Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 https://doi.org/10.1186/s13023-022-02181-4 RESEARCH Open Access Do clinical guidelines facilitate or impede drivers of treatment in Fabry disease? Derralynn A. Hughes1,2* , Patrício Aguiar3,4, Olivier Lidove5, Kathleen Nicholls6,7, Albina Nowak8,9, Mark Thomas10, Roser Torra11, Bojan Vujkovac12, Michael L. West13 and Sandro Feriozzi14 Abstract Background: Variable disease progression confounds accurate prognosis in Fabry disease. Evidence supports the long-term benefit of early intervention with disease-specific therapy, but current guidelines recommend treatment initiation based on signs that may present too late to avoid irreversible organ damage. Findings from the ‘PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease’ (PREDICT-FD) initiative included expert consensus on 27 early indicators of disease progression in Fabry disease and on drivers of and barriers to treatment initiation in Fabry disease. Here, we compared the PREDICT-FD indicators with guidance from the European Fabry Working Group and various national guidelines to identify differences in signs supporting treatment initiation and how guidelines them- selves might affect initiation. Finally, anonymized patient histories were reviewed by PREDICT-FD experts to determine whether PREDICT-FD indicators supported earlier treatment than existing guidance. Results: Current guidelines generally aligned with PREDICT-FD on indicators of renal involvement, but most lacked specificity regarding cardiac indicators. The prognostic significance of neurological indicators such as white matter lesions (excluded by PREDICT-FD) was questioned in some guidelines and excluded from most. Some PREDICT-FD patient-reported signs (e.g., febrile crises) did not feature elsewhere. Key drivers of treatment initiation in PREDICT- FD were: (A) male sex, young age, and clinical findings (e.g., severe pain, organ involvement), (B) improving clinical outcomes and preventing disease progression, and (C) a family history of Fabry disease (especially if outcomes were severe). All guidelines aligned with (A) and several advocated therapy for asymptomatic male patients. There was scant evidence of (B) in current guidance: for example, no countries mandated ancillary symptomatic therapy, and no guidance advocated familial screening with (C) when diagnosis was confirmed. Barriers were misdiagnosis and a lack of biomarkers to inform timing of treatment. Review of patient histories generally found equal or greater support for treatment initiation with PREDICT-FD indicators than with other guidelines and revealed that the same case and guideline criteria often yielded different treatment recommendations. Conclusions: Wider adoption of PREDICT-FD indicators at a national level could promote earlier treatment in Fabry disease. Clearer, more concise guidance is needed to harmonize treatment initiation in Fabry disease internationally. Keywords: Fabry disease, Guideline, Consensus, Renal, Cardiac, Neurological, Patient-reported outcome, Treatment initiation, Enzyme replacement therapy, Chaperone therapy Background Fabry disease (FD) is an X-linked, inherited disorder that *Correspondence: rmgvdah@ucl.ac.uk is estimated to affect up to 1 in 40,000 individuals [1]. 1 Lysosomal Storage Disorders Unit, Institute of Immunity Mutations in the GLA gene encoding α-galactosidase A and Transplantation, Royal Free Hospital, Royal Free London NHS Foundation Trust, Rowland Hill Street, London NW3 2PF, UK (α-Gal A) can cause lysosomal α-Gal A deficiency and Full list of author information is available at the end of the article accumulation of globotriaosylceramide (Gb3) and © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 2 of 15 globotriaosylsphingosine (LysoGb3) [2]. Nearly 1000 16 years or older in Australia, 12 years or older in Europe, GLA variants have been identified, and the effects of and in adults in North America [17–19]. Investigational several on α-Gal A enzyme activity characterized, but treatments in FD include pegunigalsidase alfa, a less the significance of many remains unknown [2]. There is immunogenic version of agalsidase alfa with an extended considerable variation among individuals with FD in both elimination half-life. Substrate reduction therapies, using symptomatic presentation and rate of disease progression glucosylceramide synthase inhibitors that prevent Gb3 [1]. Features characteristic of hemizygous male patients accumulation, are in late-stage clinical development, and in the early stages of classical disease include neuropathic both ex vivo and in vivo gene therapies are under inves- pain, abnormal hidrosis, gastrointestinal dysfunction, tigation: ex vivo approaches are in early clinical devel- angiokeratoma, cornea verticillata, and microalbuminu- opment and in vivo gene therapy methods have yielded ria; subsequently, progressive renal, cardiac, and neuro- encouraging results in animal models [20]. logical complications can occur. Presentation in classical As well as examining the clinical case for appropri- heterozygous female patients is more variable and gener- ate FD-specific treatment initiation [11], PREDICT-FD ally less severe than in male patients, and pathology in required participants to suggest and to vote on factors non-classical forms of FD in both sexes may be confined that may drive or impede treatment initiation. Here, we to one organ system [1, 3–5]. Judging prognosis and, thus, report the consensus reached on these drivers of and when to initiate FD-specific treatment is a clinical chal- barriers to treatment initiation and examine whether lenge complicated by evidence that the best outcomes current treatment guidelines might contribute to delays are associated with early treatment initiation. Long-term in starting treatment. Accordingly, we compared the studies of patients with FD who initiated disease-specific PREDICT-FD consensus with FD guidelines from dif- therapy at an early stage have shown that it has a stabi- ferent countries and with guidance issued by the Euro- lizing effect on renal and cardiac parameters [6, 7]. Stud- pean Fabry Working Group (EFWG) in 2015 [1]. The ies in vitro have implicated LysoGb3 in the formation of timelines of when these guidelines were issued and when fibrosis and, in particular, the presence of renal or cardiac disease-specific therapies were approved internationally fibrosis on biopsy seems to mark a pivotal stage in FD are shown in Fig. 1; unpublished guidelines are summa- after which disease-specific therapy becomes less effec- rized in Additional file 1: Table S1. Finally, as a prelimi- tive [8]. One study found that plasma LysoGb3 levels nary examination of whether guideline variations may 1 year after disease-specific therapy initiation were lower delay FD-specific treatment initiation, we consider some in men with classical FD who started treatment before examples of treatment recommendations by a subset of age 25 years than in those treated later in life [9]; another panel members applying different guidelines to the same found elevated baseline levels of LysoGb3 were associ- anonymized medical histories of patients with FD. ated with subsequent increased risk of adverse outcomes in