Characterizing pain in patients with Fabry disease: Findings from a web-based cross-sectional survey in the US

Characterizing pain in patients with Fabry disease: Findings from a web-based cross-sectional survey in the US | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Characterizing pain in patients with Fabry disease: Findings from a web-based cross-sectional survey in the US Eric Wallace, Dawn Laney, Ibrahim Warsi, Connie Baldwin, Jack Johnson, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3725282/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jun, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Fabry disease (FD) is a rare, progressive disorder caused by pathogenic variants of the GLA gene resulting in the accumulation of toxic metabolites. Pain is a hallmark of FD, and patients often present with heterogeneous pain profiles. This cross-sectional, web-based survey was conducted to characterize pain and pain crises in patients with FD in the United States and explore the effects of sex, disease phenotypes, and treatment on pain. Results: A total of 66 participants (mean [±SD] age: 44.0 [±12.7] years; females: 59.1%) completed the survey. Participants reported experiencing pain in upper (34.8%) and lower (43.9%) extremities several times a day and abdominal pain (31.8%) a few times a week. Overall, participants reported the nature of their pain as triggered (upper extremities: 47.0%; abdomen: 51.5%) or sudden (lower extremities: 57.6%). Female participants reported experiencing pain in upper (46.2%) and lower (48.7%) extremities several times a day and described it as sudden or triggered (48.7%) in upper extremities and sudden (61.5%) in lower extremities. Pain crises were reported in the lower extremities (80.0%), followed by the upper extremities (66.7%) and the abdomen (51.1%), and were often characterized as burning, tingling, or stabbing. A higher proportion of female participants (84.6%) than that of male participants (73.7%) reported pain crises in lower extremities. The duration of pain crises varied from 30 minutes to several days for different subgroups depending on sex and FD phenotypes. Most participants (81.0%) reported symptom improvement after 12 months of FD-specific treatment. With agalsidase beta as the most recent medication, participants reported improvement in neuropathic symptoms (burning in hands, 45.9%), with an overall mean (±SD) satisfaction score of 7.2 (±1.7). Conclusions: Pain was largely reported to be triggered across all subgroups. Consistent pain profiles were noted in participants across sex and FD phenotypes. Female participants reported pain burden similar to that of male participants, and pain crisis experience was heterogeneous across the subgroups. Most participants reported improvement in symptoms after FD-specific treatment and a high treatment satisfaction score with agalsidase beta. Abdominal pain Fabry disease Neuropathic pain Pain Pain crises Patient-reported Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 BACKGROUND Fabry disease (FD) is a rare, progressive, X-linked genetic disorder caused by pathogenic variants of the GLA gene, leading to a deficiency in the lysosomal α-galactosidase-A enzyme [ 1 ]. This enzyme deficiency results in progressive accumulation of toxic metabolites, such as globotriaosylceramide and globotriaosylsphingosine [ 2 , 3 ], and downstream activation of inflammatory pathways [ 4 , 5 ]. A combination of these mechanisms leads to severe symptoms and life-threatening complications with an increased risk of mortality [ 6 – 8 ]. Symptom severity and onset in FD depends upon the pathogenic GLA variant and is typically classified into classic and non-classic/later-onset phenotypes (appearing in both males and females) [ 9 ]. The classic phenotype is characterized by early-onset of symptoms and lower enzyme activity and involves multiple organs (noted in 1:22,000–1:40,000 males), while precise prevalence in females is unknown [ 6 , 10 – 12 ]. Symptoms in the later-onset phenotype appear in adulthood and have less multi-organ involvement but can still be life-limiting [ 6 , 10 , 11 ]. Variants associated with this phenotype are observed in 1:1390–1:9372 individuals across different populations [ 13 , 14 ]. In the United States, the primary treatments approved for managing patients with FD are intravenous enzyme replacement therapy and chaperone therapy. Enzyme replacement therapy includes agalsidase beta [ 15 ] or pegunigalsidase alfa [ 16 ]. One oral chaperone, migalastat, is available for patients with amenable variants of GLA [ 17 ]. Further, apart from these disease-specific treatments, adjunctive/symptomatic therapies, such as angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, beta blocker, anticoagulants, pain management, and H2 blocker, are used to manage renal, cardiac, cerebrovascular, peripheral nervous system and gastrointestinal (GI) symptoms [ 6 ]. Clinical presentation of FD includes early symptoms of peripheral neuropathic pain (numbness, burning, tingling, and pain) [ 18 ] and GI symptoms (abdominal pain, bloating, nausea, constipation, and diarrhea) [ 19 – 21 ]. Pain is a characteristic of FD and is one of the early symptoms that can persist throughout life [ 22 ]. Fabry-disease-related pain can be extremely distressing and is one of the significant determinants affecting patients’ quality of life [ 19 ] and disease burden [ 23 ]. Patients with FD experience both evoked and spontaneous pain, which can be chronic or episodic, indicating a range of pain presentation types [ 19 , 22 ]. These manifest as varied pain symptoms, including, but not limited to, pain crises, hypersensitivity to mechanical stimuli, and neuropathic and GI pain, with high interindividual pain heterogeneity [ 19 , 22 , 24 ]. Patients often require analgesics as adjunctive therapies to manage their debilitating pain [ 25 , 26 ]. Patients with FD also experience pain crises, described as intense, excruciating, and unbearable pain [ 26 ]. The most frequently described pain crisis begins in the lower or upper extremities and often radiates proximally [ 22 , 27 ]. Although not traditionally considered a pain crisis, abdominal GI pain can also be acute manifesting as severe abdominal pain triggered by meals or stress [ 20 ]. While pain crisis may not occur in all patients, it can be a critical diagnostic indicator of FD [ 26 ]. METHODS Study Design This observational, cross-sectional, web-based survey recruited patients with self-reported, physician-diagnosed FD in the United States. This study explored how patients with FD perceive their pain and pain crises, evaluated potential variations based on sex and phenotype and aimed to understand the effect of current treatment on Fabry symptoms. The survey included male or female patients (≥ 18 years) experiencing moderate-to-severe neuropathic pain in the upper extremities, lower extremities, or abdomen, able to read and understand English, and able/willing to provide electronic informed consent prior to participation. Patients who participated in another survey for an FD advocacy group in the past 2 months were excluded. Survey Methodology The survey was conducted among patients affiliated with the Fabry Support & Information Group, an FD patient advocacy group. An e-mail including the study invitation and a brief overview was shared with the eligible patients. Interested participants responded to the e-mail, and each received a unique weblink to administer the online survey. The survey was open for participation between April 8, 2021 and August 13, 2021. The estimated length of the survey was 30 minutes. The survey received responses in four categories: participants’ eligibility; demographics and disease characteristics; pain characteristics (neuropathic and abdominal pain severity, frequency, duration, and nature); and Fabry symptoms and severity assessed using the FD-PRO questionnaire. The FD-PRO is a 19-item instrument that assesses symptom severity for adults with FD [ 28 , 29 ]. Participants rated the severity of their symptoms in the past 24 hours on a numeric rating scale from 0 (no symptom) to 10 (symptom at its worst). Participants’ satisfaction with the current treatment was also recorded on a scale from 0 (completely dissatisfied) to 10 (most satisfied). Participants could also select “don’t know/Prefer not to answer” for any questions, as this survey was voluntary. For reporting purposes, these data have not been presented herein; however, only a maximum of 10% of participants chose this response for any question. The study received an institutional review board exemption under the 45 Code of Federal Regulations Part 46 from the Research Triangle Institute Office of Research Protection. Data Analysis All data collected via the survey were self-reported, and each question was analyzed individually among those participants who responded. Descriptive statistics were used to describe participants’ demographics, clinical characteristics, treatment history, FD treatment experience, pain profile, symptom severity, and bothersome symptoms. No imputation of missing data, statistical hypothesis testing, or sample weighting of questionnaire responses was done. Pain-related data were reported for the last 2 weeks prior to the survey completion date. Data were analyzed for the overall group and subgroups (based on sex and phenotype). Continuous variables were presented as mean, standard deviation (± SD), and categorical variables as frequencies and percentages. All analyses were performed using SAS statistical software (version 9.4). RESULTS Baseline Characteristics A total of 66 participants (mean age [± SD]: 44.0 [± 12.7] years; classic FD phenotype: 65.2%; females: 59.1%) completed the survey. The mean (± SD) time since diagnosis and time since diagnosis to the first treatment onset was 14.2 (± 11.2) years and 4.9 (± 7.4) years, respectively (Table 1 ). Most participants (77.3%) reported normal-to-mildly decreased kidney function with a mean estimated glomerular filtration rate of 67.9 (± 33.0) mL/min. Participants reported their neuropathic and abdominal pain as mild (12.1% and 18.2%), moderate (39.4% and 34.8%), severe (37.9% and 30.3%), and very severe (10.6% and 9.1%). Most participants (86.4%) received FD treatment in the past 6 months or during the survey. Agalsidase beta was the most recent treatment reported by majority of the participants (77.6%) (Table 1 ). Pain Profile Frequency and nature of pain profile Overall, a high proportion of participants reported experiencing pain in the upper (34.8%) and lower (43.9%) extremities several times a day, whereas abdominal pain (31.8%) was mostly reported a few times a week (Table 2 ). In female and classic phenotype subgroups, pain frequency in the extremities and abdomen showed a trend similar to that of the overall study population. In contrast, more male participants reported experiencing pain in the extremities and abdomen a few times a week. The majority of later-onset participants experienced pain in the lower extremities once daily. In contrast, pain in the upper extremities and abdomen was experienced up to a few times a week. It is noteworthy that a higher proportion of female participants reported pain in the upper (46.2% vs. 18.5%) and lower (48.7% vs. 37.0%) extremities several times a day than males (Supplementary Fig. 1). Among all participants, the nature of pain in the upper extremities (47.0%) and abdomen (51.5%) was described as triggered, while pain in the lower extremities (57.6%) was reported as sudden (Table 2 ). Participants (female vs. male) reported the nature of pain as either sudden or triggered in the upper extremities (48.7% vs. 40.7%, or 48.7% vs. 44.4%), sudden in the lower extremities (61.5% vs. 51.9%), and triggered in the abdomen (48.7% vs. 55.6%). In the classic phenotype subgroup, pain was described as sudden in the upper and lower extremities and triggered in the abdomen (53.5% each), while in the later-onset phenotype subgroup, the majority of participants described their