European Reference Network Research Articles

AAV-vectored base editor trans-splicing delivers dystrophin repair

AAV-vectored base editor trans-splicing delivers dystrophin repair

Impact of the COVID-19 Pandemic on Pediatric Surgical Scientific Formats: An ERNICA Survey on Challenges and Future Directions.

The aims of this survey were to assess the experiences of the transition from in-person to virtual meetings among European pediatric surgeons since the beginning of the coronavirus disease 2019 (COVID-19) pandemic and to identify preferences for future formats. An online questionnaire was circulated among members of the European Reference Network for rare Inherited and Congenital Anomalies Network (ERNICA) in 2022. Two time periods were compared (3 years before the COVID-19 pandemic vs. the year 2021). A total of 87 pediatric surgeons from 16 countries completed the survey. In addition, 27% of respondents were trainees/residents and 73% consultants/lead surgeons. Consultants participated in significantly more in-person congresses prior to the COVID-19 pandemic compared with trainees (5.2 vs. 1.9; p < 0.001). A significant increase in attendance of virtual meeting was reported during 2021 compared with pre-COVID-19 (1.4 vs. 6.7; p < 0.001). Consultants had experienced significantly less absenteeism thanks to virtual meetings compared with trainees (42/61 vs. 8/23; p < 0.05). Most surgeons considered virtual meetings more economic (82%), practical (78%), and family-friendly (66%). However, a majority reported missing social events (78%). The communication among attendees or between attendees and speakers or scientific faculty was deemed worse. A minority (14%) experienced equalized representation of trainees and consultants at virtual meetings. Most respondents (58%) agreed that future meeting strategies should focus on offering virtual formats. Regarding future congresses, respondents prefer hybrid (62%) over in-person (33%) or virtual (6%) formats. According to European pediatric surgeons, virtual learning formats hold multiple advantages and should be continued. Improved technology must meet the challenges, particularly to enhance communication, equal representation, and networking between attendees.

Venous thromboembolism complications in Cushing's syndrome: results of a secondary survey within the European Registries for Rare Endocrine Conditions (EuRRECa) and the European Reference Network on Rare Endocrine Conditions (Endo-ERN)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Pediatric Liver and Transplant Surgery: Results of an International Survey and Expert Consensus Recommendations.

Pediatric liver surgery is a complex and challenging procedure and can be associated with major complications, including mortality. Best practices are not established. The aims of this study were to evaluate surgeons' individual and institutional practices in pediatric liver surgery and make recommendations applicable to the management of children who require liver surgery. A web-based survey was developed, focusing on the surgical management of children with liver conditions. It was distributed to 34 pediatric surgery faculty members of the Biliary Atresia and Related Disorders (BARD) consortium and 28 centers of the European Reference Network-Rare Liver. Using the Delphi method, a series of questions was then created to develop ideas about potential future developments in pediatric liver surgery. The overall survey response rate was 70.6% (24/34), while the response rate for the Delphi questionnaire was 26.5% (9/34). In centers performing pediatric liver surgery, most pediatric subspecialties were present, although pediatric oncology was the least present (79.2%). Nearly all participants surveyed agreed that basic and advanced imaging modalities (including ERCP) should be available in those centers. Most pediatric liver surgeries were performed by pediatric surgeons (69.6%). A majority of participants agreed that centers treating pediatric liver tumors should include a pediatric transplant program (86%) able to perform technical variant grafts and living donor liver transplantation. Fifty-six percent of responders believe pediatric liver transplantation should be performed by specialized pediatric surgeons. Pediatric liver surgery should be performed by specialized pediatric surgeons and should be centralized in regional centers of excellence where all pediatric subspecialists are present. Pediatric hepatobiliary and transplant training needs to be better promoted amongst pediatric surgery fellows to increase this subspecialized workforce.