patients with FD [10]. However, it remains unclear Results whether treatment-related reductions in LysoGb3 levels PREDICT‑FD consensus signs and symptoms and guidance are associated with improved long-term outcomes. for treatment initiation The PRoposing Early Disease Indicators for Clini- The PREDICT-FD initiative achieved consensus on 27 cal Tracking in Fabry Disease (PREDICT-FD) initiative early signs and symptoms of FD that might influence the established expert consensus on indicators of FD pro- initiation of FD-specific treatment at an earlier stage than gression that clinicians can use to inform treatment-ini- is generally practiced [11]. Tables 1, 2, 3, and 4 summa- tiation decisions [11]. A key motivation was to investigate rize signs and symptoms identified in PREDICT-FD and whether collective clinical experience supports initiation those stipulated in different treatment guidelines. Treat- of FD-specific treatment based on signs and symptoms ment eligibility by organ involvement across the various that may present at an earlier stage of disease than do guidelines is summarized in Additional file 1: Table S2. those underpinning existing guidance [11]. There are two approved FD-specific treatment modalities: intravenous Renal involvement therapy. The ERT agalsidase alfa (Replagal®) is licensed enzyme replacement therapy (ERT) and oral chaperone Indicators of renal damage identified in PREDICT-FD (Table 1) were largely represented in treatment guide- 6.5–7 years, and the ERT agalsidase beta (Fabrazyme®) in Australia and Europe [12, 13] for use in FD from age lines. Elevated urinary albumin–creatinine ratio and early stages of chronic kidney disease were param- is licensed in Australia, Europe and North America from eters widely used to inform treatment decisions, even if (Galafold®) is only suitable for patients with an amenable age 8 years [14–16]. Chaperone therapy with migalastat thresholds for urine protein level and for glomerular fil- tration rate differed. Histological damage was not part α-Gal A mutation and is licensed for use in patients aged of consensus guidance from the EFWG and, in most Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 3 of 15 Agalsidase alfa approved Migalastat approval 2001 2004 2007 2009 2016 2017 2018 2019 European Fabry Working Group PREDICT-FD France March Lazio (Italy) Slovenia Portugal October November 2010 2015 October 2016 November 2018 June 2019 2020 2001 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Switzerland Catalonia (Spain) Australia Canada UK 2010 November 2016 September 2018 October 2019 January 2020 2003 2006 2018 2001 2004 Agalsidase beta approved Agalsidase beta approved Fig. 1 Timeline of publication of latest guidelines for FD and of disease-specific therapy approvals. As of December 31, 2017, agalsidase alfa was approved in 58 countries, excluding the USA. FD, Fabry disease countries, biopsy to detect histological damage was noted from the PREDICT-FD consensus, featured as possi- only as a confirmatory option [1]. Being a sign associated ble justification for disease-specific therapy initiation in with later-stage disease, proteinuria did not feature in Canadian, French, Portuguese, and the EFWG guidance the PREDICT-FD consensus but was nominated by most [1, 21–23]. Only Canadian guidance noted the potential guidelines. significance of acute optic neuropathy [21]. Neuropathic pain is widely recognized as an important early sign in Cardiac involvement FD, although not necessarily as justification for disease- Biomarkers indicative of cardiac damage identified in specific therapy initiation. Painful gastrointestinal neu- PREDICT-FD (Table 2) only featured in the guidelines ropathy symptoms were noted only in PREDICT-FD [21], from Canada [21]. Coverage of cardiac signs identifiable although gastrointestinal symptoms (pain, diarrhea) were with cardiac magnetic resonance imaging (cMRI) varied represented in guidance from Canada, Portugal, Slovenia, considerably by country and was absent from the EFWG and Switzerland. guidance [1]. Diastolic dysfunction, identified as an early sign of cardiac damage in PREDICT-FD [11], featured in Patient‑reported and other signs guidance from Canada, Catalonia (Spain), Slovenia, and Angiokeratoma featured only in guidelines as a support- Switzerland; only Canadian guidance noted short PR ive diagnostic sign, and only the Canadian and Slovenian interval on electrocardiogram as an early sign [21]. Guid- guidance noted that biopsies other than renal or cardiac ance with respect to cardiac indicators was often generic; might be helpful aids to diagnosis or to ratify treatment only Canadian guidelines provided very specific cardiac initiation (Table 4) [21]. Only guidance from Portugal damage criteria [21]. included abnormal hidrosis and exercise intolerance as supportive signs for treatment, and no other patient- Neurological involvement reported signs (febrile crises, progression of signs/symp- White matter lesions featured in the EFWG guidance toms) featured in any guidelines. [1] and in Portuguese guidelines [22] in female and late- onset male patients; Canadian guidelines noted that the Diagnosis of FD and treatment initiation significance of such imaging abnormalities in FD was The focus of PREDICT-FD was on indicators for FD- unclear (Table 3) [21]. Sudden hearing loss, excluded specific treatment initiation in patients who had already Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 4 of 15 Table 1 Renal signs: guideline stipulations and PREDICT-FD consensus [11] Histological Podocyte Proteinuria Elevated urine Abnormal Decline in Renal dialysis or damage inclusions ACR (including ­GFRa iohexol GFR transplant (kidney microalbuminuria) biopsy) PREDICT-FDb + + – + + + – [11] EFWGc [1] No consensus No consensus M, I; F, IIB M, I; F, IIB CKD stage 2: – Dialysis, do not cM, I; ncM, IIA; withhold treat- cF, IIA; ncF, IIB ment CKD stage 3: Transplant, NA cM, I; ncM, IIB; cF, IIB; ncF, IIB Australia [24] Alld – M, > 150 mg/d Me,f > ULN – – – F, > 300 mg/d Canadag [21] M, ­Fh Renal pathol- All, ≥ 500 mg/di – All, CKD Decline in All (considered ogy: All, ≥ 300 mg/di stage ≥ ­2j mGFR CKD stage 5) M, major criterion F, minor crite- rion Catalonia – – All, > 300 mg/d All All, CKD – All (Spain) stage ≥ ­2k Francel [23, 25] F – F, > 1 g/d – F, moderate-to- – All severe Portugal [22] Confirma- Confirma- All All All, CKD – – tory biopsy tory biopsy stage ≥ 2 if needed, all if needed, all asymptomatic asymptomatic Slovenia Confirma- – All All All CKD – – (FCGHSG) tory biopsy if needed in cF and in late- onset ­adultsm Switzerlandn Fo Fn F, > 300 mg/dp – – – Alln q r UK [26] – – All, > 300 mg/d – All, CKD stage 2 – – and ­3s Unpublished guidelines are summarized in Additional file 1: Table S1 a ­ 2; stage 3, 45–60 mL/min/1.73 m CKD: stage 2, 60–90 mL/min/1.73 m ­ 2 b Consensus was reached that FD-specific treatment should be initiated at diagnosis in male patients aged 16 years or older who are asymptomatic for organ involvement, in boys younger than 16 years old with early indicators of organ involvement, and in all patients with guideline indicators of organ involvement c Recommendations are based on class of evidence assigned: class I, treatment recommended or