pain as sudden in the lower extremities (70.6%) and triggered in the upper extremities and abdomen (47.1% each) (Supplementary Fig. 2). Table 1 Self-reported baseline characteristics and clinical profile of participants with FD Characteristics Participants ( N = 66) Age (years) , mean (±SD) 44.0 (±12.7) Sex, n (%) Male 27 (40.9) Female 39 (59.1) FD phenotype, n (%) Classic 43 (65.2) Later-onset 17 (25.8) Not sure 6 (9.1) Time since diagnosis (years) , mean (±SD) ( n = 64) 14.2 (±11.2) Time since diagnosis to first treatment (years) , mean (±SD) ( n = 56) 4.9 (±7.4) eGFR (mL/min/1.73 m 2 ) , mean (±SD) ( n = 26) 67.9 (±33.0) CKD stage a , n (%) Normal to mildly decreased kidney function 51 (77.3) Moderate to very severely decreased kidney function 12 (18.2) Not sure/Prefer not to answer 3 (4.5) Comorbidities, n (%) Cardiovascular comorbidities b 32 (48.5) No listed comorbidities 33 (50.0) Pain severity (PGIS) c Neuropathic pain, n (%) Abdominal pain, n (%) Very severe 7 (10.6) 6 (9.1) Severe 25 (37.9) 20 (30.3) Moderate 26 (39.4) 23 (34.8) Mild 8 (12.1) 12 (18.2) No pain 0 5 (7.6) Pain medication used in the past 6 months, n (%) Yes 56 (84.8) No 10 (15.2) Fabry-specific treatment status in the last 6 months, n (%) Untreated (ever or in last 6 months) 9 (13.6) Treated (currently or in last 6 months) 57 (86.4) Most recent FD treatment, n (%) Agalsidase beta Migalastat Other Overall ( n = 58) d 45 (77.6) 10 (17.2) 3 (5.2) a CKD stage was self-reported and categorized as “normal-to-mild decreased kidney function” for Stages 1–2 and “moderate to very severely decreased kidney function” for Stages 3–5. b Prior myocardial infarction, prior stroke, transient ischemic attack, unstable angina, congestive heart failure, atrial fibrillation, coronary artery disease, arrhythmia, presence of a pacemaker, presence of a defibrillator, or other heart diseases. c Pain characterization for neuropathic pain in extremities and abdominal pain was assessed through a validated questionnaire [29]. d The most recent FD treatment can include patients who were treated more than 6 months ago (one patient in this case). CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FD, Fabry disease; N, total number of participants; n , number of participants; PGIS, Patient Global Impression of Severity; SD, standard deviation Table 2 Overall pain profile by frequency and nature based on location Pain profile ( N = 66) Pain in upper extremities, n (%) Pain in lower extremities, n (%) Abdominal pain, n (%) Pain frequency Several times a day 23 (34.8) 29 (43.9) 13 (19.7) Once daily 8 (12.1) 10 (15.2) 10 (15.2) A few times a week 16 (24.2) 14 (21.2) 21 (31.8) Once a week 5 (7.6) 2 (3.0) 9 (13.6) Once in the past 2 weeks 7 (10.6) 5 (7.6) 6 (9.1) I did not experience such pain in the past 2 weeks 7 (10.6) 6 (9.1) 6 (9.1) Nature of pain Constant, chronic pain 11 (16.7) 21 (31.8) 10 (15.2) Sudden episodes of pain without a known trigger (e.g., pain crises) 30 (45.5) 38 (57.6) 24 (36.4) Pain triggered by something else, such as diet, exercise, or change in temperature 31 (47.0) 23 (34.8) 34 (51.5) Other types of pain 7 (10.6) 9 (13.6) 9 (13.6) N , total number of participants; n , number of participants Pain crises by location, sex, and Fabry disease phenotypes Of the participants who reported experiencing pain crises ( n = 45), majority reported crises in the lower extremities (80.0%), followed by the upper extremities (66.7%) and abdomen (51.1%). Pain crisis distribution was heterogenous based on sex. Males (relative to females) predominantly reported pain crises in the upper extremities (73.7% vs. 61.5%) and abdomen (68.4% vs. 38.5%), whereas a higher proportion of female participants (relative to males) reported experiencing pain crises in the lower extremities (84.6% vs. 73.7%). The anatomical location of pain crises varied based on Fabry phenotypes. Participants from the classic phenotype subgroup reported experiencing pain crises mainly in the lower extremities (82.1%) and upper extremities (75.0%) compared to the abdomen (42.9%), whereas participants from the later-onset subgroup reported a similar proportion of pain crises (69.2%) across both the extremities and abdomen. Notably, abdominal pain crises were reported by a higher proportion of later-onset phenotype participants (69.2% vs. 42.9%) than classic phenotype participants (Fig. 1). Figure 1 Pain crisis location by sex and phenotype in participants with FD FD, Fabry disease; n , number of participants Pain crisis type and duration by location Pain crises in extremities Participants often reported pain crises in the lower and upper extremities as burning (30.3% each), tingling (27.3% and 24.2%), and stabbing (22.7% and 18.2%). The pain crisis duration varied depending on the anatomical location; it ranged between a few seconds to more than a week. Participants reported experiencing pain crises in the upper extremities for a few seconds (3.3%) to several days (20.0%) and in the lower extremities ranging from a week (2.8%) to 30–60 minutes (25.0%) (Table 3 ). A consistent trend for the type and duration of pain crises was noted across sex and phenotypes. Most participants of both sexes characterized their pain crises as burning or tingling in the extremities. Participants with classic phenotype often described their pain crises in the extremities as burning, while participants with later-onset phenotype described their pain crises as shooting and spreading (Supplementary Fig. 3). Majority of the male and later-onset subgroup participants reported experiencing pain crises in the extremities for half a day to 1 day and several days, while the majority of female and classic phenotype subgroups reported their pain crises lasting 30–60 minutes (Supplementary Fig. 4). Pain crises in the abdomen Pain crises in the abdomen were mainly characterized as stabbing (18.2%). They usually lasted 30–60 minutes (34.8%) or 60 minutes to half a day (34.8%) (Table 3 ). Across subgroups, pain crises in the abdomen were reported to have characterization and duration similar to that of the overall participants (Supplementary Figs. 3 and 4). Table 3 Pain crisis type and duration profile by location Pain crisis type Pain crises in upper extremities, n (%) Pain crises in lower extremities, n (%) Pain crises in the abdomen, n (%) Burning 20 (30.3) 20 (30.3) 1 (1.5) Cold 3 (4.5) 7 (10.6) 5 (7.6) Stabbing 12 (18.2) 15 (22.7) 12 (18.2) Tingling 16 (24.2) 18 (27.3) 3 (4.5) Shooting 13 (19.7) 17 (25.8) 3 (4.5) Spreading 8 (12.1) 10 (15.2) 7 (10.6) Prickling 10 (15.2) 8 (12.1) 0 None of these terms describes my pain crises 0 2 (3.0) 6 (9.1) Pain crisis duration ( n = 30) ( n = 36) ( n = 23) A few seconds 1 (3.3) 0 0 A few minutes 3 (10.0) 3 (8.3) 1 (4.3) 30–60 minutes 6 (20.0) 9 (25.0) 8 (34.8) 60 minutes to half a day 5 (16.7) 7 (19.4) 8 (34.8) Between half a day and 1 day 4 (13.3) 8 (22.2) 2 (8.7) Several days 6 (20.0) 6 (16.7) 3 (13.0) A week 2 (6.7) 1 (2.8) 1 (4.3) More than a week 3 (10.0) 2 (5.6) 0 n , number of participants Symptom Severity and Most Bothersome Symptoms Overall, the mean (± SD) Fabry Disease Patient-Reported Outcome (FD-PRO) symptom severity score was highest for the symptom of feeling tired [6.6 (± 2.3)], followed by pain in feet and legs [5.7 (± 2.7)] and feeling too hot [5.7 (± 2.8)] (Supplementary Table 1). Lower extremity pain was the most bothersome symptom across male and later-onset subgroup participants, while pain was the most bothersome symptom for female and classic phenotype subgroup participants (Fig. 2). Figure 2 Most bothersome symptoms in participants with FD AP, abdominal pain; FD, Fabry disease; FT, feeling tired; LEP, lower extremity pain; n , number of participants; Nu, numbness; UEP, upper extremity pain Symptom Improvement with Fabry-Disease-Specific Treatment Treatment improvement in participants over time Overall, most of the participants (81.0%) with FD self-reported improvement in their symptoms after 12 months of FD-specific treatment (Fig. 3A). Cumulatively, after 5 months, 50.0% and 46.1% of participants from the male and female subgroups (Fig. 3B), respectively, and 86.7% and 35.9% of participants from the later-onset and classic phenotype subgroups (Fig. 3C), respectively, reported improvement. Of the participants who reported improvement with agalsidase beta, cumulatively, 4.4% reported improvement after 1 week of initiating treatment, 44.4% after 5 months, and 82.2% after 1 year (Fig. 3D). Figure 3 Cumulative time for treatment improvement in participants with FD Note Cumulative percentages were calculated by adding a percentage from one period to that of another period. Time until improvement was not presented to scale. The survey question was, “After initiating treatment with agalsidase beta, approximately how long did it take for you to notice an improvement in your symptoms?” Options provided for the participants were: Immediately; Less than a week; Between 1 week and less than a month; Between 1 month and less than 2 months; 2–5 months; 6–8 months; 9–11 months; 12 months; and more than a year. FD, Fabry disease Symptoms improved with agalsidase beta as the most recent treatment After receiving agalsidase beta, most participants reported improvement in their neuropathic symptoms, including burning in hands (45.9%); pain in hands, burning in feet, and sweating (40.5% each); and tingling in hands and pain in the abdomen (37.8% each) (Fig. 4). Figure 4 Participants with FD a showing symptom improvement with agalsidase beta a Participants ( n = 37) were allowed to select multiple symptoms. FD, Fabry disease Satisfaction with agalsidase beta The mean (± SD) satisfaction score was 7.2 (± 1.7) in participants who received agalsidase beta as the most recent treatment. Male [7.6 (± 1.5)] and later-onset [8.0 (± 0.9)] participants reported higher satisfaction than the overall population (Fig. 5). Figure 5 Satisfaction with agalsidase beta in participants with FD FD, Fabry disease; n , number of participants; SD, standard deviation DISCUSSION Pain, whether neuropathic or functional, is one of the early symptoms of FD, and its occurrence may signal underlying organ deterioration [ 10 , 20 ]. Fabry-disease-related pain has been studied in the past in a variety of settings, including by using registries or screening of medical records [ 7 , 22 ]. However, the present study analyzed pain and pain crises from a patient’s perspective with moderate-to-severe pain across different FD phenotypes and for both sexes. The study demonstrated a heavy burden of neuropathic pain, abdominal pain, and pain crises experienced across sex and phenotype subgroups. Neuropathic pain is a hallmark of FD [ 26 ]; participants in this study reported frequent pain, especially in the distal extremities. Most participants characterized their pain as either “triggered” or “sudden,” which is similar to prior studies that had demonstrated a predominance of evoked neuropathic pain caused by stimuli that may not trigger pain in healthy individuals, indicating a high burden of pain associated with FD [ 23 , 30 ]. Additionally, the present study demonstrated the pain crisis experience (nature, frequency, and duration) to be highly varied with regard to sex, phenotype, and anatomical location. The study indicated a heterogenous distribution of the duration of pain crisis, ranging from a few hours to a full day. Half of the participants experienced neuropathic crisis, predominantly in the lower extremities, and described it as burning in nature, while abdominal pain crisis was often described as stabbing, which also correlates with a previous study reporting severe debilitating abdominal pain in patients with FD [ 20 ]. This novel characterization of crises in both sexes and for different phenotypes from a patient’s perspective furthers the understanding of the diverse experience of pain crises. Prior data have often reported patients with later-onset FD phenotype to have less pronounced pain and sensory abnormalities when compared with the classic phenotype [ 9 , 19 , 31 ]. The present study, however, identified