Domínguez‑González et al. Orphanet Journal of Rare Diseases (2022) 17:426 https://doi.org/10.1186/s13023-022-02574-5 RESEARCH Open Access Survey on the management of Pompe disease in routine clinical practice in Spain Cristina Domínguez‑González1* , Carmina Díaz‑Marín2 , Raúl Juntas‑Morales3, Andrés Nascimiento‑Osorio4, Alberto Rivera‑Gallego5 and Jordi Díaz‑Manera6,7 Abstract Background: Despite the availability of several clinical guidelines, not all health professionals use their recommenda‑ tions to manage patients with Pompe disease, a rare genetic disorder involving high-impact therapy. Through several discussion meetings and a survey, the present study aimed to learn about the management of Pompe disease in routine clinical practice in Spain, to improve clinical care in a real-life situation. Results: The survey was sent to 42 healthcare professionals who manage patients with Pompe disease in their clini‑ cal practice. Although most respondents followed the clinical guidelines, clinical practice differed from the expert recommendations in many cases. Approximately 7% did not request a genetic study to confirm the diagnosis before starting treatment, and 21% considered that only two dried blood spot determinations suffice to establish the diag‑ nosis. About 76% requested anti-GAA antibodies when there is a suspicion of lack of treatment efficacy, though a significant percentage of respondents have never requested such antibodies. According to 31% of the respondents, significant impairment of motor function and/or respiratory insufficiency is a requirement for authorizing medication at their hospital. Up to 26% waited for improvements over the clinical follow-up to maintain treatment and withdrew it in the absence of improvement since they did not consider disease stabilization to be a satisfactory outcome. Conclusions: The results highlight the lack of experience and/or knowledge of some professionals caring for patients with Pompe disease. It is necessary to develop and disseminate simple guidelines that help to apply the expert rec‑ ommendations better or centralize patient follow-up in highly specialized centers. Keywords: Antibodies, Diagnosis, Follow-up, Guidelines, Pompe disease, Treatment Background authors. According to the age of onset, we can classify it Pompe disease (PD) is an autosomal recessive multi- into three groups: 1) Classic infantile-onset PD (IOPD), systemic disorder characterized by acid α-glucosidase which includes patients with GAA activity close to 0%, (GAA) deficiency that leads to lysosomal glycogen stor- the onset of symptoms during the first year of life, and age. The PD phenotype encompasses a continuous clini- hypertrophic cardiomyopathy; 2) Childhood or juvenile- cal spectrum with variable age of onset, progression onset PD (JOPD), that includes patients diagnosed before rate, and severity. The classification of PD differs among age 18; and 3) Adult-onset or late-onset PD (LOPD), that can present after early to late adulthood. Patients in the last two groups usually have residual GAA activity *Correspondence: cdgonzalez@salud.madrid.org (1–40%) and do not have cardiomyopathy [1–4]. Respira- 1 Neuromuscular Unit, Neurology Department, Hospital Universitario 12 de tory failure is the leading cause of morbidity and mortal- Octubre, imas12 Research Institute, Biomedical Network Research Center ity in JOPD and LOPD. One-third of all patients require on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Av. de Córdoba, s/n, 28041 Madrid, Spain ventilatory support before losing the ability to walk inde- Full list of author information is available at the end of the article pendently [3, 5–8]. © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom‑ mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Domínguez‑González et al. Orphanet Journal of Rare Diseases (2022) 17:426 Page 2 of 7 In 2006, the treatment of PD with recombinant human management of PD in Spain is not centralized in refer- alglucosidase alfa enzyme (rhGAA) was authorized in ence centers as in other European countries and with Europe. The efficacy and safety of this treatment have other therapies in Spain. For all these reasons, we have been demonstrated in many clinical studies, affording conducted a study to know the diagnosis, treatment significant improvement of motor function, at least sta- with rhGAA, and follow-up of patients with PD in real bilization of lung function, and a prolongation of sur- clinical practice in Spain through a 5-question survey. vival [9–19]. It should be emphasized that patients with The information obtained will make it possible to deter- less muscle damage at the start of treatment may obtain mine whether the treatment and follow-up of patients a more significant benefit, hence the importance of start- with PD in Spain align with international recommen- ing treatment as soon as possible [20, 21]. Several clini- dations, identify inequalities in access to high-impact cal studies suggest that starting enzyme replacement medications, and identify areas for improvement to therapy (ERT) in a better functional situation indicates optimize