indicated; class IIA, treatment should be considered; class IIB, treatment may be considered; class III, treatment not recommended d Including disease due to long-term renal accumulation of glycosphingolipids e In two samples separated by at least 1 day f In male patients, guideline abnormal albumin threshold of > 20 µg/minute is approximately equivalent to the threshold for microalbuminuria (> 30 mg/d) g Treatment initiated based on one major or two minor criteria. Minor criteria not shown are renal tubular dysfunction and hypertension for at least 1 year h If biopsy is indicated, glomerular sclerosis, tubulointerstitial atrophy, fibrosis, or vascular sclerosis constitute a major criterion in male patients and a minor criterion in female patients; biopsy not required for treatment initiation i Major criterion: persistently ≥ 500 mg/d/1.73m2; minor criterion: ≥ 300 mg/d/1.73m2 in isolation or > normal and persisting for at least 1 year j Major criterion: CKD stage 2 based on three consistent eGFRs over at least 4 months or stages 3–5 based on two consistent eGFRs over at least 2 months using CKD- EPI formula [27] in adults and the Counahan–Barrett formula [28] in children; also ≥ 15% decrease in GFR or slope greater than the age-related normal among those with hyperfiltration (GFR ≥ 135 mL/min/1.73 ­m2) determined by nuclear medicine techniques. Minor criterion: hyperfiltration in two measurements at least 1 month apart k Reduced rate in at least three determinations by CKD-EPI equation [27] l All male patients with a confirmed FD diagnosis should be offered ERT from age 18 years; ERT may be considered in children (6–18 years) with organic renal involvement m Also if necessary in asymptomatic boys with a classical mutation n ERT is practically always indicated in men, even those with mild symptoms and low organ involvement, and in patients undergoing hemodialysis or with a kidney transplant Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 5 of 15 Table 1 (continued) o Relevant, histologically proven Gb3 deposits in kidney or heart biopsies p Regardless of CKD stage q FD-specific therapy should be considered in male patients with classical mutations at diagnosis; tabulated additional considerations apply to male and female patients with later-onset disease r Persistent proteinuria > 300 mg/d in male patients; use anti-proteinuria medication for at least 12 months if proteinuria is the only presentation in female patients s CKD stage 2 based on three or more consistent GFR estimates over at least 12 months and GFR slope greater than the age-related normal; CKD stage 3 based on two or more consistent GFR estimates over at least 6 months + , achieved consensus in PREDICT-FD; ACR, albumin–creatinine ratio; cF, female patient(s) with classical disease; cM, male patient(s) with classical disease; CKD, chronic kidney disease; CKD-EPI, CKD-Epidemiology Collaboration; d, day; EFWG, European Fabry Working Group; eGFR, estimated GFR; F, female patient(s); FCGHSG, Fabry Center, General Hospital Slovenj Gradec; FD, Fabry disease; Gb3, globotriaosylceramide; GFR, glomerular filtration rate; M, male patient(s); mGFR, measured GFR; ncF, female patient(s) with non-classical disease; ncM, male patient(s) with non-classical disease; NA, not available; ULN, upper limit of normal received a diagnosis of FD; however, the need for diag- (male patients with classical disease treated at the first nosis (variously based on combinations of biochemi- sign of organ involvement; treatment considered in cal, genetic, and clinical features) is stipulated before asymptomatic boys younger than 16 years old). Austral- treatment in all guidelines reviewed (Additional file 1: ian guidelines do not differentiate between male patients Table S1). with classical FD and patients with other types of disease for subsidized treatment initiation, but instead stipulate Consensus on factors influencing treatment initiation the symptomatology that justifies ERT initiation in male in PREDICT‑FD and female patients generally [24]. The panel rated four statements describing drivers of For other patient groups, Portugal also advocates treat- treatment initiation as ‘important’ and reached consensus ment of any pediatric patient (i.e., not only male patients on three. Two statements regarding barriers to treatment with classical FD) who presents with certain signs (e.g., were deemed important and consensus was reached on renal, cardiac, pain, abnormal hidrosis). Guidance from both (Table 5). Catalonia (Spain), Portugal, Slovenia, Switzerland, and the UK associates additional criteria with initiation in Drivers women and men with late-onset disease (Additional file 1: Table S1) [26]. These include either evidence of Statement 1. “Male sex, young age, and clinical find- renal, cardiac, or cerebrovascular (except in the UK) ings, such as severe pain and signs/symptoms of involvement for which causes other than FD have been organ involvement, are key drivers of early initiation excluded or evidence of specific FD-related compli- of treatment.” cations, such as uncontrolled pain or gastrointestinal Generally, guidelines support the finding in PREDICT- symptoms. In the Lazio region of Italy, guidance for FD that male sex, pain, and organ involvement are driv- female patients with classical disease and male patients ers of treatment initiation, but age mainly pertains to with non-classical disease suggests therapy must be men with classical disease. All men with classical disease started at early clinical signs of organ involvement. Treat- should be offered disease-specific therapy. In several ment of female patients with non-classical disease may be countries, younger asymptomatic male patients with a considered when early FD symptoms appear. In terms of classical FD diagnosis can be considered for disease-spe- the type of disease-specific therapy recommended, only cific therapy: Catalonia (patients aged 16 years or older Australia, Canada, Portugal, and the UK make recom- with classical FD); Portugal and Slovenia (case-by-case mendations about chaperone therapy as well as about basis in asymptomatic male patients with classical FD ERT. In Canada, ERT rather than chaperone therapy is older than 8 years old); Switzerland (all male patients recommended in children with a confirmed diagnosis with pathogenic mutations); and the UK (male patients because the Canadian regulatory authority has restricted with classical mutations/phenotype at diagnosis). Other chaperone therapy use to adults (patients aged 16 years countries recommend considering disease-specific ther- or older in the EU and the UK). apy only when symptoms appear: Canada (the presence Statement 2. “Improving clinical outcomes and pre- of a subset of specific renal, cardiac, and neurological venting disease progression are key drivers of early signs, as well as intractable gastrointestinal symptoms initiation of FD-specific treatment.” or neuropathic pain) [21]; France (treatment of asymp- tomatic boys not justified; treatment considered with UK guidance notes that “no trial has yet addressed the early organ involvement or significant pain); and Italy appropriate starting time of Fabry-specific therapy or Table 2 Cardiac signs: guideline stipulations