that among both phenotypes, the participants experienced neuropathic and abdominal pain; the participants from the later-onset phenotype even reported sudden pain in lower extremities in a higher proportion than the classic phenotype. Furthermore, contrary to published evidence that presents females experiencing mild and intermittent pain, the present study highlighted that females experienced severe pain in the upper and lower extremities as much as several times a day [ 30 , 32 , 33 ]. Thus, despite the previous and incorrect view of females with FD presenting with minimal symptoms [ 34 ], the present study showed that female participants had a high pain burden and experienced pain symptoms similar to that of male patients. Thus, greater attention is warranted to address disease management for patients with later-onset FD and female patients with FD. Pain in FD is associated with various mechanisms and requires different therapeutic approaches through disease-specific treatment, supportive symptom management, and strategies to avoid pain triggers [ 26 ]. In the present study, most participants reported receiving pain medication (over the counter or prescription) in addition to Fabry-specific treatments for appropriate management of the multisystemic aspects of FD. Treatment guidelines recommend medications, such as carbamazepine, gabapentin, pregabalin, phenytoin, amitriptyline, duloxetine, and venlafaxine, and acute pain management with opioids (morphine, tramadol, and tilidate) [ 19 , 22 ] for managing Fabry pain. Further, looking at patient satisfaction with current treatment, participants in this study mostly reported agalsidase beta as their most recent Fabry-specific treatment and were consistently satisfied with overall symptom improvement as expressed by 82.2% of participants by 1 year after initiation of agalsidase beta. Previous studies also corroborated these findings, where agalsidase beta was beneficial in reducing pain and delaying the onset of renal, cardiovascular, and cerebrovascular events in patients with advanced FD [ 35 , 36 ]. There are certain inherent limitations of cross-sectional studies that we acknowledge, such as potential participant bias. Further, since all data in this study were self-reported, participants may have misspecified their FD phenotype. This study focused only on the descriptive analysis; hence, the subgroup results do not imply any associations. The study enrolled patients who experienced moderate-to-severe neuropathic or abdominal pain, depicting a symptomatic population; therefore, the results are not generalizable to the overall Fabry population. The study could not characterize the impact of other treatments because of a small sample size. Nonetheless, this study provided a detailed analysis of pain and pain crises from a patient’s perspective, which may aid in better understanding and overall management of pain across Fabry patients. CONCLUSIONS The present study showcases heterogenous pain presentation and, contrary to expectations, suggests that patients with later-onset FD, including females, experience pain and pain crises. Notably, female participants reported a pain burden similar to that of the male participants, adding to the increasing evidence that females with FD have high pain intensity. Further, the pain crisis experience of patients was heterogeneous among sex, phenotype, and anatomical location. Most participants on agalsidase beta reported symptom improvement and treatment satisfaction. Taken together, the present study highlights the importance of pain, a symptomatic manifestation of FD, which should be considered a critical indicator of FD across sex and phenotypes. Abbreviations AP, Abdominal pain; CKD, Chronic kidney disease; eGFR, Estimated glomerular filtration rate; FD, Fabry disease; FD-PRO, Fabry Disease Patient-Reported Outcome; FT, Feeling tired; GI, Gastrointestinal; GLA, Galactosidase alpha; LEP, Lower extremity pain; N, Total number of participants; n , Number of participants; Nu, Numbness; PGIS, Patient Global Impression of Severity; SD, Standard deviation; UEP, Upper extremity pain Declarations Ethics approval and consent to participate All participants of the study provided electronic consent prior to starting the survey. This study was submitted for institutional review board approval and deemed exempt from review. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests EW had disclosures with Sanofi, Idorsia, Amicus, Chiesi, Protalix, Walking Fish Therapeutics, Spark Therapeutics, Natera, and DaVita. DL is chair of the North American Fabry Registry Board and provides consultations for Chiesi, Sanofi, and Spark Therapeutics. She is also an investigator/coordinator in clinical trials sponsored by 4DMT, Amicus, Chiesi, Protalix, Sangamo, Sanofi, and Takeda-Shire. She is also a cofounder of ThinkGenetic, Inc. These activities were monitored and found to be compliant with the conflict-of-interest policies at the Emory University School of Medicine. IW was on an assignment at Sanofi through Integrated Resources at the time of study completion; currently, he is an employee of Evidentia Dental Research, Canada. CB and JJ are the Fabry Support & Information Group employees and provide participant outreach and recruitment support. PD and NL are employees of Sanofi and stockholders in the company. JK was an employee of Sanofi at the time this study was conducted; currently, he is an employee of Moderna. Funding This study was funded by Sanofi. Authors’ contributions IW, JK, PD, and NL were involved in conceptualization of the study and design. CB, JJ, and NL were involved in acquisition of data. NL, EW, DL, IW, CB, JJ, JK, PD, and NL were involved in analysis and interpretation of data. All authors contributed to drafting of the manuscript and critical revision of the paper for important intellectual content. Acknowledgments The authors thank all the participants of the survey. The survey programming was conducted by Valérie Derrien Ansquer, Kate Nelson, and Christina Darden of RTI Health Solutions. The analysis was conducted by Guilio Flore, Laurie Batchelder, and Bob Krupnick of IQVIA. Medical writing support for this manuscript was provided by Mrigna Malhotra and Amit Kandhare of Sanofi. References Amodio F, Caiazza M, Monda E, Rubino M, Capodicasa L, Chiosi F, et al. 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Fabry Disease Treasure Island (FL): StatPearls Publishing; 2023 [Updated 2022 Dec 24:[Available from: https://www.ncbi.nlm.nih.gov/books/NBK435996/. Hwu WL, Chien YH, Lee NC, Chiang SC, Dobrovolny R, Huang AC, et al. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum Mutat. 2009;30(10):1397–405. Wasserstein MP, Caggana M, Bailey SM, Desnick RJ, Edelmann L, Estrella L, et al. The New York pilot newborn screening program for lysosomal storage diseases: report of the first 65,000 infants. Genet Med. 2019;21(3):631–40. Prescribing information-Agalsidase beta [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103979s5309lbl.pdf. Prescribing information- Pegunigalsidase alfa [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761161s000lbl.pdf. Prescribing information-Migalastat [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208623lbl.pdf. Burlina AP, Sims KB, Politei JM, Bennett GJ, Baron R, Sommer C, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol. 2011;11:61. Burand AJ, Jr., Stucky CL. Fabry disease pain: patient and preclinical parallels. Pain. 2021;162(5):1305–21. Zar-Kessler C, Karaa A, Sims KB, Clarke V, Kuo B. Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis. Therap Adv Gastroenterol. 2016;9(4):626–34. Laney DA, Peck DS, Atherton AM, Manwaring LP, Christensen KM, Shankar SP, et al. Fabry disease in infancy and early childhood: a systematic literature review. Genetics in medicine : official journal of the American College of Medical Genetics. 2015;17(5):323-30. Üçeyler N, Ganendiran S, Kramer D, Sommer C. Characterization of pain in Fabry disease. Clin J Pain. 2014;30(10):915–20. Bashorum L, McCaughey G, Evans O, Humphries AC, Perry R, MacCulloch A. Burden associated with Fabry disease and its treatment in 12–15 year olds: results from a European survey. Orphanet J Rare Dis. 2022;17(1):266. Rickert V, Kramer D, Schubert A-L, Sommer C, Wischmeyer E, Üçeyler N. Globotriaosylceramide-induced reduction of KCa1. 1 channel activity and activation of the Notch1 signaling pathway in skin fibroblasts of male Fabry patients with pain. Exp Neurology. 2020;324:113–34. Watt T, Burlina AP, Cazzorla C, Schönfeld D, Banikazemi M, Hopkin RJ, et al. Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: findings from the Fabry Registry. Genetics in Medicine. 2010;12(11):703-12. Politei JM, Bouhassira D, Germain DP, Goizet C, Guerrero-Sola A, Hilz MJ, et al. Pain in Fabry disease: Practical recommendations for diagnosis and treatment. CNS Neurosci Ther. 2016;22(7):568–76. Desnick RJ, Brady RO. Fabry disease in childhood. The J Pediatr. 2004;144(5):S20–S6. Hamed A, DasMahapatra P, Lyn N, Gwaltney C, Hopkin RJ. Development of the Fabry Disease Patient-Reported Outcome (FD-PRO): a new instrument to measure the symptoms and impacts of Fabry disease. Orphanet J Rare Dis. 2021;16(1):285. Hamed A, DasMahapatra P, Lyn N, Gwaltney C, Iaconangelo C, Serrano D, et al. Fabry Disease Patient-Reported Outcome (FD-PRO) demonstrates robust measurement properties for assessing symptom severity in Fabry disease. Mol Genet Metab Rep. 2021;29:100824. Gibas AL, Klatt R, Johnson J, Clarke JTR, Katz J. A survey of the pain experienced by males and females with Fabry disease. Pain Res Manag. 2006;11:828–964. Biegstraaten M, Hollak CE, Bakkers M, Faber CG, Aerts JM, van Schaik IN. Small fiber neuropathy in Fabry disease. Mol Genet Metab. 2012;106(2):135–41. Chowdhury MM, Holt PJ. Pain in Anderson-Fabry's disease. The Lancet. 2001;357(9259):887. Ro LS, Chen ST, Tang LM, Hsu WC, Chang HS, Huang CC. Current perception threshold testing in Fabry's disease. Muscle & Nerve: Official Journal of the American Association of Electrodiagnostic Medicine. 1999;22(11):1531-7. Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007;9(1):34–45. Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet. 2015;52(5):353. Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007;146(2):77–86. Supplementary Files SupplementaryFigure1.tif Supplementary Figure 1 Pain frequency profile across sex (A) and phenotype (B) by location in participants with FD FD, Fabry disease; n , number of participants SupplementaryFigure2.tif Supplementary Figure 2 Nature of pain across sex (A) and phenotype (B) by location in participants with FD FD, Fabry disease; n , number of participants SupplementaryFigure3.tif Supplementary Figure 3 Pain crisis type across sex (A) and phenotype (B) by location in participants with FD FD, Fabry disease; n , number of participants SupplementaryFigure4.tif Supplementary Figure 4 Pain duration profile across sex (A) and phenotype (B) by location in participants with FD FD, Fabry disease; n , number of participants SupplementaryTable1.docx Cite Share Download PDF Status: Published Journal Publication published 16 Jun, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Reviewers agreed at journal 04 Jan, 2024 Reviewers invited by journal 02 Jan, 2024 Editor assigned by journal 07 Dec, 2023 First submitted to journal 05 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3725282","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":264858385,"identity":"2ad6f8b6-e6bc-4ece-8f39-c6a81a6d9f9f","order_by":0,"name":"Eric Wallace","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Wallace","suffix":""},{"id":264858386,"identity":"5ca01079-9840-4272-96e4-d2b2c1e7178e","order_by":1,"name":"Dawn Laney","email":"","orcid":"","institution":"Emory University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Dawn","middleName":"","lastName":"Laney","suffix":""},{"id":264858387,"identity":"ff72abcf-091b-45b7-8e33-b194a76724a7","order_by":2,"name":"Ibrahim