their clinical management in the country. a good prognosis; however, the possible benefit of treat- ing presymptomatic patients has not been demonstrated [11, 15, 22, 23]. Considering that almost one-third of all Results PD patients do not respond to treatment, it is essential to The survey was sent to 42 healthcare professionals: 5 monitor the disease properly, since treatment withdrawal treated patients with JOPD (5 pediatricians), and the should be considered if no response is observed [24]. remaining 37 (8 internal medicine physicians and 29 Numerous clinical guidelines have been published neurologists) treated patients with adult-onset PD (55% offering recommendations for diagnosing, treating, and attended more than one). The latter were geographi- following up on patients with PD [24–28]. For this work, cally distributed as follows: 3 in Alicante and Murcia, 6 we have taken as a reference the recommendations of the in Andalusia, 1 in the Balearic Islands, 4 in the Canary European group of experts on Pompe disease, as it is the Islands, 7 in Catalonia, 5 in Galicia and El Bierzo, 5 in most complete and up-to-date guide [24]. Madrid, 3 in Asturias, the Basque Country, and Nav- It is important to highlight that rhGAA is a high-cost arra, and 3 in Valencia (Fig. 1). The remaining 5 treat treatment that can be prescribed by any physician in JOPD at the National level. any health center in Spain. Furthermore, the clinical Fig. 1 Spanish reference centers across regions in Spain and the origin of the panel respondents that treated patients with adult-onset Pompe disease Domínguez‑González et al. Orphanet Journal of Rare Diseases (2022) 17:426 Page 3 of 7 When do you consider a definitive diagnosis of PD? Regarding anti‑GAA antibodies Most respondents (97.6%) considered one pathological 31% of the respondents had never requested antibodies confirmation in dried blood spot (DBS) testing and the against GAA, and 42.9% asked for anti-GAA antibody identification of biallelic pathogenic mutations in the determination regularly after the initiation of treat- genetic study as a confirmatory test for PD (Table 1). ment. A total of 76.2% requested antibodies when there Opinions were widely divergent as to whether the pres- was a suspicion of a lack of therapy efficacy (objective ence of reduced enzyme activity in two tissues allows for clinical worsening) (Table 1). Regardless of when these a diagnosis of PD despite a negative genetic result. Three antibodies are requested, almost all the respondents participants in the survey (7.1%) did not request a genetic agreed that high antibody titers do not mean treat- analysis to confirm the diagnosis before initiating treat- ment should be discontinued (only 2.4% considered ment, and 9 participants (21.4%) indicated that only two high antibody titers as a criterion for discontinuing DBS determinations were sufficient to diagnose PD. treatment). Table 1 Questions proposed in the survey N = 42 N (%) When do you consider a definitive diagnosis of Pompe disease? When two DBS determinations show pathological values of enzyme activity 9 (21.4) When a determination of enzyme activity in DBS is pathological and in addition the muscle biopsy shows PAS + vacuoles 17 (40.5) When DBS is pathological and biallelic pathogenic mutations have been identified in the genetic study 41 (97.6) When the clinical phenotype is compatible and reduced lymphocyte activity has been demonstrated, even though only one pathogenic 35 (83.3) mutation has been identified in the genetic study When reduced enzyme activity has been demonstrated in two tissues, even though the genetic study is negative 21 (50.0) When Pompe disease is suspected, I always request a confirmatory genetic study 39 (92.9) Regarding anti-GAA antibodies: I have never requested the determination of anti-GAA antibodies 13 (31.0) After the initiation of treatment, I request anti-GAA antibody determination on a regular basis 18 (42.9) If antibodies remain at high titers during follow-up, I consider discontinuing treatment 1 (2.4) I request antibodies when there is a suspicion of lack of efficacy of the treatment (objective clinical worsening) 32 (76.2) What tests do you perform during clinical follow-up to evaluate the response to treatment? MRC scale 39 (92.9) 6MWT 42 (100) Other timed tests 24 (57.1) Fatigue scale 19 (45.2) Activity or quality of life scales 30 (71.4) Muscle MRI scan 22 (52.4) Pulmonary function tests 42 (100) Do you have to do follow-up reports to keep the medication authorized? No 23 (54.8) Yes, only occasionally 5 (11.9) Yes, every 6 months 8 (19.0) Yes, annually 10 (23.8) The existence of significant impairment of motor function and/or the presence of respiratory failure is a requirement for the authorization of 13 (31.0) medication in my hospital Improvement of follow-up parameters is a prerequisite for the maintenance of treatment 11 (26.2) In what situations would you consider interrupting or stopping treatment? Never 2 (4.8) If there are no objective data of stabilization or improvement of motor and/or respiratory function during follow-up 8 (19.0) If there is evidence of