Development of tailored splice-switching oligonucleotides for progressive brain disorders in Europe: development, regulation, and implementation considerations.

Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe.

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

PURPOSE: Within 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. METHODS: Data 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. RESULTS: We 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). CONCLUSION: The "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.

[Quality of Life and Experienced Distress of Patients Suspected of having a Rare (Chronic) Health Condition - Initial Findings from the ZSE-DUO Study]. / Lebensqualität und erlebte Belastungen von Patient*innen mit Verdacht auf eine Seltene Erkrankung ­ erste Erkenntnisse aus der ZSE-DUO Studie.

OBJECTIVE: Patients suspected of having a rare (chronic) health condition have often gone a long way within the healthcare system. To date, little is known about the health-related quality of life of this group of patients. The study aims to describe the health-related quality of life and the perceived distress of patients suspected of having a rare (chronic) health condition and compare the results with standard values of the German population. METHODS: Eighty patients suspected of having a rare (chronic) health condition were recruited in the nationwide intervention study "ZSE-DUO" and reported their health-related quality of life and perceived distress using the SF-8 and the Distress-Thermometer. RESULTS: The patients rated all eight dimensions of quality of life as well as the physical and mental component scores of the SF-8 significantly lower than the general population. On average, the perceived distress was rated significantly higher. More than 90% of the sample indicated distress in the clinical range. Exhaustion, pain, limited mobility as well as worries and fears were mentioned most frequently as concrete problems, with percentages ranging from 73% to 90% of the total sample. DISCUSSION: In comparison to German reference data, patients suspected of having a rare (chronic) health condition report a massive impairment of their quality of life and a high burden, which is especially characterized by physical and emotional problems. The lack of a diagnosis could explain the high proportion of emotional problems, as it can create a form of legitimation of one's own disease experience. CONCLUSION: The present results underline the need for research on the psychosocial impact of the possible presence of a rare (chronic) health condition. The high distress and the impact on the physical and psychological quality of life domains also highlight the need for care in this patient group.

The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases.

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.

How to approach a neurogenetics diagnosis in different European countries: The European Academy of Neurology Neurogenetics Panel survey.

BACKGROUND AND PURPOSE: Seven thousand rare diseases have been identified; most of them are of genetic origin. The diagnosis of a neurogenetic disease is difficult, and management and training programs are not well defined through Europe. To capture and assess care needs, the Neurogenetics Panel of the European Academy of Neurology (EAN) has performed an explorative survey. METHODS: The survey covering multiple topics of neurogenetics was sent to all neurologists and neuropediatricians affiliated with the EAN practicing in Europe. RESULTS: We collected answers from 239 members based in 40 European member states. Even though most of the responders were aware of neurogenetic diseases, when we came to amenability of carrying out a complete genetic diagnosis, almost one-third of the responders declared they were not happy with the current way of ordering genetic analyses in their countries. Furthermore, although single-gene analysis is diffusely present in Europe, whole exome and genome sequencing are not easily accessible, with considerable variabilities among countries. Almost 10% of the responders did not know if presymptomatic and prenatal diagnosis was available in their countries, and 47.3% were not aware of which newborn screening programs were available. Finally, 96.3% of responders declared that there is a need for education and training in neurogenetics. CONCLUSIONS: We believe that this survey may be of importance for all European stakeholders in neurogenetics in identifying key priorities, targeting areas to encourage education/travel fellowships, and educational seminars in the future, because this area will only accelerate, and diagnostic requirements will expand.

European Academy of Neurology guidance for developing and reporting clinical practice guidelines on rare neurological diseases.

BACKGROUND AND PURPOSE: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. METHODS: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members. RESULTS: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. CONCLUSIONS: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs.

[Rare-disease data standards]. / Datenstandards für Seltene Erkrankungen.