and PREDICT-FD consensus [11] Early Markers Elevated Early Late Gd+ on Elevated Reduced Abnormal Abnormal Abnormal wall Symptomatic indicators of of early serum indicators of cMRI serum myocardial ECG echocardiogram motion on cardiac histological systolic/ cardiac LVH NT-proBNP T1 echocardiogram disease damage diastolic troponin relaxation (heart dysfunction time on biopsy) cMRI PREDICT-FDa + (NR) + + + + + + + + + – [11] EFWGb [1] – – – Wall thick- – – – Rhythm dis- – – – ness > 12 mm turbances with minimal/ All, I no fibrosis All, I Hughes et al. Orphanet Journal of Rare Diseases Australia [24] All Allc – Alld Alld – Allc Allc Alld – – Canadae [21] Confirmatory Grade 2 or > 2 × ULN Wall thick- Left ventricu- > ULN 1.5 T magnet Conduc- Diastolic filling – diagnosis 3 diastolic ness: lar wall M, < 901 ms tion/rhythm abnormal ­dysfunctionf M, > 12 mm F, 916 ms ­abnormalh Left F, > 11 mm atrium > 34 mL/ LVH Romhilt– m2 (2022) 17:42 Estes Moderate-to- score > ­5g severe mitral or aortic insuffi- ciency Abnormal longitu- dinal strain gradi- ent left ventricle Catalonia – Alli – Alli,j Allk – Allj Allj Alli Alli – (Spain) Francel [23, Fm – – – – Fm – Fm Fm – – 25] Portugal [22] – – LVH in adults Myocardial – – All, arrhyth- – – Dyspnea, Cardio- fibrosis mia palpitations, myopathy in Adults, syncope, tho- children conduction racic pain disturbance Slovenia Confirma- Diastolic – Hypertrophic Signs of – – Signs of fibrosis by (FCGHSG) tory biopsy if dysfunction cardiomyo- fibrosis speckle tracing needed in cF pathy and in late- onset ­adultsn Switzerlando Fp Fq – Fq – – Fq Fq – – – Page 6 of 15 Early Markers Elevated Early Late Gd+ on Elevated Reduced Abnormal Abnormal Abnormal wall Symptomatic indicators of of early serum indicators of cMRI serum myocardial ECG echocardiogram motion on cardiac histological systolic/ cardiac LVH NT-proBNP T1 echocardiogram disease damage diastolic troponin relaxation (heart dysfunction time on biopsy) cMRI UKr [26] – – – Wall thick- All – – – Alls – – ness: M, > 13 mm F, > 12 mm Unpublished guidelines are summarized in Additional file 1: Table S1 a Consensus was reached that FD-specific treatment should be initiated at diagnosis in male patients aged 16 years or older who are asymptomatic for organ involvement, in boys younger than 16 years old with early indicators of organ involvement, and in all patients with guideline indicators of organ involvement b Recommendations are based on class of evidence assigned: class I, treatment recommended or indicated; class IIA, treatment should be considered; class IIB, treatment may be considered; class III, treatment not recommended Hughes et al. Orphanet Journal of Rare Diseases c Significant life-threatening arrhythmia or conduction defect d LVH as evidenced by cMRI or echocardiogram data, in the absence of hypertension e Treatment initiated based two criteria. Many cardiac manifestations may be attributable to hypertension, so this must be ruled out or treated for 12 months. One additional criterion not shown in the table: abnormal base–apex circumferential strain gradient on cMRI f American Society of Echocardiography and/or the presence of speckle tracking abnormalities (2022) 17:42 g Additional criteria: LVM increase of 5 g/m2/y based on three measurements over at least 12 months; LVMI ≥ 20% above normal h Atrioventricular block, short PR interval, left bundle branch block, ventricular or atrial tachyarrhythmias, sinus bradycardia in the absence of negative chronotropic drugs or other causes i Echocardiographic changes: increased LVM, systolic or diastolic dysfunction, echocardiogram with persistently altered Doppler tissue j Electrocardiographic changes; LVH; arrhythmia k Alteration in cMRI suggestive of deposit l All male patients with a confirmed FD diagnosis should be offered ERT from age 18 years; ERT may be considered in children (6–18 years) with cardiac involvement m Treatment should be offered to women who develop cardiomyopathy; guideline does not specify how cardiomyopathy should be diagnosed, so various methods of diagnosis have been included except cMRI n Also if necessary in asymptomatic boys with a classical mutation o ERT is practically always indicated in men, even those with mild symptoms and low organ involvement, and in patients undergoing hemodialysis or with a kidney transplant p Relevant, histologically proven Gb3 deposits in kidney or heart biopsies q Manifest diastolic dysfunction, LVH, arrhythmias, attributable to cardiac involvement in FD r FD-specific therapy should be considered in male patients with classical mutations at diagnosis; tabulated additional considerations apply to male and female patients with later-onset disease s LVMI above normal for age and sex by 2D echocardiogram/cMRI + , achieved consensus in PREDICT-FD; 2D, two-dimensional; cF, female patient(s) with classical disease; cMRI, cardiac magnetic resonance imaging; ECG, electrocardiogram; EFWG, European Fabry Working Group; F, female patient(s); FCGHSG, Fabry Center, General Hospital Slovenj Gradec; FD, Fabry disease; Gb3, globotriaosylceramide; Gd+ , gadolinium enhancement; LVH, left ventricular hypertrophy; LVM, left ventricular mass; LVMI, LVM index; M, male patient(s); NR, achieved consensus but not recommended for safety reasons; NT-proBNP, N-terminal pro-natriuretic brain peptide; ULN, upper limit of normal; y, year Page 7 of 15 Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 8 of 15 Table 3 Neurological signs: guideline stipulations and PREDICT-FD consensus [11] White matter Neuropathic Painful GI Stroke/TIA Sudden onset Acute Silent cerebral lesions pain symptoms unilateral ischemic optic infarct on MRI suggestive of hearing loss neuropathy neuropathy PREDICT-FDa [11] – + + +b No consensus – – c d EFWG [1] All, IIB All, ­IIA – All, IIA All, ­IIBe – – Australia [24] – Allf – Allg – – – h i j Canada [21] – – – All All All – Catalonia (Spain) – Allk – Alll – – – m n France [23, 25] – Children F, children F,o ­childrenp – – Portugal [22] All adults All Abdominal pain in All adults All adults – All adults children Slovenia Allq All Allr Allq – – – (FCGHSG) Switzerlands – Ft F Fu – – – UKv [26] – Allw Allw – – – – Unpublished guidelines are summarized in Additional file 1: Table S1 a Consensus was reached that FD-specific treatment should be initiated at diagnosis in male patients aged 16 years or older who are asymptomatic for organ involvement, in boys younger than 16 years old with early indicators of organ involvement, and in all patients with guideline indicators of organ involvement b Originally classified under “Other” [11] c Recommendations are based on class of evidence assigned: class I, treatment recommended or indicated; class IIA, treatment should be considered; class IIB, treatment may be considered; class III, treatment not recommended d If neuropathic pain is controlled and does not interfere with activities of daily living, all classified as IIB e Age-adjusted hearing loss f Uncontrolled chronic pain despite the use of maximum doses of appropriate analgesia and antiepileptic medications for peripheral neuropathy g Ischemic vascular disease h Treatment initiated based on one criterion i Clinical significance of imaging abnormalities (white matter lesions, vessel