Advances in the treatment of NMDs has brought to the limelight the need for an accurate genetic diagnosis, early in the disease process, to allow treatments to be most effective.
This is the first study to specifically assess the knowledge and the needs of NMD POs concerning screening methods. We included responses from POs from 18 countries (17 are part of the EU) with ethnically and genetically heterogeneous populations and different economic backgrounds.
The knowledge of the individual POs regarding the availability of screening methods in the different countries is quite uneven, independently of being “all-NMD” or disease-specific organisations. This implies that, even in communities highly motivated and knowledgeable of the conditions they advocate for, there is a need for better information. The different European countries, through their health services, should make available in lay language accurate information regarding the different screening techniques available in their health systems.
According to the report from the JRC from 2007 on “Preimplantation Genetic Diagnosis in Europe” [ref. 10] PGD is well established in Europe and provided in many European countries. Regulations, practices, professional standards and accreditation requirements are markedly different between the Member States. According to this report, 21 European countries can offer PDG and/or IVF with an equal distribution between private and public centres. With the PGD only centres concentrating in the private sector (78%).
More than half of the countries according to the POs in our survey have PGD in place. The fact that we got conflicting responses from POs in the same country prompted us to compare our answers with the ones given by professionals in the JRC survey. The countries that were part of the JRC survey did not overlap exactly with the ones in our survey, and this made data comparison slightly difficult. Countries in our survey that were not present in the JRC survey were Bulgaria, Luxembourg, Poland, Serbia, North Macedonia, and Romania. On the other hand, we were not able to collect answer from POs from Austria, Cyprus, Finland, Hungary, Lithuania, Slovakia, Sweden and Turkey. The conflicting responses came from Spain and Romania; and in fact, Spain is one of the countries with more centres in Europe offering this service and one of the biggest cross border providers. In Romania, PGD is still quite inaccessible due to the high costs and lack of reimbursement through the public health system. [ref. 11]. POs in Czech Republic, Denmark, Italy, Luxembourg, North Macedonia, Poland, Serbia and Switzerland are unaware of the possibility of PGD in their country however it is available in , the Czech Republic, Denmark, Italy and Switzerland. [ref. 10; 12; 13]
The discrepancies we have observed in the answers might also be due to the modalities (public or private services) of PGD offer in each country. Indeed, it is conceivable that knowledge about the existence of the private laboratories might not be so accurate; explaining in part the inconsistent in the data.
Prenatal screening is, according to our survey, well disseminated across the different countries. Once more, we got a discordant answer from centres in Spain that may reflect a lack of awareness and means that there is a need for education and good dissemination of information. For Portugal and Switzerland POs stated that prenatal screening is not available. Portugal has in place since July 1997 an official text concerning organisation and procedures of prenatal diagnosis (PND) at the national level . In addition, Switzerland has a PND policy in place for foetal malformations. . There is a lack of information in the literature regarding the present policies and offers of PND across Europe. The NMDs most frequently referred to as being covered were DMD, SMA, CMT, ALS, MG, DM, LGMD and AM. The authors believe that, once more, these answers reflect a lack of information regarding the techniques and the diagnostic possibilities of PND.
In Europe, each country develops and is responsible for its health care policy, including on newborn screening. According to the report on the practices of newborn screening for rare disorders (RP-NBS) from 2016  the vast majority of European countries have laws or regulations mandating newborn screening, however in only a few of these countries there is an obligation to participate to the NBS plan. All European countries, except Albania, have NBS programs, the main differences being the number of diseases included, between 1 and 30. Most of the diseases screened are metabolic disorders (that includes some NMD), endocrinological and haematological conditions and cystic fibrosis. In our survey, POs from 4 countries (France, Serbia, North Macedonia and Switzerland) were not aware of the existence of an NBS program in their country.
POs mentioned that the same NMD, as in the PNS question, were included in the NBS programs. However, the current techniques cannot detect some of them. Additionally, most countries still base their decision to add a disease to an NBS panel in the criteria by Wilson and Jungner from 1968 . These criteria are based mostly on the fact that the disorder would benefit from earlier intervention. The approval of treatments for POMPE Disease, SMA and DMD have launched the debate across the different stakeholders regarding the need to include these diseases in the NBS programs. Historically NBS for DMD started in 1975 in the USA with the measurement of creatinine kinase on newborn male blood spots. More than ten programs were implemented over time around the globe (Wales, France, Australia, China, New Zealand, Cyprus, Belgium, Germany, Canada, Scotland, and the United States) . However, as of today none of them led to the introduction of DMD to any national screening program. The first pilot program for Pompe disease began in 2005 in Taiwan. Currently, NBS for POMPE is available in Italy  and was refused in The Netherlands in 2015 because it was not possible to distinguish between the infantile and adult forms of Pompe, which would not be eligible according to the Wilson et al criteria. The inclusion could be reconsidered if this distinction become available. With the approval of nusinersen in late 2016, spinal muscular atrophy is being considered for NBS across the world  and several pilots are running in Europe (Southern Belgium, Germany and Italy). [21; 22]. This situation raises serious issues since to achieve therapeutic benefit infants need to be screened and treated soon after birth (according to the concept of therapeutic temporal window) and on the other hand, most countries face technical and economic difficulties to implement NBS. The delay between drug approval and NBS implementation dramatically impairs patients’ conditions with very diverse outcomes from one country to another.
Health policies must acknowledge the idiosyncratic nature and varied aetiology of rare diseases, meet the needs of people diagnosed with rare diseases, take into account it rapidly moving landscape and aim to improve management and reduce the associated human, community and system cost. To achieve these goals is essential to take in consideration the Patients views regarding the different policies. In our study, we were interested in assessing the views of POs regarding screening for genetic, inherited NMDs. Independently of the ethnic and cultural heterogeneity, most POs (28 out of 30) were in favour of screening for the disease (s) relevant for the organisation irrespectively of the existence of a disease-modifying medical treatment. If we consider that only few mitochondrial diseases and more recently SMA are included in national screening programs this study reveals that screening NMD is a largely unmet need. It shows as well that Wilson and Jungner criteria should evolve to take into account today’s rare disease landscape 
The motives against screening raised by two POs were cultural and religious beliefs, together with economic problems regarding insurance companies. The legislators must be able to ensure the confidentiality of the tests and should adapt the directives to the religious and cultural background of the populations. For most POs screening should be systematic with a possibility to refuse giving space for individual decision. According to POs screening should be done at birth or early in the pregnancy. The primary motivations for screening were early access to treatment followed by shorter time to diagnosis. Not surprisingly in a disease such as SMA, where there is a treatment, the consensus was to have the screening done at birth, and the main goal was early access to treatment. For DMD, the responses were more divided with the majority considering preconception screening or early pregnancy screening stressing the need for disease prevention and genetic counselling.
In conclusion, most POs are in favour of screening, preconception, early during pregnancy or as part of NBS. The motivations seem different when we are in the presence of a disease with or without a treatment. When there is no treatment, the aim is mostly the prevention of the disease via family planning. It is also interesting to note that “a shorter time to diagnosis” is a fundamental goal of the PO so that they can break the vicious circle of delayed diagnosis and associated consequences.
The responses obtained to the questions “how to screen” and “when to screen” show that decisions regarding the diseases to be included in screening programmes depends mostly on the presence of a disease modifying treatment and on the need to reduce diagnostic delay .
The screening programmes should be flexible enough to adjust to the present fast moving landscape of treatments for NMDs. This need for flexibility is not complacent with the current status quo that implies a long and heavy process to add a disease to national screening programs.
International coordination in the domain leading to common policies would certainly be a precious asset tending to harmonize the situation from one country to another and speeding up the process of adding a disease to national screening programs. This international coordination should also anticipate market authorisation to avoid that the absence of screening program prevents drug access with dramatic consequences for the patients.
Besides, recent initiatives in the domain of Artificial Intelligence or signalling instrument could contribute to cost effective solutions. Without replacing standard biological and/or genetic diagnostic tests, it could be used prior to them to assess a risk. A signalling instrument was developed in the Netherlands that detects 80% of 12-36 months old boys with Duchenne Muscular Dystrophy .
The further important consequence of early diagnosis through newborn screening is allowing family planning of reproductive choices and disease prevention, which certainly impact on quality of life of patients and families.
Strengths and limitations
A key strength of this work is its coverage of a large number of European countries with different societal backgrounds. It also states the direct opinion of PO without any filter by clinicians and is, to our knowledge and after a literature review, the first work that tries to collect patient reported data regarding screening for inherited neuromuscular diseases in Europe. The fact that we have collect a large number of answers from Spain when compared to other countries can be seen as a bias but indeed it allowed to determine how uneven is the knowledge in one country. This aspect was substantiated every time we were able to collect answers from more than one PO in the same country. Nevertheless, it is important to consider the limitations of this work when interpreting its findings. While the survey was sent to 115 PO, we have received a limited number of answers (26% of responders) and we were only able to cover 18 European countries. Though low responder percentages are common in healthcare surveys, we accept this hinders the representativeness of this study.
We will, on a second step, try to extend our survey and collect more data in each country. This will allow to better understand if the disparity found in the Spanish PO is also present in other countries.