“Real world” medical care of patients with Fabry disease by primary care physicians, internists or general practitioners

Introduction

Fabry disease (FD) is a hereditary, X-linked disorder of glycosphingolipid metabolism (1). Glycosphingolipids are components of cell membranes, serving as receptors of carbohydrate-binding proteins and participating in transmembrane signalling processes (2). Due to a deficiency of α-galactosidase A, glycosphingolipids such as globotriaosylceramide [Gb3/GL-3 or ceramide trihexoside (CTH)] and deacetylated globotriaosylsphingosine (lyso-Gb3) accumulate in the lysosomes (3,4). The incidence of FD is often quoted as 1:40,000 to 1:117,000 (5). An Italian newborn screening, considering reduced/absent α-galactosidase A activity, reported an incidence of 1:3,100 with a ratio of 11:1 from late-onset to classical variants (6). The GLA gene is located on the long arm of the X-chromosome (Xq22) (7). Due to X inactivation, FD can also manifest in women (8,9). Over 1,100 molecular variants are known, with 60% described as missense mutations (10,11).

The clinical presentation of FD depends on the residual activity of α-galactosidase A and on the sex of the patient. In late-onset/type 2/non-classical variants, with residual enzyme activity, symptoms manifest later in life and usually involve fewer organs (12). FD is clinically variable, ranging from asymptomatic patients to multi-organ involvement and impending multi-organ failure (1). Clinical experience suggests that most FD patients initially consult their primary care provider (PCP) for cardiac or non-cardiac medical problems. Thus, PCP play a crucial role in ensuring adequate diagnosis and treatment. This is particularly challenging because PCP typically encounter FD infrequently and may be unaware of potential therapeutic approaches. Furthermore, there is a significant delay of of 13.7–16.3 years between the onset of symptoms and confirmation of FD (13).

The study team has observed similar trends in adults with congenital heart defects (ACHD), where many patients are not in specialized care, leading to a substantial health care underuse and potentially adverse effects on morbidity and mortality (14).

This study is the first to describe the real-life care situation of FD patients in Germany. It is hypothesized that a considerable number of Fabry patients remain undiagnosed due to a lack of connection to experienced centres/specialists, insufficient information about appropriate diagnostic and treatment measures, and/or the absence of necessary, up-to-date optimal treatment.

This study aims to clarify the extent, to which these issues apply to patients with FD and to elucidate the improved organization of primary, “real world” care for these patients through a questionnaire-based approach.

Methods

Study cohort

In this cross-sectional clinical study, 103 patients were recruited from (I) Department of Congenital Heart Disease and Pediatric Cardiology at German Heart Centre Munich (Technical University Munich); (II) Klinikum rechts der Isar (Technical University of Munich); (III) Institute for Congenital Metabolic Diseases of Paracelsus Medical University Salzburg; (IV) University Hospital Cologne; (V) Klinik für Herz- und Kreislauferkrankungen at German Heart Centre Munich (Technical University of Munich) and (VI) the insurance company “AOK Bayern”. While patients were recruited consecutively in institutions (I)–(V), purposive sampling was carried out in (VI). The “AOK Bayern” provided the questionnaires to their policyholders with FD in Bavaria, and the “Morbus Fabry Selbsthilfegruppe e.V.” (MFSH; German acronym for Fabry patient organization), invited its members to participate in the study online. This study was part of the nationwide VEmaH study, aiming to assess the real-life health care status and issues of FD patients in Germany and Austria. Data collection took place between August 2022 and April 2024. The study was conducted in accordance with the Declaration of Helsinki. Guidelines on Good Pharmacoepidemiological Practice (GEP) were followed.

The implementation of this health care study was approved by the ethics committees of the Technical University of Munich (VN: 484/20 S; 14.08.2020), the federate state of Salzburg (VN: 1007/2021; 08.04.2021) and the University Hospital of Cologne (VN: 21-1217; 24.07.2021). In addition, there is an approval from the Bavarian State Ministry for Health and Care. The study was registered in the German Registry of Clinical Studies (DRKS) under the reference number DRKS00022897. Informed consent was obtained from all individual participants.

Patient inclusion and classification

Inclusion criteria were (I) a confirmed diagnosis of FD; (II) patient age of at least 18 years; (III) necessary physical, cognitive and linguistic ability; and (IV) a complete, written patient information and consent form for the research project. Exclusion criteria was not meeting one of the above-mentioned inclusion criteria.