Warsi","email":"","orcid":"","institution":"Sanofi","correspondingAuthor":false,"prefix":"","firstName":"Ibrahim","middleName":"","lastName":"Warsi","suffix":""},{"id":264858388,"identity":"79f2906b-677b-45d1-8699-54db8df7fc8e","order_by":3,"name":"Connie Baldwin","email":"","orcid":"","institution":"Fabry Support and Information Group","correspondingAuthor":false,"prefix":"","firstName":"Connie","middleName":"","lastName":"Baldwin","suffix":""},{"id":264858389,"identity":"7c6b1569-32f6-4c04-9393-f726d78ccba6","order_by":4,"name":"Jack Johnson","email":"","orcid":"","institution":"Fabry Support and Information Group","correspondingAuthor":false,"prefix":"","firstName":"Jack","middleName":"","lastName":"Johnson","suffix":""},{"id":264858390,"identity":"c85b5763-ea35-43c3-981e-1d00e7d61ec5","order_by":5,"name":"Joseph Kupferman","email":"","orcid":"","institution":"Sanofi","correspondingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"","lastName":"Kupferman","suffix":""},{"id":264858391,"identity":"4e9020c3-4b4e-49e5-a7ee-a31ad0820b8f","order_by":6,"name":"Pronabesh DasMahapatra","email":"","orcid":"","institution":"Sanofi","correspondingAuthor":false,"prefix":"","firstName":"Pronabesh","middleName":"","lastName":"DasMahapatra","suffix":""},{"id":264858392,"identity":"2894e774-dd67-4560-8af3-a8342f579941","order_by":7,"name":"Nicole Lyn","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYDACZiB+wMAgA2QdAPH52YjSksDAwMPAwJYA4ku2EWUTRAuPAVhLAyHV5uzMDx8kVADV3+75/OHnDhsJPgbmh49u4NFi2cxmbJBwBqjlztltkr1n0iTYGNiMjXPwaDE4zMMmkdgG1HIjdxsDb9vhOjYGHjZpwlr+gbTkPP74t+2wBJFaGsBaGKR5idMC8ssxCR7JG2lm0rJtQL8wE/LL+cMPH3yosZHju5H8+OPbNhsJ+fbmh4/xaYECCQaFAzA2M2HlECDfQKzKUTAKRsEoGHEAAFLlQekIbADJAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9707-2446","institution":"Sanofi","correspondingAuthor":true,"prefix":"","firstName":"Nicole","middleName":"","lastName":"Lyn","suffix":""}],"badges":[],"createdAt":"2023-12-08 11:31:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3725282/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3725282/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-03812-2","type":"published","date":"2025-06-16T15:57:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49240121,"identity":"7574224f-93ce-4dc8-a4e9-c5a690b1b854","added_by":"auto","created_at":"2024-01-05 18:19:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":21957,"visible":true,"origin":"","legend":"\u003cp\u003ePain crisis location by sex and phenotype in participants with FD\u003c/p\u003e\n\u003cp\u003eFD, Fabry disease; \u003cem\u003en\u003c/em\u003e, number of participants\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/ca35157e368f40a9a6d84fac.png"},{"id":49238342,"identity":"0bf1f023-5040-453d-92f3-f3bd466121bc","added_by":"auto","created_at":"2024-01-05 18:11:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":15092,"visible":true,"origin":"","legend":"\u003cp\u003eMost bothersome symptoms in participants with FD\u003c/p\u003e\n\u003cp\u003eAP, abdominal pain; FD, Fabry disease; FT, feeling tired; LEP, lower extremity pain; \u003cem\u003en\u003c/em\u003e, number of participants; Nu, numbness; UEP, upper extremity pain\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/aa8af8d36c7d7ed3bfe4f80c.png"},{"id":49238344,"identity":"5f299425-304e-4b33-aa2b-a2a1dd265589","added_by":"auto","created_at":"2024-01-05 18:11:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":51460,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative time for treatment improvement in participants with FD\u003c/p\u003e\n\u003cp\u003eNote: Cumulative percentages were calculated by adding a percentage from one period to that of another period. Time until improvement was not presented to scale. The survey question was, “After initiating treatment with agalsidase beta, approximately how long did it take for you to notice an improvement in your symptoms?” Options provided for the participants were: Immediately; Less than a week; Between 1 week and less than a month; Between 1 month and less than 2 months; 2–5 months; 6–8 months; 9–11 months; 12 months; and more than a year.\u003c/p\u003e\n\u003cp\u003eFD, Fabry disease\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/c03cc91731f9de10cb3f7093.png"},{"id":49238345,"identity":"b8d57fb3-2ca0-46ff-ba4c-81bf468a73e8","added_by":"auto","created_at":"2024-01-05 18:11:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":21442,"visible":true,"origin":"","legend":"\u003cp\u003eParticipants with FD\u003csup\u003ea\u003c/sup\u003e showing symptom improvement with agalsidase beta\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eParticipants (\u003cem\u003en \u003c/em\u003e= 37) were allowed to select multiple symptoms.\u003c/p\u003e\n\u003cp\u003eFD, Fabry disease\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/8ebe0250d3843929f620481c.png"},{"id":49238347,"identity":"41e9ee66-0c8c-4a50-8ba4-0dd17747de3a","added_by":"auto","created_at":"2024-01-05 18:11:37","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":68800,"visible":true,"origin":"","legend":"\u003cp\u003eSatisfaction with agalsidase beta in participants with FD\u003c/p\u003e\n\u003cp\u003eFD, Fabry disease; \u003cem\u003en\u003c/em\u003e, number of participants; SD, standard deviation\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/7a4b15842014f00f1d7c913c.png"},{"id":85231277,"identity":"811e46b7-c7bb-4e15-90b0-24e1a5a6e8b6","added_by":"auto","created_at":"2025-06-23 16:04:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1408191,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/5ae32d57-317d-4c9c-8dbf-a53ddbe817da.pdf"},{"id":49238348,"identity":"f616bbc2-2fe7-4df6-a805-a17385394021","added_by":"auto","created_at":"2024-01-05 18:11:37","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":627102,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure 1 Pain frequency profile across sex (A) and phenotype (B) by location in participants with FD\u003c/p\u003e\n\u003cp\u003eFD, Fabry disease; \u003cem\u003en\u003c/em\u003e, number of participants\u003c/p\u003e","description":"","filename":"SupplementaryFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/e84bdaf314acd3c60a2992b6.tif"},{"id":49240122,"identity":"63151530-f25c-4b52-8edd-51ff3c8bfcce","added_by":"auto","created_at":"2024-01-05 18:19:37","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":640376,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure 2 Nature of pain across sex (A) and phenotype (B) by location in participants with FD\u003c/p\u003e\n\u003cp\u003eFD, Fabry disease; \u003cem\u003en\u003c/em\u003e, number of participants\u003c/p\u003e","description":"","filename":"SupplementaryFigure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/9d4a4ab9bb85b667f93a6521.tif"},{"id":49238349,"identity":"9e7ffb20-9ea9-4fe9-8683-ba784d7d4997","added_by":"auto","created_at":"2024-01-05 18:11:37","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":590870,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure 3 Pain crisis type across sex (A) and phenotype (B) by location in participants with FD\u003c/p\u003e\n\u003cp\u003eFD, Fabry disease; \u003cem\u003en\u003c/em\u003e, number of participants\u003c/p\u003e","description":"","filename":"SupplementaryFigure3.tif","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/353bb1514387c86d1677b61d.tif"},{"id":49238346,"identity":"f5fb6dfc-c661-4cb3-9dae-0d7a52844b94","added_by":"auto","created_at":"2024-01-05 18:11:37","extension":"tif","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":627226,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figure 4 Pain duration profile across sex (A) and phenotype (B) by location in participants with FD\u003c/p\u003e\n\u003cp\u003eFD, Fabry disease; \u003cem\u003en\u003c/em\u003e, number of participants\u003c/p\u003e","description":"","filename":"SupplementaryFigure4.tif","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/73c5cb24caa206635060ec95.tif"},{"id":49238351,"identity":"658a1f14-dd73-49ea-ba6c-14057ebae2b1","added_by":"auto","created_at":"2024-01-05 18:11:37","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":122926,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3725282/v1/52d594a6b90523519ef92acc.docx"}],"financialInterests":"","formattedTitle":"Characterizing pain in patients with Fabry disease: Findings from a web-based cross-sectional survey in the US","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eFabry disease (FD) is a rare, progressive, X-linked genetic disorder caused by pathogenic variants of the \u003cem\u003eGLA\u003c/em\u003e gene, leading to a deficiency in the lysosomal α-galactosidase-A enzyme [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This enzyme deficiency results in progressive accumulation of toxic metabolites, such as globotriaosylceramide and globotriaosylsphingosine [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and downstream activation of inflammatory pathways [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. A combination of these mechanisms leads to severe symptoms and life-threatening complications with an increased risk of mortality [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSymptom severity and onset in FD depends upon the pathogenic \u003cem\u003eGLA\u003c/em\u003e variant and is typically classified into classic and non-classic/later-onset phenotypes (appearing in both males and females) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The classic phenotype is characterized by early-onset of symptoms and lower enzyme activity and involves multiple organs (noted in 1:22,000\u0026ndash;1:40,000 males), while precise prevalence in females is unknown [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Symptoms in the later-onset phenotype appear in adulthood and have less multi-organ involvement but can still be life-limiting [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Variants associated with this phenotype are observed in 1:1390\u0026ndash;1:9372 individuals across different populations [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the United States, the primary treatments approved for managing patients with FD are intravenous enzyme replacement therapy and chaperone therapy. Enzyme replacement therapy includes agalsidase beta [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] or pegunigalsidase alfa [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. One oral chaperone, migalastat, is available for patients with amenable variants of \u003cem\u003eGLA\u003c/em\u003e [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Further, apart from these disease-specific treatments, adjunctive/symptomatic therapies, such as angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, beta blocker, anticoagulants, pain management, and H2 blocker, are used to manage renal, cardiac, cerebrovascular, peripheral nervous system and gastrointestinal (GI) symptoms [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical presentation of FD includes early symptoms of peripheral neuropathic pain (numbness, burning, tingling, and pain) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and GI symptoms (abdominal pain, bloating, nausea, constipation, and diarrhea) [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Pain is a characteristic of FD and is one of the early symptoms that can persist throughout life [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Fabry-disease-related pain can be extremely distressing and is one of the significant determinants affecting patients\u0026rsquo; quality of life [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and disease burden [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Patients with FD experience both evoked and spontaneous pain, which can be chronic or episodic, indicating a range of pain presentation types [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These manifest as varied pain symptoms, including, but not limited to, pain crises, hypersensitivity to mechanical stimuli, and neuropathic and GI pain, with high interindividual pain heterogeneity [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Patients