Cardiovascular risk markers in patients with spinal cord injury: the Austrian wheelchair dancer study

Journal Article Accepted manuscript Cardiovascular Risk Markers in Patients with Spinal Cord Injury: The Austrian Wheelchair Dancer Study Get access Barbara Mayr, Barbara Mayr Institute of Sports Medicine, Prevention and Rehabilitation and Research Institute of Molecular Sports Medicine and Rehabilitation, Paracelsus Medical University, Salzburg, Lindhofstraße 20, 5020 Salzburg, Austria https://orcid.org/0000-0002-2835-3938 Search for other works by this author on: Oxford Academic Google Scholar Michelle Felber, Michelle Felber Institute of Sports Medicine, Prevention and Rehabilitation and Research Institute of Molecular Sports Medicine and Rehabilitation, Paracelsus Medical University, Salzburg, Lindhofstraße 20, 5020 Salzburg, Austria Search for other works by this author on: Oxford Academic Google Scholar Vanessa Frey, Vanessa Frey Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience Salzburg, Austria. Member of the European Reference Network EpiCARE https://orcid.org/0000-0002-5337-1273 Search for other works by this author on: Oxford Academic Google Scholar Nora Renz, Nora Renz Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience Salzburg, Austria. Member of the European Reference Network EpiCARE https://orcid.org/0000-0001-8011-6684 Search for other works by this author on: Oxford Academic Google Scholar Kerstin Schwenker, Kerstin Schwenker Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience Salzburg, Austria. Member of the European Reference Network EpiCAREKarl Landsteiner Institute for Neurorehabilitation and Space Neurology, Salzburg, AustriaNeuroscience Institute, Christian Doppler University Hospital, Center for Cognitive Neuroscience Salzburg, Paracelsus Medical University, Salzburg, AustriaSpinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Austria https://orcid.org/0000-0002-0316-6108 Search for other works by this author on: Oxford Academic Google Scholar Eugen Trinka, Eugen Trinka Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience Salzburg, Austria. Member of the European Reference Network EpiCAREKarl Landsteiner Institute for Neurorehabilitation and Space Neurology, Salzburg, AustriaNeuroscience Institute, Christian Doppler University Hospital, Center for Cognitive Neuroscience Salzburg, Paracelsus Medical University, Salzburg, AustriaSpinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Austria https://orcid.org/0000-0002-5950-2692 Search for other works by this author on: Oxford Academic Google Scholar Josef Niebauer Josef Niebauer Institute of Sports Medicine, Prevention and Rehabilitation and Research Institute of Molecular Sports Medicine and Rehabilitation, Paracelsus Medical University, Salzburg, Lindhofstraße 20, 5020 Salzburg, Austria Corresponding author: Prof. Josef Niebauer, MD, PhD, MBA, University Institute of Sports Medicine, Prevention and Rehabilitation, Paracelsus Medical University, Lindhofstraße 20, 5020 Salzburg, Austria. ph.:+43(0)5 7255-23200, fax: +43(0)5 7255-23299. E-mail: j.niebauer@salk.at https://orcid.org/0000-0002-2811-9041 Search for other works by this author on: Oxford Academic Google Scholar European Journal of Preventive Cardiology, zwad128, https://doi.org/10.1093/eurjpc/zwad128 Published: 24 April 2023 Article history Received: 06 March 2023 Revision received: 18 April 2023 Accepted: 20 April 2023 Published: 24 April 2023

Pediatric Intestinal Pseudo-Obstruction: An International Survey on Diagnostic and Management Strategies in the European Reference Network for Rare Inherited and Congenital Anomalies Intestinal Failure Teams.

Pediatric intestinal pseudo-obstruction (PIPO) management is based on nutritional, medical, and surgical care while available evidence is scarce. The aim of this study was to outline the current diagnostic and management strategies in intestinal failure (IF) teams of the European Reference Network for rare Inherited and Congenital Anomalies (ERNICA) and to compare these practices to the latest PIPO international guidelines. An online survey on institutional diagnostic and management strategies of PIPO was conducted among the ERNICA IF teams. In total, 11 of 21 ERNICA IF centers from 8 countries participated. On average, 64% of teams had ≥6 and 36% had 1-5 PIPO patients under active follow-up. In total, 80 of 102 PIPO patients were parenteral nutrition (PN) dependent while each IF team had median 4 (range 0-19) PN dependent PIPO patients under follow-up. On average, each center received 1-2 new PIPO patients per year. Diagnostics mostly followed current guidelines while medical and surgical management strategies were diverse. Numbers of PIPO patients are low and management strategies are diverse among ERNICA IF teams. To improve PIPO patient care, regional reference centers with specialized multidisciplinary IF teams and continuous collaboration across centers are needed.