Questionnaire

Each patient received (I) patient information; (II) a declaration of consent; and (III) a 32-question questionnaire (see Appendix available at https://cdn.amegroups.cn/static/public/cdt-24-483-1.pdf), most of which contained multiple-choice questions.

As this study is the first investigation of the care situation of FD patients, no valid, standardised questionnaire was available. To ensure comparability, this questionnaire was designed to be structurally similar to those used in previous projects of the German VEmaH study. Eight aspects were evaluated: (I) socio-demographic variables; (II) comorbidities and secondary diseases of FD; (III) patient care structure; (IV) need for counselling; (V) information about FD and its care; (VI) quality of life (QoL); (VII) the patient’s subjective care situation; and (VIII) problems and challenges. Moreover, a validated questionnaire measuring QoL [European Quality of Life 5 Dimensions-5 Levels questionnaire (EQ-5D-5L)] from the patient’s perspective was included (15). The crosswalk-index-value (utility index) of the EQ-5D-5L was calculated using the German value set (16). Overall quality of life (OQL) was determined using the formula: OQL = [Disease Impact Visual Analog Scale (DIV) + Visual Analogue Scale (VAS)]/2. The questionnaire was completed either in person during a hospital stay or sent in via mail or fax, reflecting Patient Reported Outcome Measures (PROM). This result ensures unbiased data without interpretation, as it captures the subjective perception without clinician assessment (17).

Statistical analysis

Data analysis was performed using SPSS 28.0.0.0 (IBM Inc., 2021, Armonk, NY, USA). Descriptive statistical methods were used for data analysis and initial characterization of the study population. Gender differences were assessed and evaluated using the chi-square test. For ordinal variables, non-parametric rank correlation was calculated using Spearman-Rho. Continuous data were expressed as mean ± standard deviation/median [range], and categorical or interval-scaled variables as absolute numbers or percentages. All tests for significance were two-sided. A P value <0.05 was considered significant. Since multiple answers were permitted for some questions, the number of received responses may differ from the total number of study participants.

Results

A total of 103 patients, aged 49.3±16.2 (range, 18–94) years, were included in this cross-sectional clinical study. The mean age of the 63 female participants was 48.2±17.7 (range, 18–94) years, not differing significantly from that of the 40 male participants [51.3±13.4 (range, 25–82) years].

Comorbidities and secondary disease

Table 1 shows the frequencies of comorbidities/secondary diseases or symptoms of FD: hearing loss/tinnitus (45.6%), sensitivity to heat and cold, reduced sweating (43.7%), and gastrointestinal problems such as diarrhoea, abdominal cramps and vomiting (39.8%). Also, different cardiovascular problems were mentioned frequently. Twelve patients (11.7%) reported no comorbidities and/or secondary diseases.

Medical care structure of Fabry patients

General practitioners (GPs) provided medical care in 83.5% of the cases. In 61.2% of the cases, internists were involved in the specific care for FD, of whom 64% were nephrologists. The detailed GP care situation of FD patients, related to both general medical problems and Fabry-specific questions, is shown in Table 2.

Only 30.2% of the patient cohort was connected to a FD patient organization.

Need for counselling

The greatest need for counselling was related to old-age insurance (= specific German insurance model through which those covered are financially secure in old age; 40.0%), diet and exercise behaviour (39.8%), and resilience in everyday life (37.9%). The full spectrum of counselling needs can be seen in Figure 1.

Figure 1 Need for counselling (in percentage).

Knowledge about FD and its care

Knowledge about FD and its care was calculated using variables presented in Table 2, which included awareness of Fabry competence centres, sufficient information about Fabry-specific care centres and FD patient organizations. Awareness of FD competence centers was limited, with only 64.1% of patients being sufficiently informed about specialized FD care. Whether the GP was aware of the presence of Fabry was also considered.

Data also showed that 66.7% of the patient population was well informed about FD, while 33.3% of patients were poorly informed or not informed at all. Specialised FD centres were known to 89.7%, but only 64.1% felt sufficiently informed about them.

