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Background: Rare diseases, also referred to as orphan diseases, are characterised by their low prevalence with majority of them are chronically debilitating and life threatening. Given the low prevalence and the widely dispersed but very small patient base for each disease, there may often be a disproportion in the availability of treatments and resources to manage patients, spur research and train experts. This is especially true in Southeast Asian countries that are currently in the process of implementing or revising their universal health coverage schemes. This paper aims to examine the status of rare disease management in Southeast Asian countries. It will serve as the basis for a more active discussion on how countries in the region can address an under-recognised rare disease burden and enhance national and regional capacities.Methods: The study consists of literature reviews and key stakeholders interviews in six focus countries, including the Philippines, Singapore, Malaysia, Indonesia, Vietnam, and Thailand and five countries as best practice, comprising of France, Canada, Australia, Taiwan, and South Korea. Rare disease management initiatives across each country were examined based on the World Health Organization's framework for action in strengthening health systems.Results: The results suggest rare disease management remains challenging across Southeast Asia, as many of the focus countries face fundamental issues from basic healthcare systems to funding. Nonetheless, there are substantial improvement opportunities, including leveraging best practices from around the world and organising a multi-stakeholder and regional approach and strategy.Conclusions: Southeast Asian countries have made significant progress in the management of rare disease, but there remain key areas for substantial development opportunities. [ABSTRACT FROM AUTHOR]

Background: The objective of the study was to elaborate a conceptual framework related to the domains of patient experience along the cystic fibrosis (CF) journey from the patients and parents of children with CF to inform the design of a patient-reported experience questionnaire. Method: A collaborative research group including patients and parents with clinicians and academic researchers was set up. They identified the situations along the CF care pathway from diagnosis to paediatric care, transition to adult care and adult follow-up, transfer to transplant centres and follow-up after transplantation. Participants were recruited by CF centres in metropolitan France and overseas departments. Semi-structured interviews were conducted, transcribed verbatim and subjected to an inductive analysis conducted in duos of researchers/co-researchers using NVivo®. The conceptual framework was discussed with the research group and presented to the CF centres during two video conferences. The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888-no. 20-700). Results: The analysis led to a conceptual framework composed of domains of the CF journey, each divided into several items. 1. CF care: Management of care by the CF centre team; in-hospital care; quality of care in the community; therapeutic education and self-management support; at-home care; new therapies and research; procreation; 2. Transplant care: management of transplant and CF care; coordination with other specialties; education and self-management support; at-home care; procreation; new therapies and research; 3. Turning points along the journey: diagnosis of CF, transition to adult care, transfer to transplantation; 4. Social life with CF: housing, employment and education, social relations, social welfare and family finances. The number of patients included and the diversity of situations made it possible to achieve a sufficient richness and saturation of codes by domain to develop patient experience questionnaires. Conclusion: This conceptual framework, resulting from the participants' experience, will inform the design of a patient-reported experience tool, whose construct will be tested during the next phase of the ExPaParM project to assess its fidelity, intelligibility, and ability to report patient experience of the CF journey. [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by defective enzyme activity involved in the catalysis of glycosaminoglycans. Published data on adult patients with MPS remains scarce. Therefore, the present qualitative survey study was aimed at understanding knowledge of the disease, unmet needs, expectations, care, and overall medical management of adult/adolescent patients with MPS I, II and VI and their caregivers in France. Results: A total of 25 patients (MPS I, np = 11; MPS II, np = 9; MPS VI, np = 5) were included and about 36 in-depth interviews (caregivers alone, nc = 8; patients-caregiver pair, nc+p = 22; patients alone, np = 6) were conducted. Except one (aged 17 years), all patients were adults (median age: 29 years [17–50]) and diagnosed at median age of 4 years [0.4–30], with mainly mothers as caregivers (nc = 16/19). Patients were classified into three groups: Group A, Patients not able to answer the survey question because of a severe cognitive impairment (np = 8); Group B, Patients able to answer the survey question with low or no cognitive impairment and high motor disability (np = 10); and Group C, Patients able to answer the survey question with low or no cognitive impairment and low motor disability (np = 7). All groups were assessed for impact of disease on their daily lives based on a scale of 0–10. Caregivers in Group A were found to be most negatively affected by the disease, except for professional activity, which was most significantly impacted in Group B (4.7 vs. 5.4). The use of orthopaedic/medical equipments, was more prevalent in Groups A and B, versus Group C. Pain management was one of the global unmet need expressed by all groups. Group A caregivers expected better support from childcare facilities, disability clinics, and smooth transition from paediatric care to adult medicine. Similarly, Group B caregivers expected better specialised schools, whereas Group C caregivers expected better psychological support and greater flexibility in weekly infusion schedules for their patients. Conclusions: The survey concluded that more attention must be paid to the psychosocial status of patients and caregivers. The preference for reference centre for follow-up and treatment, hospitalizations and surgeries were evident. The most significant needs expressed by the patients and caregivers include better understanding of the disease, pain management, monitoring of complications, flexibility in enzyme replacement therapy, home infusions especially for attenuated patients, and improved transitional support from paediatric to adult medicine. [ABSTRACT FROM AUTHOR]