5610939 RARE ANAEMIA DISORDERS EUROPEAN EPIDEMIOLOGICAL PLATFORM (RADEEP)

Background: Rare Anaemia Disorders (RAD) include a highly heterogeneous group of rare and ultra-rare haematological conditions. The numbers of RAD patients included in clinical research are rarely adequate in one centre or even country. However, the lack of uniform standards for data collection has led to the implementation of patients’ registries through different approaches, gathering fragmented data and hampering collaborative projects and generation of evidence for translation into clinical practice. Aims: To promote basic and clinical research on RAD at the EU level by setting up a European epidemiological platform for the secure exchange and integration of RAD data, while securing patient rights in agreement with EU General Data Protection Regulation (GDPR). Method: The Rare Anaemia Disorders European Epidemiological Platform (RADeep) is an initiative endorsed by the European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet) under the frame of the European Blood Disorders Platform (ENROL), the ERN-EuroBloodNet umbrella for European patients’ registries on rare haematological diseases. RADeep is built in line with the ENROL and EU Rare Disease (RD) Platform. RADeep contributes to ENROL by sharing pseudonymised patient data. RADeep scope includes any type of RAD (ORPHA108997), including among others Sickle Cell Disease (SCD), Thalassaemia (THAL), enzymopathies and membranopathies. RAD patient data are collected from existing registries, hospital records or databases in the EU, with the aim to assess the prevalence, incidence and survival of RAD patients stratified by demographics and severity. Secondary objectives include the assessment of the main clinical manifestations and treatments of RAD subgroups. Results: RADeep legal frame of has been established in line with GDPR, enabling both entering medical data from available sources and re-use of data with third parties. RADeep solution is implemented ensuring interoperability with existing platforms based on the FAIRification of data through international ontologies (eg. ORPHA, HPO, ICD) and the implementation of SPIDER as the pseudonymisation tool provided by the EU-RD Platform. RADeep common data set (CDS) integrates 122 mandatory elements (including the 16 CDS for RD registration from EU-RD-Platform) and 38 optional, covering demographic and epidemiological data, clinical manifestations, laboratory exams and treatments. The modular structure of RADeep allows the expansion of the CDS with specific modules for research and clinical studies. The data collection is centralized through national contacts or scientific societies. Study sample size for SCD and THAL has been estimated on a mapping exercise, with a recruitment target of 20.627 SCD and 8.409 THAL patients in 15 EU countries. As of today, 10 ongoing collaborations represent the first pilots for data transfer to RADeep: Belgium, Cyprus, Denmark, France, Germany, Greece, Italy, Spain, Portugal, and Sweden, covering 89,6% and 95,4% of the estimated targets. Conclusion: RADeep offers a GDPR-compliant platform as the EU approach for the standardised collection of RAD patients data, key for the development of projects as the collaborations ongoing with GenoMed4ALL on artificial intelligence for personalized medicine, or INHERENT Network. RADeep will also provide the evidence to enhance clinical trials, guidelines and health policies that will allow better provision of healthcare to RAD patients accross EU.

TeleNEwCARe: An Italian case-control telegenetics study in patients with Hereditary NEuromuscular and CARdiac diseases

Telemedicine provides healthcare services remotely and represents a fundamental resource for the management of rare and fragile patients. Tele-health implementation is a main objective of the European Reference Networks (ERNs) mission to accelerate diagnosis for rare diseases.TeleNewCARe is a pilot case-control project which evaluates the efficacy and satisfaction of telegenetics for neuromuscular and cardiac adult patients, compared to face-to-face genetic counselling. The virtual sessions were co-hosted by a medical geneticist and a neurologist/cardiologist. Specific questionnaires (Clinical Genetics Satisfaction Questionnaire (CGS), Telemedicine Satisfaction Questionnaire (TSQ) and a Satisfaction Questionnaire for medical geneticists) were used to assess the effectiveness and fulfilment of telecounselling, both for patients and health care providers.Satisfaction expressed for telegenetics did not significantly differ from face-to-face counselling. The virtually enrolled patients declared they had the possibility to relate confidentially with the specialists, to share information and to be informed in an exhaustive way about their disease. Almost all patients declared themselves willing to reuse the telecounselling in the future. The multidisciplinary care was perceived as a significant added value. No overt technical problems were reported although the need for digital skills and tools can limit patients’ compliance.Our experience supports telegenetics as a valid alternative to traditional genetic counselling in cardiac and neuromuscular patients. This innovative approach facilitates multidisciplinary care, grants a periodical follow up, without forcing patients to discomfortable travelling, and allows to maintain expert care. This result meets the ERNs needs to reduce patients’ burden to access and monitor their healthcare.