often require analgesics as adjunctive therapies to manage their debilitating pain [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with FD also experience pain crises, described as intense, excruciating, and unbearable pain [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The most frequently described pain crisis begins in the lower or upper extremities and often radiates proximally [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Although not traditionally considered a pain crisis, abdominal GI pain can also be acute manifesting as severe abdominal pain triggered by meals or stress [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. While pain crisis may not occur in all patients, it can be a critical diagnostic indicator of FD [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis observational, cross-sectional, web-based survey recruited patients with self-reported, physician-diagnosed FD in the United States. This study explored how patients with FD perceive their pain and pain crises, evaluated potential variations based on sex and phenotype and aimed to understand the effect of current treatment on Fabry symptoms. The survey included male or female patients (\u0026ge;\u0026thinsp;18 years) experiencing moderate-to-severe neuropathic pain in the upper extremities, lower extremities, or abdomen, able to read and understand English, and able/willing to provide electronic informed consent prior to participation. Patients who participated in another survey for an FD advocacy group in the past 2 months were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSurvey Methodology\u003c/h2\u003e \u003cp\u003eThe survey was conducted among patients affiliated with the Fabry Support \u0026amp; Information Group, an FD patient advocacy group. An e-mail including the study invitation and a brief overview was shared with the eligible patients. Interested participants responded to the e-mail, and each received a unique weblink to administer the online survey. The survey was open for participation between April 8, 2021 and August 13, 2021. The estimated length of the survey was 30 minutes.\u003c/p\u003e \u003cp\u003eThe survey received responses in four categories: participants\u0026rsquo; eligibility; demographics and disease characteristics; pain characteristics (neuropathic and abdominal pain severity, frequency, duration, and nature); and Fabry symptoms and severity assessed using the FD-PRO questionnaire. The FD-PRO is a 19-item instrument that assesses symptom severity for adults with FD [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Participants rated the severity of their symptoms in the past 24 hours on a numeric rating scale from 0 (no symptom) to 10 (symptom at its worst). Participants\u0026rsquo; satisfaction with the current treatment was also recorded on a scale from 0 (completely dissatisfied) to 10 (most satisfied). Participants could also select \u0026ldquo;don\u0026rsquo;t know/Prefer not to answer\u0026rdquo; for any questions, as this survey was voluntary. For reporting purposes, these data have not been presented herein; however, only a maximum of 10% of participants chose this response for any question. The study received an institutional review board exemption under the 45 Code of Federal Regulations Part 46 from the Research Triangle Institute Office of Research Protection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData Analysis\u003c/h2\u003e \u003cp\u003eAll data collected \u003cem\u003evia\u003c/em\u003e the survey were self-reported, and each question was analyzed individually among those participants who responded. Descriptive statistics were used to describe participants\u0026rsquo; demographics, clinical characteristics, treatment history, FD treatment experience, pain profile, symptom severity, and bothersome symptoms. No imputation of missing data, statistical hypothesis testing, or sample weighting of questionnaire responses was done. Pain-related data were reported for the last 2 weeks prior to the survey completion date. Data were analyzed for the overall group and subgroups (based on sex and phenotype). Continuous variables were presented as mean, standard deviation (\u0026plusmn;\u0026thinsp;SD), and categorical variables as frequencies and percentages. All analyses were performed using SAS statistical software (version 9.4).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eBaseline Characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 66 participants (mean age [\u0026plusmn;\u0026thinsp;SD]: 44.0 [\u0026plusmn;\u0026thinsp;12.7] years; classic FD phenotype: 65.2%; females: 59.1%) completed the survey. The mean (\u0026plusmn;\u0026thinsp;SD) time since diagnosis and time since diagnosis to the first treatment onset was 14.2 (\u0026plusmn;\u0026thinsp;11.2) years and 4.9 (\u0026plusmn;\u0026thinsp;7.4) years, respectively (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv\u003eMost participants (77.3%) reported normal-to-mildly decreased kidney function with a mean estimated glomerular filtration rate of 67.9 (\u0026plusmn;\u0026thinsp;33.0) mL/min. Participants reported their neuropathic and abdominal pain as mild (12.1% and 18.2%), moderate (39.4% and 34.8%), severe (37.9% and 30.3%), and very severe (10.6% and 9.1%). Most participants (86.4%) received FD treatment in the past 6 months or during the survey. Agalsidase beta was the most recent treatment reported by majority of the participants (77.6%) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003ePain Profile\u003c/h2\u003e\n \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n \u003ch2\u003eFrequency and nature of pain profile\u003c/h2\u003e\n \u003cp\u003eOverall, a high proportion of participants reported experiencing pain in the upper (34.8%) and lower (43.9%) extremities several times a day, whereas abdominal pain (31.8%) was mostly reported a few times a week (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eIn female and classic phenotype subgroups, pain frequency in the extremities and abdomen showed a trend similar to that of the overall study population. In contrast, more male participants reported experiencing pain in the extremities and abdomen a few times a week. The majority of later-onset participants experienced pain in the lower extremities once daily. In contrast, pain in the upper extremities and abdomen was experienced up to a few times a week. It is noteworthy that a higher proportion of female participants reported pain in the upper (46.2% vs. 18.5%) and lower (48.7% vs. 37.0%) extremities several times a day than males (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e\n \u003cp\u003eAmong all participants, the nature of pain in the upper extremities (47.0%) and abdomen (51.5%) was described as triggered, while pain in the lower extremities (57.6%) was reported as sudden (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Participants (female vs. male) reported the nature of pain as either sudden or triggered in the upper extremities (48.7% vs. 40.7%, or 48.7% vs. 44.4%), sudden in the lower extremities (61.5% vs. 51.9%), and triggered in the abdomen (48.7% vs. 55.6%).\u003c/p\u003e\n \u003cp\u003eIn the classic phenotype subgroup, pain was described as sudden in the upper and lower extremities and triggered in the abdomen (53.5% each), while in the later-onset phenotype subgroup, the majority of participants described their pain as sudden in the lower extremities (70.6%) and triggered in the upper extremities and abdomen (47.1% each) (Supplementary Fig.\u0026nbsp;2).\u003c/p\u003e\n \u003cp\u003eTable 1 Self-reported baseline characteristics and clinical profile of participants with FD\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipants\u0026nbsp;\u003cbr\u003e (\u003cem\u003eN\u003c/em\u003e = 66)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003emean (\u0026plusmn;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e44.0 (\u0026plusmn;12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eMale\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e27 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e39 (59.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFD phenotype, \u003cem\u003en\u003c/em\u003e (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eClassic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e43 (65.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eLater-onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e17 (25.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eNot sure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e6 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime since diagnosis (years)\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003emean (\u0026plusmn;SD) (\u003cem\u003en\u0026nbsp;\u003c/em\u003e= 64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e14.2 (\u0026plusmn;11.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime since diagnosis to first treatment (years)\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003emean (\u0026plusmn;SD) (\u003cem\u003en\u0026nbsp;\u003c/em\u003e= 56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e4.9 (\u0026plusmn;7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003emean (\u0026plusmn;SD) (\u003cem\u003en\u0026nbsp;\u003c/em\u003e= 26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e67.9 (\u0026plusmn;33.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCKD stage\u003csup\u003ea\u003c/sup\u003e, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eNormal to mildly decreased kidney function\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e51 (77.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eModerate to very severely decreased kidney function\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e12 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eNot sure/Prefer not to answer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e3 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eCardiovascular comorbidities\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e32 (48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eNo listed comorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e33 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.73109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePain\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;severity (PGIS)\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.57142857142857%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeuropathic pain,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003en\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbdominal pain,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003en\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.73109243697479%\" valign=\"top\"\u003e\n \u003cp\u003eVery severe\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.57142857142857%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e7 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e6 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.73109243697479%\" valign=\"top\"\u003e\n \u003cp\u003eSevere\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.57142857142857%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e25 (37.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e20 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.73109243697479%\" valign=\"top\"\u003e\n \u003cp\u003eModerate\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.57142857142857%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e26 (39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e23 (34.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.73109243697479%\" valign=\"top\"\u003e\n \u003cp\u003eMild\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.57142857142857%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e8 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e12 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.73109243697479%\" valign=\"top\"\u003e\n \u003cp\u003eNo pain\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.57142857142857%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e5 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePain medication used in the past 6 months, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e56 (84.