QoL

QoL data are presented in Table 3. Pain and physical discomfort were the most frequent impairments of QoL (64.1%). Furthermore, 45.5% of the patients reported problems with everyday activities, and 40.8% had anxiety or depression. The German Index Value of the patient cohort was 85.1±16.0 and the VAS 71.1±20.7. Overall QoL, calculated from the Index Value and the VAS, was at 79.1±17.4.

Subjective care situation of the patient

The subjective assessment of the medical care situation, evaluated using school grades (1= best grade to 6= poor grade), showed that patients felt well cared for regarding FD (2.01±1.02) and general medicine (2.02±0.96).

Problems and challenges

FD specific treatment (enzyme replacement therapy, chaperone therapy) leads to high therapy costs. The majority (65.4%) of patients in the cohort received such cost-intensive, targeted FD treatments. Only 21.2% of the patients in our cohort took no medication (even no symptomatic therapy, e.g., pain medication) at all. There was a significant difference (P=0.002) between men and women, with female patients far more likely (n=18) to not take any medication compared to male patients (n=2). Problems due to medication prescription (e.g., prescription only in Fabry centers due to high costs of the medication) were reported by 10.1% of the patients. As any patient with a definite diagnosis of FD is entitled to treatment regardless of cost, this may be due to misinterpretation. For example, some patients see the common mutation D313Y as the cause of their symptoms, but doctors classify this mutation as a genetic variant of unclear significance (GVUS) or a benign form.

Discussion

This study, conducted as part of the VEmaH project, is the first to depict the real medical care situation of FD patients in Germany and to identify existing deficits. The questionnaire survey aimed to generate a comprehensive picture of the current care situation in everyday’s life of a FD patient. It addressed sociodemographic variables, comorbidities and secondary diseases of FD, patient care structure, counselling needs, level of information about FD and its necessity of care, QoL, the real care situation of the patients and future challenges for optimising care. According to the Fabry patient organization, there are currently an estimated diagnosed 700 Fabry patients in Germany, although the number of unreported cases may be high (18). Various studies show incidences rates ranging from 1:3,100–1:476,000 (1,6,19). This indicates that diagnostic algorithms for early detecting FD patients should be improved, and it is crucial to record the care situation of FD patients and address identifiable deficits. The present study of the status quo, being the first of its kind, contributes to this understanding.

Sex distribution

Due to the X-linked inheritance of FD, it was formerly assumed that women are only gene carriers. Thus, they still receive the diagnosis of FD less frequently than men, often exhibiting a lower symptom burden (1). Unexpectedly, 61.2% of the questionnaires were answered by women. Data from 2007 show that heterozygous women often have symptomatic FD, with 91% showing multisystemic involvement (1,20). There is no evidence that the distribution of the questionnaires represents a systematic selection bias by the AOK Bavaria (Bavaria, Germany) (50.8% females) or the participation initiated by the MFSH with a membership share of 63.2% women (21). A study from 2019 also shows a significant difference (P<0.001) in the motivation to complete a paper-pencil questionnaire, with women being more motivated than men (22).

Comorbidities and secondary disease

Published data from 2019 show that 20.3% of the world’s population suffers from hearing loss (23). The present FD survey demonstrates that hearing loss/tinnitus was the most frequently reported symptom, accounting for 45.7% (n=47). A study from 2006 showed that 86% of Fabry patients had a measurable hearing loss (24), and an average of 7 years elapses between the personal perception of hearing loss and the start of treatment (25). In contrast to the Fabry Outcome Survey, which shows that women (23.4%; n=70) are less likely affected than men (45.7%; n=142) (24), we did not find a significant difference in this regard.

Problems, such as stroke, cardiac arrhythmias, heart failure and coronary artery disease were common comorbidities in the present study population. Compared with a survey by Sims et al. (26), where 4.3% of women and 6.9% of men with FD had a stroke. Cardiac arrhythmias (20.4%) were slightly less common in this questionnaire survey than in a study by Yousef et al. (27), which showed a prevalence of 27–42% (female: 27%; male: 27–42%).

Heart failure was mentioned more frequently than in the survey by Pinderski et al. (28), with 11% in men and 6% in women in this study. This could be due to the approximately higher age difference of 11 years (49.3 vs. 38.2 years) in the cohort examined in this study.

In conclusion, cardiovascular diagnosis and therapy are important as cardiac manifestations are both common and the most frequent cause of death in Fabry patients (40.0% in males and 41.7% in females) (29).

