Developing a Framework of Cost Elements of Socioeconomic Burden of Rare Disease: A Scoping Review.

BACKGROUND AND OBJECTIVE: Rare diseases place a significant burden on patients, families, the healthcare system, and society. Evidence on the socioeconomic burden of rare disease is limited and mostly reflects diseases where treatments are available. We developed a framework encompassing recommended cost elements for studies of the socioeconomic burden of rare diseases. METHODS: A scoping review, conducted in five databases (Cochrane Library, EconLit, Embase, MEDLINE, and APA PsycINFO), identified English language publications from 2000 to 2021 presenting frameworks developed for determining, measuring or valuing costs for rare or chronic diseases. Cost elements were extracted and used to develop a literature-informed framework. Structured feedback was gathered from experts in rare diseases, health economics/health services, and policy research to revise the framework. RESULTS: Of 2990 records identified, eight papers were included and informed our preliminary framework; three focused on rare disease and five on chronic disease. Following expert input, we developed a framework consisting of nine cost categories (inpatient, outpatient, community, healthcare products/goods, productivity/education, travel/accommodation, government benefits, family impacts, and other), with several cost elements within each category. Our framework includes unique costs, added from the expert feedback, including genetic testing to inform treatment, use of private laboratories or out-of-country testing, family involvement in foundations and organizations, and advocacy costs for special access programs. CONCLUSIONS: Our work is the first to identify a comprehensive list of cost elements for rare disease for use by researchers and policy makers to fully capture socioeconomic burden. Use of the framework will increase the quality and comparability of future studies. Future work should focus on measuring and valuing these costs through onset, diagnosis, and post-diagnosis.

A MAGEL2-deubiquitinase complex modulates the ubiquitination of circadian rhythm protein CRY1.

MAGEL2 encodes the L2 member of the MAGE (melanoma antigen) protein family. Protein truncating mutations in MAGEL2 cause Schaaf-Yang syndrome, and MAGEL2 is one of a small set of genes deleted in Prader-Willi syndrome. Excessive daytime sleepiness, night-time or early morning waking, and narcoleptic symptoms are seen in people with Prader-Willi syndrome and Schaaf-Yang syndrome, while mice carrying a gene-targeted Magel2 deletion have disrupted circadian rhythms. These phenotypes suggest that MAGEL2 is important for the robustness of the circadian rhythm. However, a cellular role for MAGEL2 has yet to be elucidated. MAGEL2 influences the ubiquitination of substrate proteins to target them for further modification or to alter their stability through proteasomal degradation pathways. Here, we characterized relationships among MAGEL2 and proteins that regulate circadian rhythm. The effect of MAGEL2 on the key circadian rhythm protein cryptochrome 1 (CRY1) was assessed using in vivo proximity labelling (BioID), immunofluorescence microscopy and ubiquitination assays. We demonstrate that MAGEL2 modulates the ubiquitination of CRY1. Further studies will clarify the cellular role MAGEL2 normally plays in circadian rhythm, in part through ubiquitination and regulation of stability of the CRY1 protein.

Preclinical Testing in Translational Animal Models of Prader-Willi Syndrome: Overview and Gap Analysis.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing endocrine, musculoskeletal, and neurological dysfunction. PWS is caused by the inactivation of contiguous genes, complicating the development of targeted therapeutics. Clinical trials are now underway in PWS, with more trials to be implemented in the next few years. PWS-like endophenotypes are recapitulated in gene-targeted mice in which the function of one or more PWS genes is disrupted. These animal models can guide priorities for clinical trials or provide information about efficacy of a compound within the context of the specific disease. We now review the current status of preclinical studies that measure the effect of therapeutics on PWS-like endophenotypes. Seven categories of therapeutics (oxytocin and related compounds, K+-ATP channel agonists, melanocortin 4 receptor agonists, incretin mimetics and/or GLP-1 receptor agonists, cannabinoids, ghrelin agents, and Caralluma fimbriata [cactus] extract) have been tested for their effect on endophenotypes in both PWS animal models and clinical trials. Many other therapeutics have been tested in clinical trials, but not preclinical models of PWS or vice versa. Fostering dialogs among investigators performing preclinical validation of animal models and those implementing clinical studies will accelerate the discovery and translation of therapies into clinical practice in PWS.