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e10 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eFabry-specific treatment status in the last 6 months, \u003cem\u003en\u003c/em\u003e (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eUntreated (ever or in last 6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e9 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"76.30252100840336%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eTreated (currently or in last 6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\"\u003e\n \u003cp\u003e57 (86.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.73109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMost recent FD treatment, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.025210084033613%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAgalsidase beta\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.54621848739496%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMigalastat\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.73109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall (\u003cem\u003en\u003c/em\u003e = 58)\u003csup\u003ed\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.025210084033613%\" valign=\"top\"\u003e\n \u003cp\u003e45 (77.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.54621848739496%\" valign=\"top\"\u003e\n \u003cp\u003e10 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.69747899159664%\" valign=\"top\"\u003e\n \u003cp\u003e3 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003eCKD\u0026nbsp;stage\u0026nbsp;was self-reported\u0026nbsp;and\u0026nbsp;categorized\u0026nbsp;as \u0026ldquo;normal-to-mild decreased kidney function\u0026rdquo; for Stages 1\u0026ndash;2 and \u0026ldquo;moderate to very severely decreased kidney function\u0026rdquo; for Stages 3\u0026ndash;5.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003ePrior myocardial infarction, prior stroke, transient ischemic attack, unstable angina, congestive heart failure, atrial fibrillation, coronary artery disease, arrhythmia, presence of a pacemaker, presence of a defibrillator, or other heart diseases.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ec\u003c/sup\u003ePain characterization for neuropathic pain in extremities and abdominal pain was assessed through a validated questionnaire [29].\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ed\u003c/sup\u003eThe most recent FD treatment can include patients who were treated more than 6 months ago (one\u0026nbsp;patient in this case).\u003c/p\u003e\n \u003cp\u003eCKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FD, Fabry disease; \u003cem\u003eN,\u0026nbsp;\u003c/em\u003etotal number of participants; \u003cem\u003en\u003c/em\u003e, number of participants; PGIS, Patient Global Impression of Severity; SD, standard deviation\u003c/p\u003e\n \u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOverall pain profile by frequency and nature based on location\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePain profile\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;66)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePain in upper extremities, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePain in lower extremities, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAbdominal pain,\u003c/p\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003ePain frequency\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSeveral times a day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (34.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (43.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (19.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOnce daily\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA few times a week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOnce a week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOnce in the past 2 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI did not experience such pain in the past 2 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eNature of pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConstant, chronic pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSudden episodes of pain without a known trigger (e.g., pain crises)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (57.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePain triggered by something else, such as diet, exercise, or change in temperature\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (47.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (34.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (51.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther types of pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cem\u003eN\u003c/em\u003e, total number of participants; \u003cem\u003en\u003c/em\u003e, number of participants\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\n \u003ch2\u003ePain crises by location, sex, and Fabry disease phenotypes\u003c/h2\u003e\n \u003cp\u003eOf the participants who reported experiencing pain crises (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;45), majority reported crises in the lower extremities (80.0%), followed by the upper extremities (66.7%) and abdomen (51.1%).\u003c/p\u003e\n \u003cp\u003ePain crisis distribution was heterogenous based on sex. Males (relative to females) predominantly reported pain crises in the upper extremities (73.7% vs. 61.5%) and abdomen (68.4% vs. 38.5%), whereas a higher proportion of female participants (relative to males) reported experiencing pain crises in the lower extremities (84.6% vs. 73.7%).\u003c/p\u003e\n \u003cp\u003eThe anatomical location of pain crises varied based on Fabry phenotypes. Participants from the classic phenotype subgroup reported experiencing pain crises mainly in the lower extremities (82.1%) and upper extremities (75.0%) compared to the abdomen (42.9%), whereas participants from the later-onset subgroup reported a similar proportion of pain crises (69.2%) across both the extremities and abdomen. Notably, abdominal pain crises were reported by a higher proportion of later-onset phenotype participants (69.2% vs. 42.9%) than classic phenotype participants (Fig.\u0026nbsp;1).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFigure 1\u003c/strong\u003e Pain crisis location by sex and phenotype in participants with FD\u003c/p\u003e\n \u003cp\u003eFD, Fabry disease; \u003cem\u003en\u003c/em\u003e, number of participants\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003ePain crisis type and duration by location\u003c/h2\u003e\n \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\n \u003ch2\u003ePain crises in extremities\u003c/h2\u003e\n \u003cp\u003eParticipants often reported pain crises in the lower and upper extremities as burning (30.3% each), tingling (27.3% and 24.2%), and stabbing (22.7% and 18.2%). The pain crisis duration varied depending on the anatomical location; it ranged between a few seconds to more than a week. Participants reported experiencing pain crises in the upper extremities for a few seconds (3.3%) to several days (20.0%) and in the lower extremities ranging from a week (2.8%) to 30\u0026ndash;60 minutes (25.0%) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eA consistent trend for the type and duration of pain crises was noted across sex and phenotypes. Most participants of both sexes characterized their pain crises as burning or tingling in the extremities. Participants with classic phenotype often described their pain crises in the extremities as burning, while participants with later-onset phenotype described their pain crises as shooting and spreading (Supplementary Fig.\u0026nbsp;3).\u003c/p\u003e\n \u003cp\u003eMajority of the male and later-onset subgroup participants reported experiencing pain crises in the extremities for half a day to 1 day and several days, while the majority of female and classic phenotype subgroups reported their pain crises lasting 30\u0026ndash;60 minutes (Supplementary Fig.\u0026nbsp;4).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003ePain crises in the abdomen\u003c/h2\u003e\n \u003cp\u003ePain crises in the abdomen were mainly characterized as stabbing (18.2%). They usually lasted 30\u0026ndash;60 minutes (34.8%) or 60 minutes to half a day (34.8%) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Across subgroups, pain crises in the abdomen were reported to have characterization and duration similar to that of the overall participants (Supplementary Figs.\u0026nbsp;3 and 4).\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePain crisis type and duration profile by location\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePain crisis type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePain crises in upper extremities, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePain crises in lower extremities, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePain crises in the abdomen, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBurning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStabbing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTingling\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShooting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (19.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (25.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpreading\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrickling\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNone of these terms describes my pain crises\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePain crisis duration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cstrong\u003en\u003c/strong\u003e\u0026thinsp;\u003cstrong\u003e=\u0026thinsp;30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cstrong\u003en\u003c/strong\u003e\u0026thinsp;\u003cstrong\u003e=\u0026thinsp;36)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cstrong\u003en\u003c/strong\u003e\u0026thinsp;\u003cstrong\u003e=\u0026thinsp;23)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA few seconds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA few minutes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u0026ndash;60 minutes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (34.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 minutes to half a day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (19.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (34.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBetween half a day and 1 day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSeveral days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMore than a week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u003cem\u003en\u003c/em\u003e, number of participants\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eSymptom Severity and Most Bothersome Symptoms\u003c/h2\u003e\n \u003cp\u003eOverall, the mean (\u0026plusmn;\u0026thinsp;SD) Fabry Disease Patient-Reported Outcome (FD-PRO) symptom severity score was highest for the symptom of feeling tired [6.6 (\u0026plusmn;\u0026thinsp;2.3)], followed by pain in feet and legs [5.7 (\u0026plusmn;\u0026thinsp;2.7)] and feeling too hot [5.7 (\u0026plusmn;\u0026thinsp;2.8)] (Supplementary Table\u0026nbsp;1). Lower extremity pain was the most bothersome symptom across male and later-onset subgroup participants, while pain was the most bothersome symptom for female and classic phenotype subgroup participants (Fig.\u0026nbsp;2).