperature during shipment, and subsequently stored at 4 °C. Diagnostic tests were performed at ARCHIMED Life Science GmbH (Vienna, Austria).

**4.4.2. Diagnostic Algorithm**

Screening for FD was carried out by measuring the activity of α-GalA in men and both α-GalA activity and lyso-Gb₃ levels in women, using DBS samples. Samples were analyzed in replicates, and borderline results were re-tested before a 2nd card was requested and/or genetic testing was performed. In patients with decreased α-GalA activity (<1.2 µmol/L/h), increased Lyso-Gb₃ (>3.5 ng/mL), or both, GLA sequencing was performed.
#### 4.4.3. α-GalA Activity Determination

α-GalA activity was determined using a validated and accredited fluorimetric method. DBS samples were added to 70-well microlitre plates and incubated overnight at 37 °C with 4-methylumbelliferyl-α-D-galactopyranoside as the substrate and N-acetyl-D-galactosamine as an inhibitor for α-N-acetylgalactosaminidase. Each plate contained an internal standard for quality control purposes. The reaction was stopped with 300 µL ethylenediamine (pH 11.3) [70].

#### 4.4.4. Lyso-Gb₃ Determination

Lyso-Gb₃ concentrations were measured by highly-sensitive electrospray ionization liquid chromatography-tandem mass spectrometry (ESI LC-MS/MS) using a modified method based on Gold et al. [71] as previously described [72,73]. A 7-point serum calibrator, an internal standard for lyso-Gb₃ quantification (analytic range from 0–120 ng/mL; lower limit of quantification: 1.5 ng/mL), and three calibrator levels for quality control were used.

### 4.5. Genetic Analysis

The GLA mutations were identified by Sanger DNA sequencing using standard methods [46].

### 4.6. Diagnosis Validation Committee

A multidisciplinary diagnosis validation committee (DVC) was in charge of confirming or excluding FD diagnosis for patients with a GLA genetic variant. The committee included the nephrologist in charge of the patient, two senior nephrologists (FS and BK), and a senior geneticist with recognized expertise in FD (DPG). The diagnosis was confirmed in the case of the following associations: (1) Biochemical abnormalities (α-GalA activity <1.2 µmol/L/h and/or lyso-Gb3 >3.5 ng/mL), (2) A likely pathogenic (class 4) or pathogenic (class 5) genetic variant and (3) A compatible phenotype. Variants were assessed using gnomAD, ClinVar, and HGMD2018.2 [42,58,74,75]. Unpublished variants were interpreted according to the ACMG/AMP 2015 guidelines [74].

### 4.7. Statistical Analysis

Descriptive statistics were used for clinical characteristics and laboratory parameters. Categorical variables were expressed as absolute counts and percentages (%). Continuous variables of normal distribution were summarized by the mean and standard deviation (SD), and continuous variables of non-normal distribution by the median and interquartile range (IQR). Group comparisons were performed using Chi-squared tests for categorical variables and Student's t-tests for continuous variables; where distributional assumptions for these tests were violated, the Fisher's exact and Mann-Whitney-Wilcoxon tests, respectively, were used.

The prevalence of FD was determined by the proportion of patients with a confirmed diagnosis. The prevalence among included and screened patients was the main endpoint. The prevalence of FD was then estimated among the total population of patients aged 18 to 74, based on the following hypotheses: (1) Non-included eligible patients, and patients with an absence of health insurance or guardianship or tutelage, have a prevalence of FD identical to that of screened patients; (2) Patients excluded due to a renal diagnosis unrelated to FD do not have FD.

Statistical significance was defined as *p*-value < 0.05. All statistical analyses were performed using the SAS statistical software version 9.3 (SAS Institute, Cary, NC, USA).
**Author Contributions:** Conception and design: F.S., L.G., B.K., O.M., G.C., V.d.P., I.D., L.L., D.P.G. and L.J. Formal analysis and interpretation of data: F.S., L.G., O.M., C.C., I.D., L.L. and D.P.G. Funding: F.S. and L.J. Investigation: F.S., B.K., O.M., G.C., V.d.P., FABRYDIAL Study Group, L.L., FABRYDIAL Study Group, L.J. and D.P.G. Project administration: F.S., L.J. and D.P.G. Supervision: F.S., L.J. and D.P.G. Writing—original draft: F.S. Writing—review: F.S., O.M., C.C., I.D., L.L., L.T.T.P., L.J. and D.P.G. Writing revised manuscript: D.P.G. Final approval of the version to be published: F.S., L.G., B.K., O.M., G.C., V.d.P., C.C., I.D., L.L., L.T.T.P., T.G., FABRYDIAL Study Group, L.J. and D.P.G. All authors have read and agreed to the published version of the manuscript.

**Funding:** Funding for this Investigator Sponsored Study was provided by Sanofi (reference: ISS 69HCL16_0536). Sanofi was not involved in the study design, conduct, protocol review, manuscript preparation, or decision to submit the manuscript for publication. Researchers had full intellectual independence from the funder regarding this research.