dolichoectasia, cerebral microbleeds) alone is unclear and not an indication for ERT j Pain in isolation does not warrant ERT. A 12-month trial of ERT may be considered based on agreed outcomes (e.g. reduced need for analgesics, reduced school/work time lost, reduced hospital admission for pain crises) k Chronic pain, uncontrolled with drugs, that alters quality of life l Ischemic cardiopathy; imaged vascular ischemic lesions attributable to FD m All male patients with a confirmed FD diagnosis should be offered ERT from age 18 years n Major painful crises refractory to analgesic treatment with carbamazepine, diphenylhydantoin, gabapentin, amitryptiline in children aged 6–18 years o Severe cochlear damage p Cochleo-vestibular involvement (hearing loss assessed by audiogram; vertigo of vestibular origin) in children aged 6–18 years q Central and/or autonomic nervous system involvement consistent with FD r Treatment initiation in classical male patients and girls with abdominal pain and postprandial diarrhea; additional confirmation of disease progression required in adult cF and in both sexes with the late-onset phenotype s ERT is practically always indicated in men, even those with mild symptoms and low organ involvement, and in patients undergoing hemodialysis or after kidney transplantation t Therapy-resistant pain u Cerebrovascular manifestations (insult, transient ischemic attack); dizziness v FD-specific therapy should be considered in male patients with classical mutations at diagnosis; tabulated additional considerations apply to male and female patients with later-onset disease w Uncontrolled pain or GI symptoms requiring altered lifestyle or interfering with quality of life + , achieved consensus in PREDICT-FD; cF, female patient(s) with classical disease; EFWG, European Fabry Working Group; ERT, enzyme replacement therapy; F, female patient(s); FCGHSG, Fabry Center, General Hospital Slovenj Gradec; FD, Fabry disease; GI, gastrointestinal; MRI, magnetic resonance imaging; TIA, transient ischemic attack the group of patients most likely to benefit from therapy. the course of the disease. Conversely treatment late in However, this is a chronic, slowly progressive disorder the course of the disease may have limited efficacy” [26]. and the aim of treatment is to delay/reverse progres- Guidelines from other nations do not typically include sion or stabilise current parameters. It is anticipated that statements of this kind, nor do any guidelines mandate treatment will be most successful when started early in optimization of ancillary therapy (e.g., cardioprotective Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 9 of 15 Table 4 Patient-reported and other signs: guideline stipulations and PREDICT-FD consensus [11] Angiokeratoma Organ biopsy Non-pain GI Sweating Febrile crises Patient-reported symptoms abnormalities progression of or heat/exercise symptoms/signs intolerance PREDICT-FDa [11] + + + + + + EFWGb [1] Diagnostic sign – Aged < 16 years All, IIA Aged ≥ 16 years All, IIB Australia [24] – – – – – – Canada [21] Diagnostic sign Diagnostic/prognostic Allc – – – Catalonia (Spain) – – – – – – Franced [23, 25] Diagnostic sign – – – – – Portugal [22] – – All, recurrent diarrhea All – – attributable to FD Slovenia (FCGHSG) Diagnostic sign Confirmatory skin Postprandial ­diarrheae Alle – – biopsy if needed in asymptomatic boys with classical disease Switzerlandf – – F – – – UKg [26] – – – – – – Unpublished guidelines are summarized in Additional file 1: Table S1 a Consensus was reached that FD-specific treatment should be initiated at diagnosis in male patients aged 16 years or older who are asymptomatic for organ involvement, in boys younger than 16 years old with early indicators of organ involvement, and in all patients with guideline indicators of organ involvement b Recommendations are based on class of evidence assigned: class I, treatment recommended or indicated; class IIA, treatment should be considered; class IIB, treatment may be considered; class III, treatment not recommended c Significant GI symptoms unresponsive to other measures for at least 6 months or associated with poor growth or significant reduction in quality of life d All male patients with a confirmed FD diagnosis should be offered ERT from age 18 years e Central and/or autonomic nervous system involvement consistent with FD f ERT is practically always indicated in men, even those with mild symptoms and low organ involvement, and in patients undergoing hemodialysis or with a kidney transplant g FD-specific therapy should be considered in male patients with classical mutations at diagnosis; tabulated additional considerations apply to male and female patients with later-onset disease + , achieved consensus in PREDICT-FD; EFWG, European Fabry Working Group; ERT, enzyme replacement therapy; F, female patient(s); FCGHSG, Fabry Center, General Hospital Slovenj Gradec; FD, Fabry disease; GI, gastrointestinal; M, male patient(s) Table 5 Drivers and barriers associated with early treatment initiation in FD that achieved consensus in PREDICT-FD Drivers 1. Male sex, young age, and clinical findings, such as severe pain and signs/symptoms of organ involvement, are key drivers of early initiation of treatment (4.8) 2. Improving clinical outcomes and preventing disease progression are key drivers of early initiation of FD-specific treatment (4.6) 3. A family history of FD, especially if severe or with major organ involvement or premature death, is a key driver of early initiation of treatment (4.4) Barriers 1. A lack of biomarkers predicting which patients will progress and which will respond to treatment is a key barrier to early initiation of treat- ment (4.1) 2. Misdiagnosis is a key barrier to early initiation of treatment (3.9) Data in parentheses are the mean of agreement scores awarded by 21 panel members based on a 5-point pivoted Likert scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree). The criterion for consensus was an agreement rating of at least 4 awarded by more than 67% of those who voted Bold indicates the consensus statements describing the possible impact of PREDICT-FD FD, Fabry disease; PREDICT-FD, PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 10 of 15 medications or psychosocial support), although some levels [9, 10]. It remains unclear, however, whether treat- (e.g., Italy) summarize symptomatic therapy options. ment-related reductions in LysoGb3 are associated with improved outcomes. Statement 3. “A family history of FD, especially if severe or with major organ involvement or prema- Statement 2. “Misdiagnosis is a key barrier to early ture death, is a key driver of early initiation of treat- initiation of treatment.” ment.” Failure to diagnose FD and misdiagnoses will both A recommendation to screen for FD among blood delay initiation of treatment, but this problem is more relatives of individuals who have received a recent diag- likely caused by a lack of awareness of FD than by short- nosis does not generally feature in national guidelines. comings of treatment guidelines. Approval for lysosomal storage disease-specific therapy in Portugal is granted by a national committee, and pedi- Consensus on the possible impact of PREDICT‑FD gree analysis