Etiology and Outcome of Adult and Pediatric Acute Liver Failure in Europe.

Acute liver failure (ALF) is rare but life-threatening. Common causes include intoxications, infections, and metabolic disorders. Indeterminate etiology is still frequent. No systematic data on incidence, causes, and outcome of ALF across Europe are available. Via an online survey we reached out to European Reference Network Centers on rare liver diseases. Numbers and etiology of ALF cases during 2020 were retrieved and diagnostic and treatment availabilities assessed. In total, 455 cases (306 adult, 149 pediatric) were reported from 36 centers from 20 countries. Intoxication was the most common cause in adult and pediatric care. The number of cases with indeterminate etiology is low. Diagnostic tools and specific treatment options are broadly available within this network. This is the first approach to report on etiology and outcome of ALF in the pediatric and adult population in Europe. High diagnostic yield and standard of care reflects the expert status of involved centers.

The observational clinical registry (cohort design) of the European Reference Network on Rare Adult Solid Cancers: The protocol for the rare head and neck cancers.

Care for head and neck cancers is complex in particular for the rare ones. Knowledge is limited and histological heterogeneity adds complexity to the rarity. There is a wide consensus that to support clinical research on rare cancer, clinical registries should be developed within networks specializing in rare cancers. In the EU, a unique opportunity is provided by the European Reference Networks (ERN). The ERN EURACAN is dedicated to rare adults solid cancers, here we present the protocol of the EURACAN registry on rare head and neck cancers (ClinicalTrials.gov Identifier: NCT05483374). Registry-based cohort study including only people with rare head and neck cancers. to help describe the natural history of rare head and neck cancers;to evaluate factors that influence prognosis;to assess treatment effectiveness;to measure indicators of quality of care. Settings and participants It is an hospital based registry established in hospitals with expertise in head and neck cancers. Only adult patients with epithelial tumours of nasopharynx; nasal cavity and paranasal sinuses; salivary gland cancer in large and small salivary glands; and middle ear will be included in the registry. This registry won't select a sample of patients. Each patient in the facility who meets the above mentioned inclusion criteria will be followed prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for the patient follow-up. Variables Data will be collected on patient characteristics (eg. patient demographics, lifestyle, medical history, health status); exposure data (eg. disease, procedures, treatments of interest) and outcomes (e.g. survival, progression, progression-free survival, etc.). In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will be also collected. Statistical methods The data analyses will include descriptive statistics showing patterns of patients' and cancers' variables and indicators describing the quality of care. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause specific mortality will be used to determine independent predictors of overall survival, recurrence etc. Variables to include in the multivariable regression model will be selected based on the results of univariable analysis. The role of confounding or effect modifiers will be evaluated using stratified analysis or sensitivity analysis. To assess treatment effectiveness, multivariable models with propensity score adjustment and progression-free survival will be performed. Adequate statistical (eg. marginal structural model) methods will be used if time-varying treatments/confounders and confounding by indication (selective prescribing) will be present. The registry initiated recruiting in May 2022. The estimated completion date is December 2030 upon agreement on the achievement of all the registry objectives. As of October 2022, the registry is recruiting. There will be a risk of limited representativeness due to the hospital-based nature of the registry and to the fact that hospital contributing to the registry are expert centres for these rare cancers. Clinical Follow-up could also be an issue but active search of the life status of the patients will be guaranteed.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol

Background Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials. Methods and analysis The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions. Ethics and dissemination Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.

Exploring the values, preferences, and information needs of patients with NKX2-1-related disorders: A qualitative study protocol.