Background: Preliminary data suggest that COVID-19 pandemic has generated a switch from face-to-face to remote care for individuals with chronic diseases. However, few data are available for rare and undiagnosed diseases (RUDs). We aimed to assess the impact of the COVID-19 pandemic on the activities of the French reference network for RUDs in 2020. Results: In this longitudinal retrospective study, we extracted and analyzed the data of the French national registry for RUDs collected between Jan 1, 2019 and Dec 31, 2020. We compared the annual longitudinal evolution of face-to-face and remote care activities between 2019 and 2020 focusing on adult and pediatric patients. Compared to 2019, rare diseases (RD) care activities showed a decrease in 2020 (− 12%) which occurred mostly during the first lockdown (− 45%) but did not catch up completely. This decrease was mainly in face-to-face care activities. Telehealth activities showed a 9-fold increase during the first lockdown and was able to cover for one third of the decrease in RD activities. Finally, the total number of patients receiving care was lower in 2020(− 9%) with a drastic decrease of cases with newly confirmed diagnosis (− 47%). Conclusion: Although telehealth was quickly introduced during the COVID-19 pandemic, RUD patient care was strongly affected in France with a decline in the number of patients treated and new patients recruited. This is likely to result in delays in patient diagnosis and care over the next few years. [ABSTRACT FROM AUTHOR]

In France, all patients followed by Rare Disease (RD) expert centers have to be registered in the National Rare Disease Registry (BNDMR). This database collects a minimum data set including diagnosis coded using the Orphanet nomenclature. Overall, 753,660 patients were recorded from 2007 to March 2022 including 493,740 with at least one rare disease diagnosis. Among these rare disease diagnoses, 1,300 diagnoses gathered between 10 and 70 patients and 792 gathered more than 70 patients, corresponding to more than one patient per million inhabitants. A total of 47 rare disease diagnoses with point prevalence or incidence reported in the literature below 1/1,000,000 have more than 70 patients in the BNDMR, suggesting larger BNDMR cohorts than expected from reported literature. As a conclusion, our national RD registry is a great resource to facilitate patients' recruitment in clinical research and a better understanding of RD natural history and epidemiology. [ABSTRACT FROM AUTHOR]

Background: Transition from childhood to adulthood (TCA) is usually difficult in rare, progressive and multisystemic diseases. New treatments and modalities of care for many lysosomal diseases (LD) can increase life expectancy, and a successful TCA can help patient who reach adulthood to avoid disruption to health care. In France, some TCA initiatives have been taken by referral centers but in view of the problems encountered by Vaincre les Maladies Lysosomales (VML), the LD patient association, they seem to be insufficient. The aim of this study is to determine the current state of the TCA process and to identify actions to improve it through interviews with patient families and physicians in LD referral centers. The study is based upon an observational, non-interventional, cross-sectional, national survey which used two anonymous questionnaires. These questionnaires, developed by a scientific committee including representatives from VML and medical specialists in LD, were sent to patients who were receiving care in pediatric departments at age 15 years or older. Questionnaires were also sent to their referral pediatricians.Results: Fifty-four patients were included. Forty-two questionnaires were completed by patients and their corresponding physicians and 12 were completed by physicians only. The majority of the patients (80%) were informed that transfer to adult healthcare would occur, but 52% were informed after their eighteenth birthday. Forty-eight percent indicated that they were informed that a TCA coordinator would be appointed; for 39% the time frame for the transfer was communicated, and 31% were informed of the composition of the adult medical team. Among the actions that patients rated as "important/very important", and considered to be a priority in their comments, the most frequently cited were the provision of explanatory documents on the TCA (94%), the transmission of the medical file from the pediatric sector to the adult sector (94%) and a joint consultation with both pediatrician and adult unit physician (91%). Physicians were in agreement concerning the primary importance of the last two actions.Conclusion: This study provides a basis for the deployment, on the national level, of transition programs which include specific actions that patients view as priorities. [ABSTRACT FROM AUTHOR]