**Institutional Review Board Statement:** In line with the French legislation, ethical review and approval for this study were waived by the local institutional review board (Comité de Protection des Personnes CPP Sud-Est II; Lyon, France; dated 2 December 2015; reference: CAL2015.69) because it was qualified as non-interventional. The study received approval from the French National Data Protection Agency (Reference Methodology MR-003—Commission National Informatique et Libertés, number 17-002).

**Informed Consent Statement:** All eligible patients were invited to participate in the study. Patient consent was waived because the study was qualified as non-interventional by local institutional review board (reference: CAL2015.69). However, all patients were given a written explanatory document, and were free to object to the processing of their personal medical data. The study was conducted in accordance with the Declaration of Helsinki.

**Data Availability Statement:** The main data underlying this publication are available in the article. In accordance with French regulations, additional data, since they are not necessary to answer the authors' scientific question, namely the prevalence of Fabry disease, cannot be shared.

**Acknowledgments:** The following were members of the FABRYDIAL Study group (F.S.G.): ACHICHE Jedjiga, ADEM Arezki, ADJEL Hibba, AL ADIB Mohamad, AUDARD Vincent, BEAUDREUIL Severine, BELGUESMIA Zaineb, BERERHI Lynda, BERGUIGNAT Marine, BOUBENIDER Samir, BOUCHARD Sarah, BOULLENGER Fanny, BRAVANT Estelle, BRUCKER Marie, CARDOZO Jorge, CAUDWELL Valérie, CHAKIR Mohammed Amine, CHAUVEAU Philippe, COLAS Sandra, COULIBALY Moussa, CREPUT Caroline, DE PRECIGOUT Valerie, DELAHOUSSE Michel, DELCLAUX Caroline, DEMONTIS Renato, DEPRELE Carole, DEPREZ Karine, DIACONITA Mirella, DIET Carine, DOUILLET Marine, DUPUIS Emmanuel, EL ESPER Najeh, EPRON Catherine, FARAH Ibrahim, FRANKO Benoit, FRAOUI Raba, GERMAIN Dominique P., GHAFARI Thomas, GUERAOUI Abdallah, HAESEBAERT Julie, HALLONET Patrick, HAMANI Abdelaziz, HANNOUN Jacques, HELOU Sébastien, HERTIG Alexandre, HILAIRE PAPOULAR Frédérique, HOUSSET Pierre, IAMANDI Laurentiu, JABER Waddah, JACQ Dominique, JEAN Guillaume, JOLY Amélie, JUIL-LARD Laurent, KARAASLAN Huseyin, KERD Héla, KINTEGA Roland, KNEBELMANN Bertrand, KOLKO Anne, KONAN Michel, KOOCHAKI POUR Zoé, KOSSARI Niloufar, LACAILLE Antoine, LACRAZ Adeline, LAMRIBEN Larbi, LASSALLE Mathilde, LEPEYTRE Fanny, LINO-DANIEL Marie, MACARY Audrey, MAGAUD Laurent, MAILLIEZ Sébastien, MANSOUR Janette, MAROUN Naine, MASSY Ziad, MEIER Pascal, MERCADAL Lucile, METIVIER Fabien, MICHEL Pierre-Antoine, MICHEL CATHERINE Catherine, MOHAJER Mederick, MONGE Matthieu, MONKAM Régine, MOUZAOUI Fariza, NAKHLA Magued, NGANGO Liliane, PALACIN Pedro, PAMBRUN Emilie, PANAYE Marine, PASTURAL Myriam, PELLE Gaelle, POUX Jean-Michel, POYET Anais, QINGUILLON Wen, QUERON Véronique, RAIMBOURG Quentin, RENAUD Henri, RIDEL Christophe, ROSTOKER Guy, ROUEFF Stéphane, ROUSSEAU Philippe, SAKSI Salima, SARRAJ Aymen, SCHOTT-PETHELAZ Anne-Marie, SEIDOWSKY Alexandre, SELLAL Melissa, SENIUTA Piotr, SENS Florence, SURY Aurore, SZELAG Jean-Christophe, TEOBULLE Dan, THIBAUDIN Damien, TOUSSAINT Stéphane, TRAN THI PHUONG Liên, URENA Pablo Antonio, VECINA Frédérique, VILLAR Emmanuel, WEIS Lise, YAHIAOUI Yasmina, ZINS Brigitte. The authors thank all REIN registry participants, FABRYDIAL research coordinators, associated investigators, and nursing and administrative teams from the different participating centers who made this study possible.
**Conflicts of Interest:** F.S., G.C. and L.J. received travel grants from Sanofi. B.K. received travel grants from Sanofi and Amicus Therapeutics. D.P.G. is a consultant for Chiesi, Idorsia, Takeda, and Sanofi. V.d.P., O.M., L.T.T.P. and T.G. declare no conflicts of interest.

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