The use of standardized data formats (data standards) in healthcare supports four main goals: (1) exchange of data, (2) integration of computer systems and tools, (3) data storage and archiving, and (4) support of federated databases. Standards are especially important for rare-disease research and clinical care.In this review, we introduce healthcare standards and present a selection of standards that are commonly used in the field of rare diseases. The Human Phenotype Ontology (HPO) is the most commonly used standard for annotating phenotypic abnormalities and supporting phenotype-driven analysis of diagnostic exome and genome sequencing. Numerous standards for diseases are available that support a range of needs. Online Mendelian Inheritance in Man (OMIM) and the Orphanet Rare Disease Ontology (ORDO) are the most important standards developed specifically for rare diseases. The Mondo Disease Ontology (Mondo) is a new disease ontology that aims to integrate data from a comprehensive range of current nosologies. New standards and schemas such as the Medical Action Ontology (MAxO) and the Global Alliance for Genomics and Health (GA4GH) phenopacket are being introduced to extend the scope of standards that support rare disease research.In order to provide optimal care for patients with SE in different healthcare settings, it will be necessary to better integrate standards for rare disease with electronic healthcare resources such as the Fast Healthcare Interoperability Resources (FHIR) standard for healthcare data exchange.

[Healthcare networks for people with rare diseases: integrating data and expertise]. / Versorgernetzwerke für Menschen mit Seltenen Erkrankungen: Daten und Expertise bündeln.

In the European Union (EU), rare diseases (RDs) are diseases that affect no more than 5 in 10,000 people. Due to their rarity, clinical expertise and quality-assured care structures are scarce, and research is more difficult compared to other diseases. However, these problems can be overcome by means of national and transnational RD care networks. Data and expertise are pooled in these networks.In the EU, the European Reference Networks (ERNs) for Rare and Complex Diseases cooperate across borders. Important services provided by ERNs using health data include diagnostic coding of RDs, conducting virtual cross-border case conferences, and establishing European registries that are used to measure and improve the quality of care. In ERNs, local data generation and documentation combine with network-wide data infrastructures. This paper describes the data-based services in and for RD healthcare networks: (1) diagnostic coding, (2) cross-border case conferences, and (3) ERN registries for RD patient care. The final section discusses the integration of the networks into national healthcare systems.In order to achieve the best possible benefit for SE patients, ERN activities and structures need to be better integrated into national healthcare systems. In Germany, the Medical Informatics Initiative and the German Reference Networks play a central role in this regard.

[se-atlas.de-Medical care atlas for people with rare diseases]. / se-atlas.de ­ Versorgungsatlas für Menschen mit Seltenen Erkrankungen.

In the European Union a disease is classified as rare if it affects no more than 5 out of 10,000 people. Currently, there are more than 6000 rare diseases, consisting of a large and heterogeneous number of different diseases that are complex in their symptomatology, multidimensional and therefore difficult to classify in everyday medical practice. This complicates the diagnosis and treatment as well as finding a suitable contact person, as there are only a few experts for each individual rare disease. The medical care atlas for rare diseases www.se-atlas.de enables the search for care facilities and patient organizations for specific rare diseases by disease name and presents the search results geographically. It also provides an overview of all German centers for rare diseases, which are a contact point for patients with an unclear diagnosis. The se-atlas serves as a compass through the heterogeneous amount of information on care facilities for rare diseases and provides low-threshold information for a broad user group, from affected persons to members of the medical care team.

[Model for personalized diagnostics and treatment in neurology-German Academy for Rare Neurological Diseases]. / Model für personalisierte Diagnostik und Therapie in der Neurologie ­ Deutsche Akademie für Seltene Neurologische Erkrankungen.

The German Academy for Rare Neurological Diseases (DASNE) founded in 2017 on the Wartburg in Eisenach, aims to pave the way for an optimized personalized management of patients in all age groups with rare neurological diseases. By bringing rare neurological disease experts together and through forming a dynamic national network the DASNE, initiated by the Centers for Rare Diseases in Lübeck and Tübingen, will continuously foster mutual exchange. Members of the DASNE are renowned experts covering the whole spectrum of rare neurological disorders including pediatric neurology. Through case presentations and multidisciplinary discussion both at yearly meetings and on an internet platform, the main aims of DASNE are to establish a German expertise and reference network for rare neurological disorders. Further main aims are to provide continuous medical education for younger academics in the field of rare neurological disorders and facilitate translation.