of candidates is mandated before they can Nine statements reached consensus among the PRE- be proposed. Slovenia and the UK include assessment DICT-FD panel regarding the potential impact of the of family pedigree during follow-up (Additional file 1: initiative (Table 6). One of the barriers to treatment (the Table S1) [26]. lack of consolidated biomarkers) featured in two of the statements (1 and 9), timing of therapy was the focus Barriers of three statements (2, 3, and 8), and improvements in patient management and, therefore, outcomes were com- Statement 1. “A lack of biomarkers predicting which mon themes of three more statements (4, 5, and 7). patients will progress and which will respond to treatment is a key barrier to early initiation of treat- Review of case histories against different guidelines ment.” In total, 17 anonymized case histories from six countries Plasma levels of Gb3 and LysoGb3 feature in guidelines were supplied by panel members, six of whom reviewed as diagnostic aids, but guidelines also provide evidence some of or all these histories and provided recommen- for this being a barrier, in that no biomarkers were availa- dations for treatment initiation based on guidance from ble to inform clinicians about when to initiate treatment, their own country, the EFWG, and the PREDICT-FD likely responsiveness to treatment, or patient prognosis. consensus criteria. The proportions of respondents who An association between elevated levels of LysoGb3 and recommended treatment in each case are presented in adverse long-term outcomes has been reported and there Table 7 and the breakdown by respondent and guideline is evidence that initiating FD-specific treatment earlier type is in Additional file 1: Table S3. Panel members were rather than later in life is associated with lower LysoGb3 unanimous in supporting the decision to initiate or to Table 6 Consensus statements describing the possible impact of PREDICT-FD Impact 1. Findings from the initiative could help to stimulate research, for example, into predictive biomarkers of disease progression (4.3) 2. Findings from the initiative could help to improve communication between HCPs and patients with FD regarding when to start (and stop) disease-specific therapy (4.1) 3. Findings from the initiative could lead to the earlier initiation of disease-specific treatment in patients with FD (4.1) 4. Findings from the initiative could help to improve outcomes and/or quality of life of patients with FD (4.0) 5. Findings from the initiative could help to improve clinical practice and the overall management of patients with FD (4.0) 6. Findings from the initiative could help to support negotiations relating to reimbursement of treatment (4.0) 7. Findings from the initiative could help to increase HCP awareness and understanding of the need for individualized assessment and regular multi disciplinary follow-up of patients with FD (4.0) 8. Findings from the initiative could lead to the achievement of consensus on when to start (and stop) disease-specific treatment in patients with FD (4.0) 9. Findings from the initiative could lead to the modification of national treatment guidelines to include predictive biomarkers of disease pro‑ gression (3.9) Data in parentheses are the mean of agreement scores awarded by 21 panel members based on a 5-point pivoted Likert scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree). The criterion for consensus was an agreement rating of at least 4 awarded by more than 67% of those who voted Bold indicates the consensus statements describing the possible impact of PREDICT-FD FD, Fabry disease; HCP, healthcare professional; PREDICT-FD, PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 11 of 15 Table 7 Percentage of responding panel members (N = 6) who recommended that treatment should be initiated, based on evaluation of each case history against PREDICT-FD criteria, EFWG guidance, and their own country’s guidelines Case PREDICT-FD EFWG Country Case PREDICT-FD EFWG Country 1 3 (60) 2 (50) 3 (60) 10 2 (50) 1 (25) 2 (40) 2 4 (100) 4 (100) 4 (100) 11 2 (67) 2 (67) 3 (75) 3 3 (100) 1 (33) 1 (33) 12 2 (67) 3 (100) 4 (100) 4 3 (100) 3 (100) 3 (100) 13 2 (100) 2 (100) 4 (100) 5 2 (67) 2 (67) 2 (67) 14 3 (100) 3 (100) 4 (100) 6 3 (100) 3 (100) 4 (100) 15 2 (100) 2 (100) 2 (67) 7 2 (100) 2 (100) 3 (100) 16 2 (100) 2 (100) 3 (100) 8 1 (33) 1 (33) 1 (25) 17 2 (100) 2 (100) 3 (100) 9 1 (50) 1 (50) 2 (67) Data are n (%). Shaded rows indicate cases for which disease-specific therapy initiation was recommended unanimously, irrespective of which set of guidelines was used EFWG, European Fabry Working Group; PREDICT-FD, PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease continue FD-specific treatment in eight of the 17 cases and updating guideline recommendations to provide, irrespective of the guidance followed. In only three cases for example, the level of granularity on cardiac indica- (3, 10, and 12) did the same panel member give differ- tors seen in Canadian guidance would help to address ent recommendations depending on which guidance was regional treatment inequalities. considered. Discrepant recommendations based on dif- Guidance from Canada and Catalonia (Spain) covered ferent country guidelines were seen in eight cases (1, 3, 5, the broadest set of cardiac indicators, and Canadian guid- 8–11, and 15), but discrepant recommendations among ance provided specific criteria for most of these, notably panel members were also made based on PREDICT-FD those assessed by cMRI. All the reviewed national or criteria (seven cases: 1, 5, and 8–12) and on the EFWG regional guidelines included cardiac indicators, but most criteria (seven cases: 1, 3, 5, and 8–11). In most cases, a could have been defined more precisely or expanded to recommendation to treat was as likely or more likely to include other measures. Synthesis of detailed cardiac be given based on the PREDICT-FD criteria than on the criteria for treatment initiation in FD may be possible EFWG or country criteria. Case 12 was the only instance from the various guidelines examined. Countries were of treatment initiation being unanimously recommended mostly aligned on renal indicators, although attitudes based on the EFWG and country guidelines, but not to confirmatory renal biopsy varied. The value of such PREDICT-FD criteria. histological evidence is undisputed, but some countries exclude it whereas others recommend it in justifying dis- Discussion ease-specific therapy. Most guidelines included metrics Comparison of the PREDICT-FD consensus criteria for patients with proteinuria, typically a manifestation with wide-ranging international guidance for disease- of FD presenting later than some other renal indicators. specific therapy initiation in FD has identified incon- However, retaining such indicators in guidance is useful sistencies that could be addressed to harmonize early to allow for delayed diagnosis. In terms of neurological treatment of patients with FD. Differences in indicators signs, few countries considered white matter lesions to be of cardiac involvement were particularly evident across supportive of treatment initiation, Canadian guidelines the various guidelines reviewed. Delayed treatment ini- noting