Background: Until very recently, preconception genetic testing was only conducted in particular communities, ethnic groups or families for which an increased risk of genetic disease was identified. To detect in general population a risk for a couple to have a child affected by a rare, recessive or X-linked, genetic disease, carrier screening is proposed in several countries. We aimed to determine the current public opinion relative to this approach in France, using either a printed or web-based questionnaire.Results: Among the 1568 participants, 91% are favorable to preconception genetic tests and 57% declare to be willing to have the screening if the latter is available. A medical prescription by a family doctor or a gynecologist would be the best way to propose the test for 73%, with a reimbursement from the social security insurance. However, 19% declare not to be willing to use the test because of their ethic or moral convictions, and the fear that the outcome would question the pregnancy. Otherwise, most participants consider that the test is a medical progress despite the risk of an increased medicalization of the pregnancy.Conclusion: This first study in France highlights a global favorable opinion for the preconception genetic carrier testing under a medical prescription and a reimbursement by social security insurance. Our results emphasize as well the complex concerns underpinned by the use of this screening strategy. Therefore, the ethical issues related to these tests include the risk of eugenic drift mentioned by more than half of the participants. [ABSTRACT FROM AUTHOR]

Background: Castleman disease (CD) is a rare non-malignant lymphoproliferation of undetermined origin. Two major disease phenotypes can be distinguished: unicentric CD (UCD) and multicentric CD (MCD). Diagnosis confirmation is based on histopathological findings in a lymph node. We attempted to survey all cases of paediatric CD identified to date in France to set up a national registry aiming to improve CD early recognition, treatment and follow-up, within the context of a new national reference center (http://www.castleman.fr).Methods: In 2016, we e-mailed a questionnaire to members of the French paediatric immunohaematology society, the paediatric rheumatology society and the Reference Centre for Castleman Disease to retrospectively collect cases of paediatric CD (first symptoms before age 18 years). Anatomopathological confirmation was mandatory.Results: We identified 23 patients (12 girls) with a diagnosis of UCD (n = 17) and MCD (n = 6) between 1994 and 2018. The mean age at first symptoms was 11.47 ± 4.23 years for UCD and 8.3 ± 3.4 years for MCD. The mean diagnosis delay was 8.16 ± 10.32 months for UCD and 5.16 ± 5.81 years for MCD. In UCD, the initial symptoms were isolated lymph nodes (n = 10) or lymph node associated with other symptoms (n = 7); fever was present in 3 patients. Five patients with MCD presented fever. No patients had HIV or human herpesvirus 8 infection. Autoinflammatory gene mutations were investigated in five patients. One patient with MCD carried a K695R heterozygous mutation in MEFV, another patient with MCD and Duchenne myopathy carried two variants in TNFRSF1A and one patient with UCD and fever episodes carried two heterozygous mutations, in IL10RA and IL36RN, respectively. Treatment of UCD was mainly surgical resection, steroids, and radiotherapy. Treatment of MCD included tocilizumab, rituximab, anakinra, steroids, chemotherapy, and splenectomy. Overall survival after a mean of 6.1 ± 6.4 years of follow-up, was 100% for both forms.Conclusion: Paediatric CD still seems underdiagnosed, with a significant diagnosis delay, especially for MCD, but new international criteria will help in the future. Unlike adult CD, which is strongly associated with HIV and human herpesvirus 8 infection, paediatric CD could be favored by primary activation of innate immunity and may affect life expectancy less. [ABSTRACT FROM AUTHOR]

Background: Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated.Methods: Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad.Results: Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives.Conclusions: High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms ("Medicine France Genomics 2025" Plan), in families without molecular diagnosis. [ABSTRACT FROM AUTHOR]