NKX2-1-related disorders have a prevalence of 1:500,000 and are therefore considered a rare condition according to the European Commission's definition. The European Reference Network of Rare Neurological Disorders is developing the first clinical practice guideline on the management of this condition, with the support of the Andalusian Health Technology Assessment Area, Endo-ERN, ERN-Lung and Imegen, within the framework of the ERNs Guidelines programme (DG SANTE/2018/B3/030). Within the scope of this programme, it becomes necessary to explore the patient perspective in order to include it in the ongoing clinical practice guideline and accompanying patient information booklet. This study will use qualitative methods to explore the values, preferences and information needs of patient with NKX2-1-related disorders and their caregivers. Participants will come from a variety of countries throughout Europe. One focus group and four semi-structured interviews will be conducted. Pairs will analyse the data using Grounded Theory. The Andalusian Regional Ministry of Health's Ethics Coordinating Committee for Biomedical Research (Sevilla, Andalucía, Spain) has approved this study protocol (29/03/2022). This is the first study to explore the values, preferences, and information needs of patients with NKX2-1-related disorders. The proposed study's findings will contribute to the generation of useful knowledge that will provide guidance to improve the care given to patients with the studied condition. While this study will provide valuable insights into the perspectives of patients with NKX2-1-related disorders, the findings are unlikely to be generalizable to patients with other conditions.

Mapping of the current transition of care practice for patients with pituitary disease at Endo-ERN reference centers.

Rare endocrine conditions present specific diagnostic and management challenges for healthcare providers, one of which is the understudied transition of care. Despite the need for guidance regarding transition, consensus on structured and protocolled approaches is lacking. Therefore, we aimed to map the current clinical practice and identify unmet needs regarding transition of care for patients with pituitary disease in the reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). A survey-based, cross-sectional study using the EU Survey tool was performed and completed by 46 physicians (n) from 30 RCs (N). Transition is a common practice among RCs (n = 44/46), usually accomplished by a multidisciplinary team meeting (N = 20/30). Criteria for start and end of transition were defined in half of the RCs, with 16.7% of centers providing dissimilar answers. Transition readiness was assessed by >75% of the RCs, mostly by unvalidated means (e.g. subjective opinions, informal consultations). Pituitary-specific transition assessment tool was applied in one RC only. Transition protocols were present in only 9% of RCs, while in many RCs, transition decisions were taken in combined adult-pediatric meetings or based on clinicians' personal judgment. A minority of physicians evaluated the effectiveness of transition-related interventions (n = 11/46) or medical outcomes (n = 8/46). Patient-reported outcome measures were infrequently used (n = 4/46). Identified unmet needs included the development of guidelines (n = 5/46) and EU-wide approach (n = 2/46). This study exemplifies the unmet needs for a structural definition of the transition period and transition management for patients with rare hypothalamic and pituitary conditions from healthcare providers' perspective.

Evaluation of Tofacitinib in Primary Sclerosing Cholangitis and Associated Colitis: A Multicenter, Retrospective Study

Evaluation of Tofacitinib in Primary Sclerosing Cholangitis and Associated Colitis: A Multicenter, Retrospective Study

Outcome of COVID-19 infections in patients with adrenal insufficiency and excess.

Information on clinical outcomes of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce. A collaboration between the European Society of Endocrinology (ESE) Rare Disease Committee and European Reference Network on Rare Endocrine Conditions via the European Registries for Rare Endocrine Conditions allowed the collection of data on 64 cases (57 adrenal insufficiency (AI), 7 Cushing's syndrome) that had been reported by 12 centres in 8 European countries between January 2020 and December 2021. Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID-19 infection was confirmed by testing. Primary insufficiency was present in 45/57 patients; 19 were affected by Addison's disease, 19 by congenital adrenal hyperplasia and 7 by primary AI (PAI) due to other causes. The most relevant comorbidities were hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2.0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patients. Two patients were administered i.m. injection of 100 mg hydrocortisone, and 11/64 were admitted to the hospital. Two patients had to be transferred to the intensive care unit, one with a fatal outcome. Four patients reported persistent SARS-CoV-2 infection, all others complete remission. This European multicentre questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcomes in case of duly dose adjustments and emphasizes the importance of patient education on sick day rules.

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

PurposeWithin the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. MethodsData from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. ResultsWe identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). ConclusionThe “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.

Incidence of Isolated Biliary Atresia during the COVID Lockdown in Europe: Results from a Collaborative Project by RARE-Liver.