that their clinical significance in FD is unclear. tiation because of differences in access to disease-specific Among the drivers of treatment initiation identified therapy may lead to worse outcomes in FD and could by PREDICT-FD, some could be more widely addressed be largely avoided if guidelines were aligned. Guide- in guidelines than currently. Early treatment initiation lines revised or issued most recently were most likely to to optimize clinical outcomes requires early diagnosis include specific early disease indicators identified in the of male patients with classical FD and careful follow-up PREDICT-FD initiative, and only the four most recently of non-classical male and female patients for early clini- issued country guidelines included recommendations cal signs/symptoms of organ involvement as described about chaperone therapy. Expanding guidance at coun- in many guidelines. Studies in untreated symptomatic try level to bring early disease indicators identified in women with FD indicate that guidelines can be applied PREDICT-FD to the attention of managing clinicians inconsistently in different patient groups [29, 30]. Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 12 of 15 The recommendation to treat early is based largely initiation or continuation in nearly half of the cases upon expert opinion, so it is important to collect more reviewed, irrespective of which criteria formed the supportive research data. For example, there may be an basis for assessment. Furthermore, in only three cases optimal age for FD-specific treatment initiation in each did applying different guidance cause a panel mem- patient group. It is likely that techniques such as cMRI ber to change their decision. Case histories were cho- and monitoring of biomarkers may not be widely acces- sen to exemplify occasions when the decision to treat sible. In these cases, local guidelines could be amended to was equivocal based on country guidance and, in eight encourage prompt referral to a regional specialist center. cases, different decisions about treatment initiation Guidelines could also recommend screening relatives of were reached based on the same criteria. Thus, ambigu- individuals with a recent diagnosis of FD to try to iden- ity exists in clinical guidelines and emphasizes the utility tify asymptomatic cases requiring follow-up and possibly of a more standardized approach. Increasing the granu- treatment. larity of criteria against which patients are assessed may Two barriers to treatment initiation have a substan- help to address this. Pragmatism must also be exercised tial impact on effective management of FD: lack of bio- when devising guidance. Anecdotally, there were cases markers and misdiagnosis. Tests for a small number of in which confirmatory renal biopsy had been conducted biomarkers are conducted in some centers but are not simply to satisfy the requirements of a guideline. This widely available, and their prognostic value for disease highlights how such invasive procedures can become a progression and/or treatment responsiveness remains barrier to treatment. unclear. LysoGb3 has been associated with negative clini- Our study has limitations. Comparison of the guideline cal outcomes in FD [10], and treatment early in life rather criteria had to be qualitative because most indicators for than later is associated with lower LysoGb3 levels [9], but treatment initiation were not described or measured uni- direct confirmation of its prognostic value is still needed. formly across the guidelines. Comparative performance Moreover, biomarker tests can yield false-positive results. of case studies against the various guidelines could pro- For example, heterophile antibodies can cause false- vide insights about specific differences that translate positive data in high-sensitivity troponin assays [31], into treatment delays, but a more structured prospective and troponin levels are influenced by factors other than approach with a larger sample size than used here would myocardial injury that are common in FD, including cer- be needed. At a superficial level, most of the case histo- ebrovascular or renal disease [32, 33]. Regarding misdi- ries considered were as likely or more likely to receive a agnosis, the awareness and index of suspicion of rare positive treatment recommendation based on PREDICT- diseases are often low among non-specialist clinicians, FD than on other criteria, but in all cases the sample probably leading to misattribution of FD signs/symptoms size was very small. Also, all authors participated in the and impeding research into prognostic biomarkers. PREDICT-FD consensus initiative [11], which may have In addition to considering drivers of and barriers to introduced bias to the interpretation of cases. As is com- treatment initiation, the PREDICT-FD expert panel was mon with rare diseases, wider knowledge of FD among asked to speculate about the possible impact of the ini- general clinicians could accelerate diagnosis, and iden- tiative. The need for biomarker research echoed discus- tification of biomarkers to inform likely outcomes with sions of barriers to treatment and is clearly a source of treatment would improve patient management. frustration. However, should PREDICT-FD raise disease awareness, such research endeavors may follow, and find- Conclusions ings relating to the timing of treatment initiation and When an FD diagnosis has been confirmed, disease-spe- cessation may translate into changes in clinical practice. cific treatment should be offered as soon as possible to Early treatment initiation has been the principal focus male patients with classical disease, and it should be con- of PREDICT-FD and expansion of treatment criteria sidered at the earliest signs of organ involvement in other at the national level based on the consensus findings of patient groups to try to stabilize or even to reverse dis- PREDICT-FD could help to realize this. As well as the ease progression. Although guidance is generally aligned potential for improved patient outcomes, harmonizing on early indicators of renal involvement, the PREDICT- treatment decisions facilitates consistent communication FD consensus identified several early signs of cardiac about such decisions among specialists, patients, and involvement not yet widely adopted; Canadian guidelines their primary care physicians. [21] could be valuable to clinicians seeking cardiac met- Given the differences among the guidelines reviewed, rics for patient assessment. Comparison of PREDICT-FD we undertook a preliminary investigation of how this and a range of treatment guidelines in FD has revealed might affect treatment decisions at the patient level. considerable scope to harmonize international guidance Expert panel members unanimously supported treatment on treatment initiation. If these findings catalyze changes Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 13 of 15 in clinical practice, they may improve outcomes and Supplementary Information quality of life for patients with FD in the long term. The online version contains supplementary material available at https://​doi.​ org/​10.