Background: Duchenne Muscular Dystrophy (DMD) is a rapidly progressive, lethal neuromuscular disorder, present from birth, which occurs almost exclusively in males. We have reviewed contemporary evidence of burden, epidemiology, illness costs and treatment patterns of DMD. This systematic review adhered to published methods with information also sought from the web and contacting registries. Searches were carried out from 2005 to June 2015. The population of interest was individuals with clearly defined DMD or their carers.Results: Nine thousand eight hundred fifty titles were retrieved from searches. Fifty-eight studies were reviewed with three assessed as high, 33 as medium and 22 as low quality. We found two studies reporting birth and four reporting point prevalence, three reporting mortality, 41 reporting severity and/or progression, 18 reporting treatment patterns, 12 reporting quality of life, two reporting utility measures, three reporting costs of illness and three treatment guidelines. Birth prevalence ranged from 15.9 to 19.5 per 100,000 live births. Point prevalence per 100,000 males was for France, USA, UK and Canada, 10.9, 1.9, 2.2 and 6.1 respectively. A study of adult DMD patients at a centre in France found median survival for those born between 1970 and 1994 was 40.95 years compared to 25.77 years for those born between 1955 and 1969. Loss of ambulation occurred at a median age of 12 and ventilation starts at about 20 years. There was international variation in use of corticosteroids, scoliosis surgery, ventilation and physiotherapy. The economic cost of DMD climbs dramatically with disease progression - rising as much as 5.7 fold from the early ambulatory phase to the non-ambulatory phase in Germany.Conclusions: This is the first systematic review of treatment, progression, severity and quality of life in DMD. It also provides the most recent description of the burden, epidemiology, illness costs and treatment patterns in DMD. There are evidence gaps, particularly in prevalence and mortality. People with DMD seem to be living longer, possibly due to corticosteroid use, cardiac medical management and ventilation. Future research should incorporate registry data to improve comparability across time and between countries and to investigate the quality of life impact as the condition progresses. [ABSTRACT FROM AUTHOR]

Background: Rare peritoneal cancers represent complex clinical situations requiring a specific and multidisciplinary management. Because of their rarity, lack of awareness and knowledge often leads to diagnostic delays and misdiagnosis. And patients are not systematically referred to expert centers as they should be. Clinicians and researchers also face unique challenges with these rare cancers, because it is hard to conduct adequately powered, controlled trials in such small patient population. This is how an observational patient registry constitutes a key instrument for the development of epidemiological and clinical research in the field of these rare cancers. It is the appropriate tool to pool scarce data for epidemiological research and to assess the impact of diagnostic and therapeutic strategies. We aimed to provide the outlines and the framework of the RENAPE observational registry and share our experience in the establishment of a national patient registry.Results: The RENAPE observational registry has been launched in 2010 thanks to institutional supports. It concerns only patients with a histological diagnosis confirming a peritoneal surface malignancy. A web secured clinical database has been implemented based on data management procedures according to the principles of international recommendations and regulatory statements. A virtual tumor bank is linked in order to the conduct translational studies. Specialized working groups have been established to continuously upgrade and evolve the common clinical and histological data elements following the last classifications and clinical practices. They contribute also to standardize clinical assessment and homogenize practices.Conclusions: The RENAPE Registry may improve awareness and understanding of the rare peritoneal tumors into the incidence, prevalence, recurrence, survival and mortality rates, as well as treatment practices thereby enabling therapeutic intervention to be evaluated and ultimately optimized.Trial Registration: ClinicalTrials.gov Identifier: NCT02834169. [ABSTRACT FROM AUTHOR]