Gastrointestinal symptomatology, such as diarrhoea, vomiting or abdominal pain was reported by 39.8% (n=41) of participants (female: 39.6%, n=25; male: 40.0%, n=16). A study from 2007 shows a prevalence of 52% regarding gastrointestinal symptoms in Fabry patients, with women being more frequently affected compared to men (30). Further research is needed on the pathophysiology and therapeutic influence on these symptoms.

Heat and cold sensation disorders as well as reduced sweating, characteristic of FD, were found in the present study with a prevalence of 43.7% (41.9% in women vs. 46.3% in men). In the literature heat perception disorders occur at a median age of 12 years in male patients and 18 years in female patients. The Fabry Outcome Survey reveals that 44% of women and 48% of men suffer from heat intolerance, often accompanied by hypohidrosis (31). The median age of manifestation, which is significantly earlier than the average age of the patient population in both women and men, suggests that these sensory disturbances, should they manifest, are usually already present before the diagnosis of FD is made. This may explain the similar prevalence rates.

Informedness of GPs

There is no literature on GP care for Fabry patients. The knowledge of GPs about the presence of FD is important because patients usually use the GP as the first point of contact for acute problems. Therefore, GPs play a decisive role in further Fabry-specific care, which can only be provided if the GP is informed about this disease (14). In the present study, 86.4% of the treating GPs were aware of their patient’s FD. Even in the case of FD-specific problems, GPs often remain the first point of contact.

Medical care structure

The present study showed that 64.2% of patients are treated by their GP in collaboration with an internal medicine specialist. This Fabry-specialised care is mostly provided by nephrologists, although only 17.5% of patients participating in this cross-sectional study suffer from renal dysfunction and only 1.0% require dialysis. But analysis of registry data reported proteinuria in 44% of males and 33% of females leading to end-stage renal disease (ESRD) in 17% of males (30). There are probably several reasons for the dominance of nephrologists in centres für rare diseases. First, proteinuria is an early manifestation of Fabry nephropathy; second, nephrologists often deal with other multisystem diseases (32); and third, FD competence centres are often affiliated with nephrology clinics.

Counselling needs

The present study shows that the counselling needs of FD patients are manifold. The increased need for counselling on retirement pension is due to multiple disabilities FD may suffer from, often resulting in premature retirement, the advanced median age of the patient, and the reduced life expectancy as well as physical limitations and mental health impairments. In our study, we also found a high interest in counselling on dietary behaviour, which is clinically relevant due to possible gastrointestinal involvement and disruption of the enteric nervous system in FD. Similar information deficits have also been shown by Francini-Pesenti et al. (32), who found that nutrition is hardly addressed in FD (32). Counselling on physical activity behaviour was also requested due to the reduced physical potential of many FD patients.

Level of knowledge about care structures and Fabry patient organizations

The fact that only about two thirds of the patient collective have full knowledge of the institutions relevant in FD indicates a considerable information deficit. Future research could explore the reasons for the disproportionate lack of affiliation to these institutions. Patient organisations are an important instrument in the long-term care of chronically ill people (33). A telephone health survey of the Robert Koch Institute (RKI) on chronic diseases shows that 9% of all adults (men 7.7%; women 9.9%) have contacted such a group at least once (34). The German Fabry patient organization (MFSH) offers patient-specific information and the opportunity to exchange ideas with other individuals also affected by the disease, which is a relevant and helpful component of follow-up programmes (35). Only 61.2% of the interviewed patients were aware of the MFSH, with women being more often informed than men. A comparison of the data from the present study with the RKI telephone health survey shows that women with FD are 3.7 times and men 4.3 times more likely affiliated to patient organizations than other chronically sick patients. FD patients are presumably more frequently connected to a patient organization group than the general population, since the general population also includes people without diseases, who usually do not participate in a patient support organisation.

Quality of life (EQ-5D-5L)

In order to investigate the care situation of FD patients besides the care structure, the index value of mobility, self-care, daily problems as well as pain and anxiety was calculated by the standardised EQ-5D-5L questionnaire. The mean value was 85.1, with women having a lower value than men. In comparison, a Spanish survey using the same questionnaire in patients with diabetes mellitus, a multisystem disease, found a mean value of 74.2 (36). It is questionable whether the lower Index Value in diabetes mellitus is due to the severity of the disease or whether the two patient collectives do not allow for a representative comparison. Here, the average patient age could be of importance. A study from 2021 by Marten et al. (37) showed a negative correlation between patient age and the EQ-5D-5L Index Value.

Limitations

The present study is the first to deal with the real-life medical care situation of Fabry patients. Therefore, no comparative data from the scientific literature are available, providing an opportunity for future research projects.

The study has a geographical limitation, as the majority of questionnaire responses came from Germany. It is not known whether the AOK Bavaria is a representative mean of the German population. Since part of the patient recruitment took place primarily via this health insurance fund, a selection bias may exist. For data protection reasons, it was unfortunately not possible to specify the exact variants in these patients. Therefore, the benign D313Y variant may also be included to a small extent in our study population.

Furthermore, participation in this study was voluntary. Therefore, a volunteer bias can result in a distortion of the study results. In this case, people with a certain characteristic are more likely to participate in the study. Patients interested in their disease may not represent the overall FD population. Thus, the results and interpretations should be considered only with certain restrictions.

Fabry competence centres offer specialised, interdisciplinary therapy, but many patients and referring physicians may not be fully aware of these facilities. Most patients in this study were recruited by FD centers, and patients in these competence centres have been in continuous follow-up for years or even decades.

Conclusions

Despite the availability of multidisciplinary care across at least 24 FD competence centres throughout Germany, these facilities are infrequently consulted, primarily due to a lack of patient and GP awareness. Thus, the study results indicate relevant shortcomings in the medical care of FD patients. Furthermore, one third of the patients is mainly treated by GPs for both general medical issues and FD-specific problems, highlighting a lack of interdisciplinary treatment. It can also be an expression of a two-part care structure, where Fabry centres, often at a university, are responsible for confirming the diagnosis and making treatment decisions, and the GPs are responsible for prescribing the FD medication and carrying out the infusion. Fabry patients require immediate information on available care structures. There is a clear need for information dissemination among both patients and the GPs responsible for their care. Patient organizations, which are an important element in the care of chronically ill patients, are underutilized by FD patients. The lack of motivation, but also the lack of knowledge could be improved through education on the benefits of such groups.

The study also reveals a substantial and varied need for counselling among FD patients, which is currently inadequately addressed. The most frequently requested counselling pertains old-age insurance, daily resilience, nutrition and exercise behaviour. Consequently, a comprehensive counselling concept should be developed and made accessible to both patients and GPs. The data suggest that this care issue may be even more pronounced in other countries with less established or limited care structures. Thus, international research projects should be initiated to better understand and address the medical care of Fabry patients.

Acknowledgments

The authors thank the “Deutsche Herzstiftung e.V.”, “Herzkind e.V.”, “Sanofi Genzyme” and also the German health insurance company AOK-Bayern for providing sustainable support to foster research and practice in the field of congenital cardiology and Fabry disease.

Footnote

Provenance and Peer Review: The article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy for the series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part VI”. The article has undergone external peer review.

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-483/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-483/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-483/coif). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part VI” was commissioned by the editorial office without any funding or sponsorship. H.K. served as the unpaid Guest Editor of the series, and received Grant (IIS) Sanofi Genzyme. O.M. received support from Lilly, Novartis and AbbVie. T.T. received funding from the Deutsche Herzstiftung (F/21/20), the Else Kröner-Fresenius Foundation (Clinician Scientist Grant) and the DZHK (81X2300513). T.T. has received speaker and travel grants from: Pfizer, Alnylam, Novartis, Astra Zeneca, Bayer, Bristol Myers Squibb, Alexion and Boehringer Ingelheim and research grants from Pfizer which are all unrelated to this work. S.F. received research funding from Sanofi in the form of an Investigator-Initiated Study (IIS) grant. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The implementation of this health care study was approved by the ethics committees of the Technical University of Munich (VN: 484/20 S; 14.08.2020), the federate state of Salzburg (VN: 1007/2021; 08.04.2021) and the University Hospital of Cologne (VN: 21-1217; 24.07.2021). In addition, there is an approval from the Bavarian State Ministry for Health and Care. The study was registered in the German Registry of Clinical Studies (DRKS) under the reference number DRKS00022897. Informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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