​1186/​s13023-​022-​02181-4. Methods Details of the PREDICT-FD Delphi consensus meth- Additional file 1: Supplementary data. odology have been reported previously [11]. Briefly, as part of round 1 of the Delphi consensus, the expert Acknowledgements panel provided suggestions of key drivers and barriers The authors thank Mark Rolfe, PhD (ORCiD: https://​orcid.​org/​0000-​0002-​9248-​ 1563) of Oxford PharmaGenesis, Oxford, UK for providing administrative, medi- associated with early initiation of FD-specific treatment cal writing, and editorial support, which, in accordance with Good Publication and of the possible impact of PREDICT-FD on patients Practice 3 (GPP3) guidelines (http://​www.​ismpp.​org/​gpp3), has been funded and clinical practice. The panel’s suggestions were com- by an unrestricted independent educational grant (IME-GBR-15474) from Shire International GmbH, Zug, Switzerland, now part of Takeda Pharmaceutical piled by an independent administrator, consolidated Company Ltd. into short statements by the non-voting chairs of the initiative, and submitted to the panel for importance Authors’ contributions DAH and SF were co-chairs of the PREDICT-FD initiative, conceived the work rating as part of round 2 of the consensus. Those state- reported here, including inviting the PREDICT-FD panel members to partici- ments meeting predefined importance criteria in round pate, and both directed and contributed to the drafting of the manuscript, 2 were resubmitted to the panel for agreement rating as including critical review at all stages of its development. PA, OL, KN, AN, MT, RTB, BV, and MLW were members of the PREDICT-FD expert panel, provided part of round 3; statements meeting agreement criteria expert input about interpretation of their respective country guidelines in the in round 3 achieved consensus. context of the PREDICT-FD consensus, contributed to drafting of the manu- After the PREDICT-FD consensus initiative, panel script, and provided critical review at all stages of its development. All authors approved publication of the manuscript in its current form. All authors read members were asked to provide local guidelines for and approved the final manuscript. disease-specific therapy of FD. National FD treatment guidelines were supplied by panel members from Aus- Funding Administration and coordination of the PREDICT-FD initiative and medical tralia [24], Canada [21], France [23, 25], Portugal [22], writing support were funded by an unrestricted independent educational and the UK [26]. Unpublished guidelines from Swit- Grant (IME-GBR-15474) from Shire International GmbH, Zug, Switzerland, now zerland, for the Lazio region of Italy, and for Catalonia part of Takeda Pharmaceutical Company. Shire/Takeda were not involved in the planning, design, or delivery of the initiative. No reimbursement or fund- (Spain), and institutional guidelines from the National ing was offered to the expert panel, to the co-chairs, or to any other organiza- Fabry Center, General Hospital Slovenj Gradec (Slove- tion participating in the initiative. nia) were also supplied. The Australian guidelines are Availability of data and materials for FD-specific treatment subsidized by the national All data generated or analyzed during this study are included in this published Life-Saving Drugs Program. Guidelines were reviewed article and its Additional files. and compared to determine areas of discrepancy with PREDICT-FD and to establish what relationship they Declarations may have to the identified treatment drivers and bar- Ethics approval and consent to participate riers. Signs stipulated in guidelines as possible justifi- No patient-level data are reported in this study and no ethical approval was cation for initiating therapy in different patient groups sought. were extracted and compared with those identified in Consent for publication PREDICT-FD [11]. Anonymized patient case histories Not applicable. were provided by the PREDICT-FD co-chairs and by certain panel members after the consensus phase of Competing interests DAH: advisory boards for Amicus Therapeutics, Sanofi, and Shire (now part of the initiative was complete. No information regarding Takeda); consulting fees from Amicus Therapeutics, Idorsia Pharmaceuticals, patients’ identities was disclosed by the managing phy- Sanofi, and Shire (now part of Takeda); fees from Amicus Therapeutics, Sanofi, sicians to anyone involved in the investigation reported and Shire (now part of Takeda). PA: research grant and fees from Shire (now part of Takeda); fees from Amicus Therapeutics, BioMarin Pharmaceutical, here. Sanofi, and Ultragenyx Pharmaceutical. OL: travel grants and speaker fees from Amicus Therapeutics, Sanofi Genzyme, and Shire HGT. KN: research sup- port and/or fees from Amicus Therapeutics, Idorsia Pharmaceuticals, Protalix Abbreviations Biotherapeutics, Sanofi, and Shire (now part of Takeda); advisory boards for α-Gal A: Alpha galactosidase A; cMRI: Cardiac magnetic resonance imaging; Amicus Therapeutics, Sanofi, and Shire (now part of Takeda). AN: fees and EFWG: European Fabry Working Group; ERT: Enzyme replacement therapy; EU: research support from Amicus Therapeutics, Sanofi Genzyme, and Shire (now European Union; FD: Fabry disease; Gb3: Globotriaosylceramide; GLA: Gene part of Takeda). MT: advisory boards for Amicus Therapeutics, Sanofi, and Shire encoding α-Gal A; LysoGb3: Globotriaosylsphingosine; PREDICT-FD: PRopos- (now part of Takeda); travel grants and speaker fees from Amicus Therapeutics, ing Early Disease Indicators for Clinical Tracking in FD. Hughes et al. Orphanet Journal of Rare Diseases (2022) 17:42 Page 14 of 15 Sanofi, and Shire (now part of Takeda); research funding from 4D Molecular with Fabry disease. J Med Genet. 2021. https://​doi.​org/​10.​1136/​jmedg​ Therapeutics, Amicus Therapeutics, AVROBIO, and Idorsia Pharmaceuticals. enet-​2020-​107338. RTB: travel grants, speaker fees, or consultation fees from Amicus, Sanofi 11. Hughes DA, Aguiar P, Deegan PB, Ezgu F, Frustaci A, Lidove O et al. Early Genzyme, and Takeda. BV: speaker fees and travel support from Greenovation, indicators of disease progression in Fabry disease that may indicate the Sanofi Genzyme, and Shire (now part of Takeda); advisory board fees from need for disease-specific treatment initiation: findings from the opinion- Sanofi Genzyme. MLW: advisory boards for Amicus Therapeutics, Sanofi, and based PREDICT-FD modified Delphi consensus initiative. BMJ Open. Shire (now part of Takeda); fees from Amicus Therapeutics, Sanofi, and Shire 2020;10(10):e035182. (now part of Takeda); research funding from Amicus Therapeutics, Idorisia 12. Replagal SmPC. https://​www.​ema.​europa.​eu/​en/​docum​ents/​produ​ct-​ Pharmaceuticals, Protalix Biotherapeutics, and Shire (now part of Takeda). SF: infor​mation/​repla​gal-​epar-​produ​ct-​infor​mation_​en.​pdf. 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Orphanet Journal of Rare Diseases (2022) 17:42 Page 15 of 15 33. Hajjari J, Janus SE, Albar Z, Al-Kindi SG. Myocardial injury and the risk of stroke in patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort study). Angiology. 2021:33197211005595. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Ready to submit your research ? Choose BMC and benefit from: • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions