Navigating care for rare: Clinical practice guidelines for rare genetic neurodevelopmental disorders

Approximately 1-3% of the general population lives with intellectual disabilities, for which a genetic aetiology can now be identified in up to 50% of individuals. Although individually rare, collectively rare genetic neurodevelopmental disorders (RGNDs) affect many individuals and families across Europe and beyond. People living with these conditions are vulnerable to a range of physical and mental health problems, depending on the underlying genetic aetiology. Common comorbidities include epilepsy, movement disorders, scoliosis, gastrointestinal symptoms and feeding difficulties, recurrent infections, and hearing and vision impairments. Additionally, these individuals may experience neurodevelopmental and psychiatric conditions such as autism, attention deficit hyperactivity disorder (ADHD), schizophrenia, and anxiety. Consequently, they often require lifelong, multidisciplinary care, ideally with health monitoring and treatment personalised to their genetic diagnosis. Yet, they frequently encounter fragmented healthcare, complicated by unfamiliarity with their rare condition among healthcare professionals and a lack of evidence-based guidelines. Clinical practice guidelines (CPGs, here: guidelines) are systematically developed recommendations for diagnosing and treating medical conditions. Guidelines are developed by multidisciplinary expert panels based on systematic reviews of the literature and an assessment of the benefits and harms of alternative care options. Guidelines can assist healthcare professionals and patients in making informed decisions. However, developing guidelines for rare conditions presents unique challenges, including scarce research and small expert groups. Given the small patient populations, research and policy for rare diseases require cross-border collaboration. This PhD thesis is situated within the European Reference Network ITHACA (Intellectual disability, TeleHealth, Autism, and Congenital Anomalies), a network of European centres of expertise and patient advocacy groups that aims to improve healthcare for rare (multiple) malformation syndromes and intellectual and other neurodevelopmental disorders, amongst others, through the development of guidelines. Evidence-based medicine integrates the best available evidence, clinical expertise and the values of the patient to arrive at the right medical decision. This thesis aims to advance evidence-based medicine for rare genetic neurodevelopmental disorders by improving guideline development. The first chapters of this thesis provide a general overview of available guidelines and their quality, and of quality criteria for rare disease guidelines. The subsequent chapters address the different steps of the guideline development process, including (1) priority-setting of guideline topics and clinical questions, (2) partnering with patients and collaborating effectively in guideline panels, (3) using evidence-based methods, and (4) integrating values of individuals and families/carers in recommendations. Then, (5) the ERN-ITHACA guideline on the transition to adult healthcare is presented as an example of guideline development within ERN-ITHACA. Finally, the findings and their implications for research and practice are discussed.