Background: In 2009, a worldwide supply constraint of imiglucerase led to treatment modifications or interruptions for patients with Gaucher disease (GD) type 1. In France, joint treatment recommendations were issued to protect the most vulnerable patients. This observational study evaluated the impact of imiglucerase treatment modifications on the clinical and biological course of GD. Methods: Retrospective data on patients' characteristics, treatment, clinical and biological parameters from 01 June 2009 to 31 October 2010 were collected during a single visit. Results: Ninety-nine GD1 patients, aged 7-84 years, were included (median age 47 years); 10 were children. Patients experienced a median of 4 different treatment modifications. Median change from pre-supply constraint dose (92 U/kg/4-weeks) was -69, -51, -29 and -60 U/kg/4-weeks at 3, 6, 9 and 12 months after first modification, respectively, with imiglucerase discontinuation reported for 70%, 47%, 29% and 55% of patients at these timepoints. Replacement with another ERT was reported for 35 patients. Results show a statistically significant decrease in hemoglobin (-0.8 g/L/month) and platelets (-5905.103/mm3/month) and an increase in chitotriosidase (+537 nmol/ mL/h/month) and angiotensin-converting enzyme (+4 IU/L/month) in the subgroup of 61 patients who discontinued treatment for at least 3 months; this magnitude of change was not seen in the subgroup (32 patients) treated with reduced imiglucerase for at least 3 consecutive months. GD-related events were spontaneously reported by the study investigators for 39% of the whole study population, including asthenia/fatigue (8%), bone infarction and bone pain (4% each), and hepatomegaly (3%). A Kaplan-Meier estimate of the probability for a patient to present a bone, hematological or visceral event during the constraint was 37% for patients who discontinued the treatment and 10% for patients treated with a reduced imiglucerase dose. Conclusion: The release of recommendations and individuals' close follow-up allowed satisfactory management of patients during the imiglucerase supply constraint in France. This study suggests that during this period, lowering the dose of imiglucerase had less impact on the outcomes of patients than interrupting treatment. However, general effects (such as fatigue, bone pain) reported in some patients, emphasize the importance of maintaining appropriate individualized dosing. [ABSTRACT FROM AUTHOR]

Background: Fabry disease (FD) is a rare, X-linked, inherited lysosomal disease caused by absent or reduced α-galactosidase A activity. Due to the heterogeneity of disease presentation and progression, generic patient-reported outcome (PRO) tools do not provide accurate insight into patients' daily lives and impact of disease specific treatments. Also, the French National Health Authority, (HAS) actively encourages a patient-centric approach to improve the quality of care throughout the patient journey. In response to this initiative, we aimed to develop and validate a specific, self-reported, Patient Needs Questionnaire for people living with Fabry disease to appraise patient needs and expectations towards their treatment (PNQ Fabry). This endeavour was led with the help of French patient associations (APMF & VML) and dedicated expert centres. PNQ Fabry was developed according to the FDA/EMA methodologies and best practices for the development of PRO tools in rare diseases. Our approach comprised of three steps, as follows: concept elicitation and item generation, item reduction, and final validation of the questionnaire through a two-stage survey.Results: Intrinsic and extrinsic reliability was established, using a validated benchmark questionnaire. With the invaluable help of patient associations, we recruited a satisfactory population in this rare disease setting, to ensure robust participation to validate our PNQ (final number of questionnaires: 76). At the end of the process, a 26-item patient-reported questionnaire was obtained with excellent psychometric properties, exhibiting very satisfactory measurement outcomes for reliability and validity. The results of this initiative demonstrate that the PNQ Fabry is accurate, suitable and tailored to FD patients, as it addresses themes identified during patient interviews, that were further validated through statistical analyses of quantitative surveys. An ongoing phase IV study is using this tool.Conclusion: We believe the PNQ Fabry will be a reliable and insightful tool in clinical practice, to improve patient management in FD. [ABSTRACT FROM AUTHOR]

Background: The Cystic Fibrosis (CF) center in Roscoff (Brittany) has been involved in therapeutic education programs (TEP) since 2006 and took part in the pilot phase of the French quality improvement program (QIP) since 2011. The aim was to improve the nutritional status of children with cystic fibrosis aged 2-12 years old in order to optimize their health status as they enter adolescence.Methods: A multidisciplinary quality team was created in order to select and address a specific health problem among our pediatric population. Following analysis of yearly indicators for our CF center, our team chose to improve quality of care concerning nutritional status of children aged 2-12 years old. Factors influencing efficacy were studied, tools were developed to implement a new nutritional program, results were analyzed on a real-time basis.Results: Over the 3 year period, all patients from 2 years of age, were monitored with the new follow-up program (2012: N = 34; 2014: N = 44). Each patient was followed up at every clinic visit, their BMI z-score was calculated to decide their nutritional risk and personalize their follow-up program consequently. Between 1/1/2012 and 31/12/2014, the mean BMI z-score of the open cohort improved from -0.49 to -0.22.Conclusions: Since 2014, focus on nutrition using the newly-adapted program has become routine practice at each follow-up visit. Patients and parents expressed a high level of satisfaction (75% very satisfied). The follow-up program aimed at improving nutritional status for children aged 2-12 years old was successfully implemented and integrated into routine practice; it was therefore extended to all children with CF (1 month - 18 years) in our center. The relationship among professional and patients and parents was strengthened. [ABSTRACT FROM AUTHOR]