progressive clinical worsening 32 (76.2) 6MWT six-minute walk test; DBS dried blood spots; GAA​α-glucosidase, acid; MRC Medical Research Council; MRI magnetic resonance imaging; PAS periodic acid-Schiff Domínguez‑González et al. Orphanet Journal of Rare Diseases (2022) 17:426 Page 4 of 7 What tests do you perform during clinical follow‑up neuromuscular diseases, which in this case, fail to cen- to assess treatment response? tralize the management of these low-prevalence, high- Most of the respondents chose the Medical Research complexity patients. Council (MRC) scale (92.9%), the six-minute walk test Based on the survey results, several discrepancies have (6MWT) (100%), and pulmonary function tests (100%) been identified between the usual practice of physicians (Table 1). The least common tests were activity or qual- who care for patients with PD in Spain and the latest ity of life scales (71.4%), other timed tests (57.1%), mus- published expert recommendations [24–28]. cle MRI (52.4%), and fatigue scales (45.2%). Among those According to the European guidelines, the diagnosis of using the MRC scale, 64.1% evaluated 10–20 muscles, the disease must be made by a certified laboratory and while 35.9% only explored 5–10 muscles. should be confirmed through enzyme analysis in leuko- cytes, fibroblasts, or skeletal muscle and/or genetically via mutation analysis (preferably by both methods) [24]. Do you have to do follow‑up reports to keep Moreover, although DBS has recently become available the medication authorized? and is a good PD screening test, it always requires diag- 54.8% of the respondents answered no, and 54.7% nostic confirmation [29]. However, according to the sur- answered yes (23.8% report annually, 19% every six vey results, some clinicians do not use the criterion of months, and 11.9% only occasionally) (Table 1). The reduced enzyme activity in two tissues to establish the results by region were highly diverse. In Catalonia, all diagnosis of PD in patients with inconclusive genetic test- respondents made follow-up reports, versus only one in ing. Others do not confirm the DBS results with genetic Alicante and Murcia or Basque Country and Navarra, analysis, which can influence the accuracy of diagnosis. and none in the Balearic Islands. The European consensus recommends discontinuing According to 31% of the respondents, significant treatment if high antibody titers are detected that sig- impairment of motor function and/or respiratory insuf- nificantly counteract the effect of ERT, which, although ficiency is a requirement for authorizing medication at rare, is also possible in adults [24]. For this reason, most their hospital. This affirmation was particularly frequent guidelines recommend determining these antibodies in in Andalusia (50%), Catalonia (57.1%), and in Asturias, patients receiving ERT every three months for two years Navarre, and the Basque Country (100%). On the other and then annually [25, 28]. In the survey, although many hand, 26.2% considered the improvement of follow-up respondents request anti-GAA antibodies when there is a parameters a prerequisite for maintaining treatment. suspicion of lack of treatment efficacy, a significant per- This statement was particularly frequent in the Canary centage of those surveyed have never requested them due Islands (75%). to the complexity of their determination in real clinical practice. It is interesting to note that recent publications In what situations would you consider interrupting have described that anti-GAA antibody titers decrease as or stopping treatment? patients are exposed to treatment, and only a few studies Most respondents (76.2%) interrupted or stopped treat- have correlated antibody titers to clinical outcomes on a ment when there was evidence of progressive clinical prospective basis [30–33]. Thus, most PD experts agree worsening. Only two respondents chose never to inter- that the determination of antibodies over time is not very rupt treatment and 19% did so when there was no objec- helpful in LOPD patients, and they will rarely interfere tive evidence of stabilization or improvement of motor with the response to treatment. This justifies the need to and/or respiratory function during follow-up (Table 1). update the current recommendations, published in 2017. During the follow-up of patients, most respondents chose to use pulmonary function tests, the 6MWT, and Discussion the MRC scale to evaluate the response to treatment. This The present survey on the management of patients with is in accordance with the recommendations of several PD in routine clinical practice yielded highly variable clinical guidelines [26–28]. Other assessments recom- results, with occasional deviation from the recommen- mended by these guidelines and less frequently employed dations established in the clinical guidelines. The data in clinical practice include the evaluation of nutritional obtained also reveal the inequality in access to treatment status, the Rasch-built Pompe-specific Activity (R-PAct) throughout Spain, the absence of homogeneous crite- scale, and fatigue scales [26–28]. To promote the use of