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFigure 2\u003c/strong\u003e Most bothersome symptoms in participants with FD\u003c/p\u003e\n \u003cp\u003eAP, abdominal pain; FD, Fabry disease; FT, feeling tired; LEP, lower extremity pain; \u003cem\u003en\u003c/em\u003e, number of participants; Nu, numbness; UEP, upper extremity pain\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSymptom Improvement with Fabry-Disease-Specific Treatment\u003c/h2\u003e\n \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\n \u003ch2\u003eTreatment improvement in participants over time\u003c/h2\u003e\n \u003cp\u003eOverall, most of the participants (81.0%) with FD self-reported improvement in their symptoms after 12 months of FD-specific treatment (Fig.\u0026nbsp;3A). Cumulatively, after 5 months, 50.0% and 46.1% of participants from the male and female subgroups (Fig.\u0026nbsp;3B), respectively, and 86.7% and 35.9% of participants from the later-onset and classic phenotype subgroups (Fig.\u0026nbsp;3C), respectively, reported improvement. Of the participants who reported improvement with agalsidase beta, cumulatively, 4.4% reported improvement after 1 week of initiating treatment, 44.4% after 5 months, and 82.2% after 1 year (Fig.\u0026nbsp;3D).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFigure 3\u003c/strong\u003e Cumulative time for treatment improvement in participants with FD\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNote\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCumulative percentages were calculated by adding a percentage from one period to that of another period. Time until improvement was not presented to scale. The survey question was, \u0026ldquo;After initiating treatment with agalsidase beta, approximately how long did it take for you to notice an improvement in your symptoms?\u0026rdquo; Options provided for the participants were: Immediately; Less than a week; Between 1 week and less than a month; Between 1 month and less than 2 months; 2\u0026ndash;5 months; 6\u0026ndash;8 months; 9\u0026ndash;11 months; 12 months; and more than a year.\u003c/p\u003e\n \u003cp\u003eFD, Fabry disease\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eSymptoms improved with agalsidase beta as the most recent treatment\u003c/h2\u003e\n \u003cp\u003eAfter receiving agalsidase beta, most participants reported improvement in their neuropathic symptoms, including burning in hands (45.9%); pain in hands, burning in feet, and sweating (40.5% each); and tingling in hands and pain in the abdomen (37.8% each) (Fig.\u0026nbsp;4).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFigure 4\u003c/strong\u003e Participants with FD\u003csup\u003ea\u003c/sup\u003e showing symptom improvement with agalsidase beta\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003eParticipants (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;37) were allowed to select multiple symptoms.\u003c/p\u003e\n \u003cp\u003eFD, Fabry disease\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eSatisfaction with agalsidase beta\u003c/h2\u003e\n \u003cp\u003eThe mean (\u0026plusmn;\u0026thinsp;SD) satisfaction score was 7.2 (\u0026plusmn;\u0026thinsp;1.7) in participants who received agalsidase beta as the most recent treatment. Male [7.6 (\u0026plusmn;\u0026thinsp;1.5)] and later-onset [8.0 (\u0026plusmn;\u0026thinsp;0.9)] participants reported higher satisfaction than the overall population (Fig.\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFigure 5\u003c/strong\u003e Satisfaction with agalsidase beta in participants with FD\u003c/p\u003e\n \u003cp\u003eFD, Fabry disease; \u003cem\u003en\u003c/em\u003e, number of participants; SD, standard deviation\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003ePain, whether neuropathic or functional, is one of the early symptoms of FD, and its occurrence may signal underlying organ deterioration [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Fabry-disease-related pain has been studied in the past in a variety of settings, including by using registries or screening of medical records [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, the present study analyzed pain and pain crises from a patient\u0026rsquo;s perspective with moderate-to-severe pain across different FD phenotypes and for both sexes. The study demonstrated a heavy burden of neuropathic pain, abdominal pain, and pain crises experienced across sex and phenotype subgroups.\u003c/p\u003e \u003cp\u003eNeuropathic pain is a hallmark of FD [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]; participants in this study reported frequent pain, especially in the distal extremities. Most participants characterized their pain as either \u0026ldquo;triggered\u0026rdquo; or \u0026ldquo;sudden,\u0026rdquo; which is similar to prior studies that had demonstrated a predominance of evoked neuropathic pain caused by stimuli that may not trigger pain in healthy individuals, indicating a high burden of pain associated with FD [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdditionally, the present study demonstrated the pain crisis experience (nature, frequency, and duration) to be highly varied with regard to sex, phenotype, and anatomical location. The study indicated a heterogenous distribution of the duration of pain crisis, ranging from a few hours to a full day. Half of the participants experienced neuropathic crisis, predominantly in the lower extremities, and described it as burning in nature, while abdominal pain crisis was often described as stabbing, which also correlates with a previous study reporting severe debilitating abdominal pain in patients with FD [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This novel characterization of crises in both sexes and for different phenotypes from a patient\u0026rsquo;s perspective furthers the understanding of the diverse experience of pain crises.\u003c/p\u003e \u003cp\u003ePrior data have often reported patients with later-onset FD phenotype to have less pronounced pain and sensory abnormalities when compared with the classic phenotype [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The present study, however, identified that among both phenotypes, the participants experienced neuropathic and abdominal pain; the participants from the later-onset phenotype even reported sudden pain in lower extremities in a higher proportion than the classic phenotype. Furthermore, contrary to published evidence that presents females experiencing mild and intermittent pain, the present study highlighted that females experienced severe pain in the upper and lower extremities as much as several times a day [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Thus, despite the previous and incorrect view of females with FD presenting with minimal symptoms [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], the present study showed that female participants had a high pain burden and experienced pain symptoms similar to that of male patients. Thus, greater attention is warranted to address disease management for patients with later-onset FD and female patients with FD.\u003c/p\u003e \u003cp\u003ePain in FD is associated with various mechanisms and requires different therapeutic approaches through disease-specific treatment, supportive symptom management, and strategies to avoid pain triggers [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In the present study, most participants reported receiving pain medication (over the counter or prescription) in addition to Fabry-specific treatments for appropriate management of the multisystemic aspects of FD. Treatment guidelines recommend medications, such as carbamazepine, gabapentin, pregabalin, phenytoin, amitriptyline, duloxetine, and venlafaxine, and acute pain management with opioids (morphine, tramadol, and tilidate) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] for managing Fabry pain.\u003c/p\u003e \u003cp\u003eFurther, looking at patient satisfaction with current treatment, participants in this study mostly reported agalsidase beta as their most recent Fabry-specific treatment and were consistently satisfied with overall symptom improvement as expressed by 82.2% of participants by 1 year after initiation of agalsidase beta. Previous studies also corroborated these findings, where agalsidase beta was beneficial in reducing pain and delaying the onset of renal, cardiovascular, and cerebrovascular events in patients with advanced FD [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are certain inherent limitations of cross-sectional studies that we acknowledge, such as potential participant bias. Further, since all data in this study were self-reported, participants may have misspecified their FD phenotype. This study focused only on the descriptive analysis; hence, the subgroup results do not imply any associations. The study enrolled patients who experienced moderate-to-severe neuropathic or abdominal pain, depicting a symptomatic population; therefore, the results are not generalizable to the overall Fabry population. The study could not characterize the impact of other treatments because of a small sample size. Nonetheless, this study provided a detailed analysis of pain and pain crises from a patient\u0026rsquo;s perspective, which may aid in better understanding and overall management of pain across Fabry patients.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThe present study showcases heterogenous pain presentation and, contrary to expectations, suggests that patients with later-onset FD, including females, experience pain and pain crises. Notably, female participants reported a pain burden similar to that of the male participants, adding to the increasing evidence that females with FD have high pain intensity. Further, the pain crisis experience of patients was heterogeneous among sex, phenotype, and anatomical location. Most participants on agalsidase beta reported symptom improvement and treatment satisfaction. Taken together, the present study highlights the importance of pain, a symptomatic manifestation of FD, which should be considered a critical indicator of FD across sex and phenotypes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAP, Abdominal pain; CKD, Chronic kidney disease; eGFR, Estimated glomerular filtration rate; FD, Fabry disease; FD-PRO, Fabry Disease Patient-Reported Outcome; FT, Feeling tired; GI, Gastrointestinal; GLA, Galactosidase alpha; LEP, Lower extremity pain; \u003cem\u003eN,\u0026nbsp;\u003c/em\u003eTotal number of participants; \u003cem\u003en\u003c/em\u003e, Number of participants; Nu, Numbness; PGIS, Patient Global Impression of Severity; SD, Standard deviation; UEP, Upper extremity pain\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eAll participants of the study provided electronic consent prior to starting the survey. This study was submitted for institutional review board approval and deemed exempt from review.\u0026nbsp;\u003c/p\u003e\n\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e\n\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003eEW\u003c/strong\u003e had disclosures with Sanofi, Idorsia, Amicus, Chiesi, Protalix, Walking Fish Therapeutics, Spark Therapeutics, Natera, and DaVita.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDL\u003c/strong\u003e is chair of the North American Fabry Registry Board and provides consultations for Chiesi, Sanofi, and Spark Therapeutics. She is also an investigator/coordinator in clinical trials sponsored by 4DMT, Amicus, Chiesi, Protalix, Sangamo, Sanofi, and Takeda-Shire.\u0026nbsp;She is also a cofounder of ThinkGenetic, Inc.\u0026nbsp;These activities were monitored and found to be compliant with the conflict-of-interest policies at the Emory University School of Medicine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIW\u003c/strong\u003e was on an assignment at Sanofi through Integrated Resources at the time of study completion; currently, he is an employee of Evidentia Dental Research, Canada.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCB\u003c/strong\u003e and \u003cstrong\u003eJJ\u003c/strong\u003e are the Fabry Support \u0026amp; Information Group employees\u0026nbsp;and provide participant outreach and recruitment support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;NL\u0026nbsp;\u003c/strong\u003eare\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eemployees of Sanofi and stockholders in the company.