[European Reference Networks : Consequences for healthcare in Germany]. / Europäische Referenznetzwerke : Konsequenzen für die Gesundheitsversorgung in Deutschland.

Starting in 2017, European Reference Networks (ERNs) for rare disease patients will be established in the European Union. ERNs will pool expertise in clinical centres and will establish cross-border exchange mechanisms in order to facilitate access to diagnosis and care. The integration of ERNs in the German healthcare system will pose a significant challenge. The main issues include: (i) competition between national and European interests in the conflict of national responsibility and intended cross-border availability of healthcare services, (ii) the lack of a funding concept, and (iii) the establishment of ERNs in EU member states in which implementation of national action plans for people with rare diseases is lagging behind. The lower implementation pace of the centre model that is part of the German action plan and the higher level of detail of the ERNs in terms of services and activities provided will likely lead to an appreciation that achieved patient benefits are attributed to ERNs.

A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson's disease.

BACKGROUND: There is growing interest in having objective assessment of health-related outcomes using technology-based devices that provide unbiased measurements which can be used in clinical practice and scientific research. Many studies have investigated the clinical manifestations of Parkinson's disease using such devices. However, clinimetric properties and clinical validation vary among the different devices. METHODS: Given such heterogeneity, we sought to perform a systematic review in order to (i) list, (ii) compare and (iii) classify technological-based devices used to measure motor function in individuals with Parkinson's disease into three groups, namely wearable, non-wearable and hybrid devices. A systematic literature search of the PubMed database resulted in the inclusion of 168 studies. These studies were grouped based on the type of device used. For each device we reviewed availability, use, reliability, validity, and sensitivity to change. The devices were then classified as (i) 'recommended', (ii) 'suggested' or (iii) 'listed' based on the following criteria: (1) used in the assessment of Parkinson's disease (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no). RESULTS: Seventy-three devices were identified, 22 were wearable, 38 were non-wearable, and 13 were hybrid devices. In accordance with our classification method, 9 devices were 'recommended', 34 devices were 'suggested', and 30 devices were classified as 'listed'. Within the wearable devices group, the Mobility Lab sensors from Ambulatory Parkinson's Disease Monitoring (APDM), Physilog®, StepWatch 3, TriTrac RT3 Triaxial accelerometer, McRoberts DynaPort, and Axivity (AX3) were classified as 'recommended'. Within the non-wearable devices group, the Nintendo Wii Balance Board and GAITRite® gait analysis system were classified as 'recommended'. Within the hybrid devices group only the Kinesia® system was classified as 'recommended'.

Quantitative home-based assessment of Parkinson's symptoms: the SENSE-PARK feasibility and usability study.

BACKGROUND: Currently, assessment of symptoms associated with Parkinson's disease is mainly performed in the clinic. However, these assessments have limitations because they provide only a snapshot of the condition. METHODS: The feasibility and usability of an objective, continuous and relatively unobtrusive system (SENSE-PARK System), which consists of wearable sensors (three worn during the day and one worn at night), a smartphone-based App, a balance board and computer software, was tested 24/7 over 12 weeks in a study including 22 PD patients. During the first four weeks of the study, patients did not get feedback about their performance, during the last eight weeks they did. The study included seven clinical visits with standardized interviews, and regular phone contact. The primary outcome was the number of drop-outs during the study. As secondary outcomes, the Post-Study System Usability Questionnaire (PSSUQ), score and information obtained from the standardized interviews were used to evaluate the usability of the system. RESULTS: All patients completed the study. The participants rated the usability of the SENSE-PARK System with a mean score of 2.67 (±0.49) on the PSSUQ. The interviews revealed that most participants liked using the system and appreciated that it signaled changes in their health condition. CONCLUSIONS: This 12 week controlled study demonstrates that the acceptance level of PD patients using the SENSE-PARK System as a home-based 24/7 assessment is very good. Particular emphasis should be given to a user-friendly design. Motivation to wear such a system can be increased by providing direct feedback about the individual health condition.

Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes.

Structural variants (SVs), including large deletions, duplications, inversions, translocations, and more complex events have the potential to disrupt gene function resulting in rare disease. Nevertheless, current pipelines and clinical decision support systems for exome sequencing (ES) tend to focus on small alterations such as single nucleotide variants (SNVs) and insertions-deletions shorter than 50 base pairs (indels). Additionally, detection and interpretation of large copy-number variants (CNVs) are frequently performed. However, detection of other types of SVs in ES data is hampered by the difficulty of identifying breakpoints in off-target (intergenic or intronic) regions, which makes robust identification of SVs challenging. In this paper, we demonstrate the utility of SV calling in ES resulting in a diagnostic yield of 0.4% (23 out of 5825 probands) for a large cohort of unsolved patients collected by the Solve-RD consortium. Remarkably, 8 out of 23 pathogenic SV were not found by comprehensive read-depth-based CNV analysis, resulting in a 0.13% increased diagnostic value.

Quality assurance for next-generation sequencing diagnostics of rare neurological diseases in the European Reference Network.

In the past decade, next-generation sequencing (NGS) has revolutionised genetic diagnostics for rare neurological disorders (RND). However, the lack of standardised technical, interpretative, and reporting standards poses a challenge for ensuring consistent and high-quality diagnostics globally. To address this, the European Reference Network for Rare Neurological Diseases (ERN-RND) collaborated with the European Molecular Genetics Quality Network (EMQN) to establish an external quality assessment scheme for NGS-based diagnostics in RNDs. The scheme, initiated in 2021 with a pilot involving 29 labs and followed by a second round in 2022 with 42 labs, aimed to evaluate the performance of laboratories in genetic testing for RNDs. Each participating lab analysed genetic data from three hypothetical cases, assessing genotyping, interpretation, and clerical accuracy. Despite a majority of labs using exome or genome sequencing, there was considerable variability in gene content, sequencing quality, adherence to standards, and clinical guidance provision. Results showed that while most labs provided correct molecular diagnoses, there was significant variability in reporting technical quality, adherence to interpretation standards, reporting strategies, and clinical commentary. Notably, some labs returned results with the potential for adverse medical outcomes. This underscores the need for further harmonisation, guideline development, and external quality assessment in the evolving landscape of genomic diagnostics for RNDs. Overall, the experience with the scheme highlighted the generally good quality of participating labs but emphasised the imperative for ongoing improvement in data analysis, interpretation, and reporting to enhance patient safety.

Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.

BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. METHODS: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. RESULTS: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. CONCLUSIONS: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities.

Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report.

Rare diseases (RD) have a prevalence of not more than 1/2000 persons in the European population, and are characterised by the difficulty experienced in obtaining a correct and timely diagnosis. According to Orphanet, 72.5% of RD have a genetic origin although 35% of them do not yet have an identified causative gene. A significant proportion of patients suspected to have a genetic RD receive an inconclusive exome/genome sequencing. Working towards the International Rare Diseases Research Consortium (IRDiRC)'s goal for 2027 to ensure that all people living with a RD receive a diagnosis within one year of coming to medical attention, the Solve-RD project aims to identify the molecular causes underlying undiagnosed RD. As part of this strategy, we developed a phenotypic similarity-based variant prioritization methodology comparing submitted cases with other submitted cases and with known RD in Orphanet. Three complementary approaches based on phenotypic similarity calculations using the Human Phenotype Ontology (HPO), the Orphanet Rare Diseases Ontology (ORDO) and the HPO-ORDO Ontological Module (HOOM) were developed; genomic data reanalysis was performed by the RD-Connect Genome-Phenome Analysis Platform (GPAP). The methodology was tested in 4 exemplary cases discussed with experts from European Reference Networks. Variants of interest (pathogenic or likely pathogenic) were detected in 8.8% of the 725 cases clustered by similarity calculations. Diagnostic hypotheses were validated in 42.1% of them and needed further exploration in another 10.9%. Based on the promising results, we are devising an automated standardized phenotypic-based re-analysis pipeline to be applied to the entire unsolved cases cohort.