ria in accordance with the experts’ recommendations, scales for evaluating treatment response, it is necessary and the lack of optimization of a treatment with a high to make them more widely known and available. economic cost. All of this was noted despite the exist- The European consensus, based on the available evi- ence of a robust network of reference centers for rare dence and discussion among experts, recommends Domínguez‑González et al. Orphanet Journal of Rare Diseases (2022) 17:426 Page 5 of 7 starting treatment when the patient has symptoms (i.e. Conclusions the patient should have skeletal muscle weakness or res- The present survey results on the management of PD piratory muscle involvement as observed using clinical in Spain (a rare disease with a high-impact treatment) assessments) and not starting treatment in pre-sympto- reveal some professionals’ lack of experience or knowl- matic patients due to the lack of sufficient evidence to edge. Developing and disseminating simple guidelines support it. Therefore, any patient with symptoms should that help understand and follow the recommendations start treatment [24]. However, a considerable part of is necessary. It might even be interesting to suggest that those surveyed consider that there must be a significant the follow-up of these patients be carried out in the exist- deterioration in motor function and/or the presence ing reference centers. The inequity detected in access to of respiratory failure as a requirement for rhGAA to be rhGAA and the discrepancies with the current evidence authorized in their hospital or that an improvement in justify the need to involve the Administration in the monitored parameters is required to maintain treatment. homogenization and optimization of the clinical manage- To maintain authorization of the treatment, the Euro- ment of patients with PD. pean guidelines state that both an improvement and sta- bilization in motor and/or respiratory function suggests Methods that the treatment is beneficial and should be contin- Study design ued [24]. They recommend stopping therapy in cases of The present study involved a survey to gather opinions serious adverse events that cannot be controlled, severe on the management of PD in real clinical practice in comorbidity that limits the patient’s life expectancy, or if Spain. The study was conducted in several phases: 1) pro- the patient should decide [26]. In addition, they recom- ject definition and creation of the scientific committee; 2) mend stopping treatment if the patient shows a substan- generation of materials to be presented at meetings based tial deterioration in motor and respiratory functions but on the current state of the art in the diagnosis and treat- restarting it if the progression of the disease accelerates ment of PD; 3) a total of 10 online meetings conducted by after stopping the ERT [24]. A large majority of respond- an expert to discuss the diagnosis, treatment indication, ents in our survey agreed with these recommendations. clinical management, and follow-up of patients with PD However, 26.2% of those surveyed in this study do not and to identify controversies; 4) creation and distribution consider stabilization a beneficial effect of the ERT and of an online survey to collect the opinion of the respond- recommend its suspension in these cases. ents on the management of PD, and 5) a final meeting The variety in the responses suggests that there is no with the scientific committee to discuss the results. standardized diagnosis or care protocol in the country and that published guidelines are not always followed. Participants Consequently, patient care is based on the expertise of The study involved three types of professionals: a scien- each physician. On the other hand, some answers seem tific committee, a technical team, and a panel of respond- to depend more on the center than on the health care ents. The scientific committee consisted of 10 experts region involved and, in many cases, the authorization in the management of PD, whose role was to lead sev- to start and stop ERT does not rely only on the doctor eral discussion meetings and to develop a survey to but also on the pharmacy committee of the center, which know the usual clinical practice in the management of may not follow the clinical guideline recommendations. PD. The technical team, which directed and supervised The discrepancies observed in our study with the pub- the entire process, was responsible for the instrumental lished evidence highlight the need to establish clear and implementation of the method (literature search, sur- straightforward diagnostic and therapeutic guidelines vey distribution, analysis of the responses, and statistical for this disease or to restrict the indication and follow- interpretation of the survey). The scientific committee up of high-impact treatments to reference centers for chose the panel of respondents among health profession- PD. In Spain, there are seven major reference centers for als treating patients with PD. This panel consisted of 42 rare neuromuscular diseases designated by the Spanish professionals (8 internal medicine physicians, 29 neu- Ministry of Health (Fig. 1) [34]. These centers can also be rologists, and five pediatricians) with experience in the essential in avoiding inequalities in access to medicines management of PD from all over Spain (Fig. 1). depending on the area of residence. The main limitations of this study are those inher- Discussion meetings ent to studies based on online surveys, i.e., differences Through ten meetings with healthcare professionals in understanding and interpretation of the questions, who attend to patients with PD, the scientific committee closed-ended questions, non-response bias, and lack of presented the most recent scientific evidence about this personalization, among others. Domínguez‑González et al. Orphanet Journal of Rare Diseases (2022) 17:426 Page 6 of 7 disease, showing the main recommendations of clinical an external reviewer of the company’s educational material and has presented at congresses on behalf of the company. He has received research funding. guidelines on the diagnosis, treatment, and follow-up of CDM has received fees from Sanofi-Genzyme for participating in the Tracking patients. During these meetings, the management of the on Pompe program. RJM has received honoraria for speaking activities and disorder was discussed, and the most relevant controver- congresses from Sanofi. ANO has received speaker and consultancy fees from Sanofi, and is an investigator in clinical trials sponsored by Sanofi. ARG has sies were identified and collected in a worksheet. Each received fees from Sanofi Genzyme for lectures and travel and from Takeda for session was held online, lasted 2 h, was moderated by a lectures. scientific committee member, and was attended by 4–6 Author details physicians. 1 Neuromuscular Unit, Neurology Department, Hospital Universitario 12 de Octubre, imas12 Research Institute, Biomedical Network Research Center Survey on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Av. de Córdoba, s/n, 28041 Madrid, Spain. 2 Neurology Department, Hospital General Universitario Based on the controversies identified in the discussion de Alicante Doctor Balmis, Instituto de Investigación Biosanitaria de Alicante meetings, a 5-question survey of diagnostic and treat- (ISABIAL), Alicante, Spain. 3 Neuromuscular Unit, Neurology Department, ment practices in patients with PD was developed. Each Hospital Universitario Vall d’Hebron. Peripheral Nervous System Group, Vall d’Hebron Institute of Research (VHIR), Barcelona, Spain. 4 Neuromuscular question included several answers, and the respond- Unit, Neurology Department, Hospital Sant Joan de Déu, Applied Research ents could choose any. The purpose of the survey was in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Center to ascertain the disparity of opinions about the man- for Biomedical Research Network On Rare Diseases (CIBERER), ISCIII, Barcelona, Spain. 5 Systemic Rare Diseases Unit, Department of Internal Medicine, Hospital agement of the disease and to identify opportunities for Universitario Alvaro Cunqueiro, Vigo, Spain. 6 John Walton Muscular Dystrophy improvement in the diagnosis, treatment, and follow-up Research Center, Newcastle University Translational and Clinical Research Insti‑ of patients with PD. The results were analyzed anony- tute, Newcastle Upon Tyne, UK. 7 Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. mously, without differentiating between the profession- als’ responses belonging to reference centers and the rest. Received: 13 July 2022 Accepted: 20 November 2022 Abbreviations 6MWT: Six-minute walk test; DBS: Dried blood spot; ERT: Enzyme replacement therapy; GAA​: Acid α-glucosidase; IOPD: Infantile-onset PD; JOPD: Juvenile- onset PD; LOPD: Late-onset PD; MRC: Medical Research Council; MRI: Magnetic References resonance imaging; PD: Pompe disease; R-PAct: Rasch-built Pompe-specific 1. van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet. Activity; rhGAA​: Recombinant human alglucosidase alfa enzyme. 2008;372(9646):1342–53. 2. Wokke JH, Escolar DM, Pestronk A, Jaffe KM, Carter GT, van den Berg LH, Acknowledgements et al. 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Patel TT, Banugaria SG, Case LE, Wenninger S, Schoser B, Kishnani PS. • rapid publication on acceptance The impact of antibodies in late-onset Pompe disease: a case series and • support for research data, including large and complex data types literature review. Mol Genet Metab. 2012;106(3):301–9. 31. Fernández-Simón E, Carrasco-Rozas A, Gallardo E, González-Quereda • gold Open Access which fosters wider collaboration and increased citations L, Alonso-Pérez J, Belmonte I, et al. Study of the effect of anti-rhGAA • maximum visibility for your research: over 100M website views per year antibodies at low and intermediate titers in late onset Pompe patients treated with ERT. Mol Genet Metab. 2019;128(1–2):129–36. At BMC, research is always in progress. 32. Filosto M, Cotti Piccinelli S, Ravaglia S, Servidei S, Moggio M, Musumeci O, et al. Assessing the role of anti rh-GAA in modulating response to ERT in a Learn more biomedcentral.com/submissions