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJK\u0026nbsp;\u003c/strong\u003ewas an employee of Sanofi at the time this study was conducted; currently, he is an employee of Moderna.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study was funded by Sanofi.\u003c/p\u003e\n\n\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e\n\u003cp\u003eIW, JK, PD, and NL were involved in conceptualization of the study and design. CB, JJ, and NL were involved in acquisition of data. NL, EW, DL, IW, CB, JJ, JK, PD, and NL were involved in analysis and interpretation of data. All authors contributed to drafting of the manuscript and critical revision of the paper for important intellectual content.\u003c/p\u003e\n\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe authors thank all the participants of the survey. The survey programming was conducted by Val\u0026eacute;rie Derrien Ansquer, Kate Nelson, and Christina Darden of RTI Health Solutions. The analysis was conducted by Guilio Flore, Laurie Batchelder, and Bob Krupnick of IQVIA. Medical writing support for this manuscript was provided by Mrigna Malhotra and Amit Kandhare of Sanofi.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAmodio F, Caiazza M, Monda E, Rubino M, Capodicasa L, Chiosi F, et al. An overview of molecular mechanisms in Fabry disease. Biomolecules. 2022;12(10):1460.\u003c/li\u003e\n\u003cli\u003eEl-Abassi R, Singhal D, England JD. Fabry\u0026apos;s disease. J Neurol Sci. 2014;344(1-2):5\u0026ndash;19.\u003c/li\u003e\n\u003cli\u003eNajafian B, T\u0026oslash;ndel C, Svarstad E, Gubler MC, Oliveira JP, Mauer M. Accumulation of globotriaosylceramide in podocytes in Fabry nephropathy is associated with progressive podocyte loss. J Am Soc Nephrol. 2020;31(4):865\u0026ndash;75.\u003c/li\u003e\n\u003cli\u003eRozenfeld P, Feriozzi S. Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol Genet Metab. 2017;122(3):19\u0026ndash;27.\u003c/li\u003e\n\u003cli\u003eBiancini GB, Vanzin CS, Rodrigues DB, Deon M, Ribas GS, Barschak AG, et al. Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy. Biochim Biophys Acta. 2012;1822(2):226\u0026ndash;32.\u003c/li\u003e\n\u003cli\u003eOrtiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet metab. 2018;123(4):416-27.\u003c/li\u003e\n\u003cli\u003eMacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001;38(11):769\u0026ndash;75.\u003c/li\u003e\n\u003cli\u003eMacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38(11):750\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003eArends M, Wanner C, Hughes D, Mehta A, Oder D, Watkinson OT, et al. Characterization of classical and nonclassical Fabry disease: A multicenter study. J Am Soc Nephrol. 2017;28(5):1631-41.\u003c/li\u003e\n\u003cli\u003eGermain DP. Fabry disease. Orphanet J Rare Dis. 2010;5(1):1\u0026ndash;49.\u003c/li\u003e\n\u003cli\u003eAzevedo O, Gago MF, Miltenberger-Miltenyi G, Robles AR, Costa MA, Pereira O, et al. Natural history of the late-onset phenotype of Fabry disease due to the p.F113L mutation. Mol Genet Metab Rep. 2020;22:100565.\u003c/li\u003e\n\u003cli\u003eBokhari SRA, Zulfiqar H, Hariz A. Fabry Disease Treasure Island (FL): StatPearls Publishing; 2023 [Updated 2022 Dec 24:[Available from: https://www.ncbi.nlm.nih.gov/books/NBK435996/.\u003c/li\u003e\n\u003cli\u003eHwu WL, Chien YH, Lee NC, Chiang SC, Dobrovolny R, Huang AC, et al. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G\u0026gt;A (IVS4+919G\u0026gt;A). Hum Mutat. 2009;30(10):1397\u0026ndash;405.\u003c/li\u003e\n\u003cli\u003eWasserstein MP, Caggana M, Bailey SM, Desnick RJ, Edelmann L, Estrella L, et al. The New York pilot newborn screening program for lysosomal storage diseases: report of the first 65,000 infants. Genet Med. 2019;21(3):631\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003ePrescribing information-Agalsidase beta [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103979s5309lbl.pdf.\u003c/li\u003e\n\u003cli\u003ePrescribing information- Pegunigalsidase alfa [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761161s000lbl.pdf.\u003c/li\u003e\n\u003cli\u003ePrescribing information-Migalastat [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208623lbl.pdf.\u003c/li\u003e\n\u003cli\u003eBurlina AP, Sims KB, Politei JM, Bennett GJ, Baron R, Sommer C, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol. 2011;11:61.\u003c/li\u003e\n\u003cli\u003eBurand AJ, Jr., Stucky CL. Fabry disease pain: patient and preclinical parallels. Pain. 2021;162(5):1305\u0026ndash;21.\u003c/li\u003e\n\u003cli\u003eZar-Kessler C, Karaa A, Sims KB, Clarke V, Kuo B. Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis. Therap Adv Gastroenterol. 2016;9(4):626\u0026ndash;34.\u003c/li\u003e\n\u003cli\u003eLaney DA, Peck DS, Atherton AM, Manwaring LP, Christensen KM, Shankar SP, et al. Fabry disease in infancy and early childhood: a systematic literature review. Genetics in medicine : official journal of the American College of Medical Genetics. 2015;17(5):323-30.\u003c/li\u003e\n\u003cli\u003e\u0026Uuml;\u0026ccedil;eyler N, Ganendiran S, Kramer D, Sommer C. Characterization of pain in Fabry disease. Clin J Pain. 2014;30(10):915\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eBashorum L, McCaughey G, Evans O, Humphries AC, Perry R, MacCulloch A. Burden associated with Fabry disease and its treatment in 12\u0026ndash;15 year olds: results from a European survey. Orphanet J Rare Dis. 2022;17(1):266.\u003c/li\u003e\n\u003cli\u003eRickert V, Kramer D, Schubert A-L, Sommer C, Wischmeyer E, \u0026Uuml;\u0026ccedil;eyler N. Globotriaosylceramide-induced reduction of KCa1. 1 channel activity and activation of the Notch1 signaling pathway in skin fibroblasts of male Fabry patients with pain. Exp Neurology. 2020;324:113\u0026ndash;34.\u003c/li\u003e\n\u003cli\u003eWatt T, Burlina AP, Cazzorla C, Sch\u0026ouml;nfeld D, Banikazemi M, Hopkin RJ, et al. Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: findings from the Fabry Registry. Genetics in Medicine. 2010;12(11):703-12.\u003c/li\u003e\n\u003cli\u003ePolitei JM, Bouhassira D, Germain DP, Goizet C, Guerrero-Sola A, Hilz MJ, et al. Pain in Fabry disease: Practical recommendations for diagnosis and treatment. CNS Neurosci Ther. 2016;22(7):568\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003eDesnick RJ, Brady RO. Fabry disease in childhood. The J Pediatr. 2004;144(5):S20\u0026ndash;S6.\u003c/li\u003e\n\u003cli\u003eHamed A, DasMahapatra P, Lyn N, Gwaltney C, Hopkin RJ. Development of the Fabry Disease Patient-Reported Outcome (FD-PRO): a new instrument to measure the symptoms and impacts of Fabry disease. Orphanet J Rare Dis. 2021;16(1):285.\u003c/li\u003e\n\u003cli\u003eHamed A, DasMahapatra P, Lyn N, Gwaltney C, Iaconangelo C, Serrano D, et al. Fabry Disease Patient-Reported Outcome (FD-PRO) demonstrates robust measurement properties for assessing symptom severity in Fabry disease. Mol Genet Metab Rep. 2021;29:100824.\u003c/li\u003e\n\u003cli\u003eGibas AL, Klatt R, Johnson J, Clarke JTR, Katz J. A survey of the pain experienced by males and females with Fabry disease. Pain Res Manag. 2006;11:828\u0026ndash;964.\u003c/li\u003e\n\u003cli\u003eBiegstraaten M, Hollak CE, Bakkers M, Faber CG, Aerts JM, van Schaik IN. Small fiber neuropathy in Fabry disease. Mol Genet Metab. 2012;106(2):135\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eChowdhury MM, Holt PJ. Pain in Anderson-Fabry\u0026apos;s disease. The Lancet. 2001;357(9259):887.\u003c/li\u003e\n\u003cli\u003eRo LS, Chen ST, Tang LM, Hsu WC, Chang HS, Huang CC. Current perception threshold testing in Fabry\u0026apos;s disease. Muscle \u0026amp; Nerve: Official Journal of the American Association of Electrodiagnostic Medicine. 1999;22(11):1531-7.\u003c/li\u003e\n\u003cli\u003eWang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007;9(1):34\u0026ndash;45.\u003c/li\u003e\n\u003cli\u003eGermain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet. 2015;52(5):353.\u003c/li\u003e\n\u003cli\u003eBanikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007;146(2):77\u0026ndash;86.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Abdominal pain, Fabry disease, Neuropathic pain, Pain, Pain crises, Patient-reported","lastPublishedDoi":"10.21203/rs.3.rs-3725282/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3725282/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Fabry disease (FD) is a rare, progressive disorder caused by pathogenic variants of the \u003cem\u003eGLA\u003c/em\u003e gene resulting in the accumulation of toxic metabolites. Pain is a hallmark of FD, and patients often present with heterogeneous pain profiles. This cross-sectional, web-based survey was conducted to characterize pain and pain crises in patients with FD in the United States and explore the effects of sex, disease phenotypes, and treatment on pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 66 participants (mean [±SD] age: 44.0 [±12.7] years; females: 59.1%) completed the survey. Participants reported experiencing pain in upper (34.8%) and lower (43.9%) extremities several times a day and abdominal pain (31.8%) a few times a week. Overall, participants reported the nature of their pain as triggered (upper extremities: 47.0%; abdomen: 51.5%) or sudden (lower extremities: 57.6%). Female participants reported experiencing pain in upper (46.2%) and lower (48.7%) extremities several times a day and described it as sudden or triggered (48.7%) in upper extremities and sudden (61.5%) in lower extremities. Pain crises were reported in the lower extremities (80.0%), followed by the upper extremities (66.7%) and the abdomen (51.1%), and were often characterized as burning, tingling, or stabbing. A higher proportion of female participants (84.6%) than that of male participants (73.7%) reported pain crises in lower extremities. The duration of pain crises varied from 30 minutes to several days for different subgroups depending on sex and FD phenotypes. Most participants (81.0%) reported symptom improvement after 12 months of FD-specific treatment. With agalsidase beta as the most recent medication, participants reported improvement in neuropathic symptoms (burning in hands, 45.9%), with an overall mean (±SD) satisfaction score of 7.2 (±1.7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Pain was largely reported to be triggered across all subgroups. Consistent pain profiles were noted in participants across sex and FD phenotypes. Female participants reported pain burden similar to that of male participants, and pain crisis experience was heterogeneous across the subgroups. Most participants reported improvement in symptoms after FD-specific treatment and a high treatment satisfaction score with agalsidase beta.\u003c/p\u003e","manuscriptTitle":"Characterizing pain in patients with Fabry disease: Findings from a web-based cross-sectional survey in the US","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-05 18:11:32","doi":"10.21203/rs.3.rs-3725282/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-01-04T09:13:41+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-02T14:33:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-07T08:19:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2023-12-05T05:33:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8f99b8e5-9c68-44af-8ad7-1abe3ba1f5fa","owner":[],"postedDate":"January 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-23T15:58:52+00:00","versionOfRecord":{"articleIdentity":"rs-3725282","link":"https://doi.org/10.1186/s13023-025-03812-2","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-06-16 15:57:05","publishedOnDateReadable":"June 16th, 2025"},"versionCreatedAt":"2024-01-05 18:11:32","video":"","vorDoi":"10.1186/s13023-025-03812-2","vorDoiUrl":"https://doi.org/10.1186/s13023-025-03812-2","workflowStages":[]},"version":"v1","identity":"rs-3725282","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3725282","identity":"rs-3725282","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}