Biliary atresia (BA) is a rare cholangiopathy where one of the proposed aetiological mechanisms is an infectious viral trigger. Coronavirus disease-19 (COVID) lockdown restrictions were implemented to reduce the transmission of infections. Strictness of lockdown varied across European countries. This study aimed to investigate if there was an association between strictness of lockdown and change in isolated BA (IBA) incidence in Europe. We approached European centres involved in the European Reference Network RARE-LIVER. We included IBA patients born between 2015 and June 2020. We calculated the number of IBA patients born per centre per month. The Stringency Index (SI) was used as lockdown strictness indicator. The association between percentage change of mean number of IBA patients born per month and the SI was assessed. We included 412 IBA patients from thirteen different centres. The median number of patients per month did not change: 6 (1-15) pre-lockdown and 7 (6-9) during lockdown (p = 0.34). There was an inverse association between SI and percentage change in IBA (B = -0.73, p = 0.03). Median age at Kasai portoenterostomy (days) did not differ between time periods (51 (9-179) vs. 53 (19-126), p = 0.73). In this European study, a stricter COVID-lockdown was seemingly accompanied by a simultaneous larger decrease in the number of IBA patients born per month in the lockdown. Results should be interpreted with caution due to the assumptions and limitations of the analysis.

Antiseizure Medication Withdrawal Practice Patterns: A Survey Among Members of the American Academy of Neurology and EpiCARE.

To describe neurologist practice patterns, challenges, and decision support needs pertaining to withdrawal of antiseizure medications (ASMs) in patients with well-controlled epilepsy. We sent an electronic survey to (1) US and (2) European physician members of the American Academy of Neurology and (3) members of EpiCARE, a European Reference Network for rare and complex epilepsies. Analyses included frequencies and percentages, and we showed distributions through histograms and violin plots. We sent the survey to 4,923 individuals; 463 consented, 411 passed eligibility questions, and 287 responded to at least 1 of these questions. Most respondents indicated that they might ever consider ASM withdrawal, with respondents treating mostly children being more likely ever to consider withdrawal (e.g., medical monotherapy: children 96% vs adults 81%; p < 0.05). The most important factors when making decisions included seizure probability (83%), consequences of seizures (73%), and driving (74%). The top challenges when making decisions included unclear seizure probability (81%), inadequate guidelines (50%), and difficulty communicating probabilities (45%). Respondents would consider withdrawal after a median of 2-year seizure freedom, but also responded that they would begin withdrawal on average only when the postwithdrawal seizure relapse risk in the coming 2 years was less than 15%-30%. Wide variation existed in the use of words or numbers in respondents' counsel methods, for example, percentages vs frequencies or probability of seizure freedom vs seizure. The most highly rated point-of-care methods to inform providers of calculated risk were Kaplan-Meier curves and showing percentages only, rather than pictographs or text recommendations alone. Most surveyed neurologists would consider withdrawing ASMs in seizure-free individuals. Seizure probability was the largest factor driving decisions, yet estimating seizure probabilities was the greatest challenge. Respondents on average indicated that they may withdraw ASM after a minimum seizure-free duration of 2 years, yet also on average were willing to withdraw when seizure risk decreased below 15%-30%, which is lower than most patients' postwithdrawal risk at 2-year seizure freedom and lower than the equivalent even of a first seizure of life. These findings will inform future efforts at developing decision support tools aimed at optimizing ASM withdrawal decisions.

Management of rare movement diseases in different world regions

To evaluate the management of rare movement disorders (RMD) at the international level and identify care needs to be addressed, the Rare Movement Disorders Study Group of the International Parkinson and Movement Disorders Society (MDS) has conducted an exploratory survey. We sent an online survey to experts in Africa, Asia, Oceania and American continents following the classification of the MDS Regional Sections: Africa, Asia and Oceania (A&O), and Pan-America. We did not include Europe as the European Reference Network for Rare Neurological Diseases recently performed a similar care needs survey across European countries. We obtained responses from experts from 20 African, 26 A&O and 19 Pan-American countries. According to the respondents, only 55% of African countries had movement disorders experts, while these were present in 96% of A&O and 91% of Pan-American. Access to care for patients with RMD was stated difficult in 70% of African, 54% of A&O, and 65% of Pan-American countries. Africa was the region with greatest difficulties in accessing diagnostic tests. However, in Pan-America and A&O, large inequalities were observed between countries with quite variable access to therapeutic options such as deep brain stimulation. The survey results reflect wide variability in the management of RMD and provide evidence that a worldwide care-focused network is highly warranted. Scientific and medical organisations should raise awareness of deficits in managing RMD and care disparities among regions. The goals should be to facilitate the training of professionals, establish improvement strategies, and increase support and budgeting for these diseases.