Rare Diseases

Volha Skrahina 1,4, Hanaa Gaber 1, Eva-Juliane Vollstedt 2, Toni M Förster 1, Tatiana Usnich 2, Filipa Curado 1, Norbert Brüggemann 2, Jefri Paul 1, Xenia Bogdanovic 1, Selen Zülbahar 1, Maria Olmedillas 1, Snezana Skobalj 1, Najim Ameziane 1, Peter Bauer 1, Ilona Csoti 3, Natalia Koleva-Alazeh 3, Ulrike Grittner 1, Ana Westenberger 1, Meike Kasten 2, Christian Beetz 1, Christine Klein 2, Arndt Rolfs 1, ROPAD Study Group

• ¹CENTOGENE GmbH, Rostock, Germany.
• ²Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
• ³Parkinson-Center, Gertrudisklinik Biskirchen, Leun, Germany.
• ⁴Arcensus, Rostock, Germany

Background: Genetic stratification of Parkinson’s disease (PD) patients facilitates gene-tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson’s Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants.

Methods: Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD-linked genes, and (3) genome sequencing.

Results: Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers.

Conclusions: The ROPAD screening protocol is feasible for high-throughput genetic characterization of PD participants and subsequent prioritization for gene-focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: GBA; LRRK2; Parkinson’s disease; genetic factors; observational clinical study

https://pubmed.ncbi.nlm.nih.gov/33314351/

While the utilization of gene editing technologies is spreading like wildfire, this purpose of this talk is to take a hard look at the ethical aspects of modifying the human genome.  While somatic gene therapy affects the individual patient only, genetic alteration of germline cells: sperm, oocytes and embryos, will be passed on to the offspring. With increasing easy access to emerging technologies, notoriously CRISPR, there is growing concern that, in the absence of clear guidelines and professional (non-governmental for now) regulation, there is a concrete risk of abuse, overuse and misuse.  Examples of ethically challenged somatic and germline gene editing are discussed, along with cases of successful, careful, somatic gene therapy.  As is frequently the case, the moral discussion lags behind the rapid development and spread of the technology.  The gap between “gene therapy” and “gene editing” may be widening, presenting some tough questions: What genes should be edited?  Who should make these decisions?  Can society form an effective firewall against abuse without governmental intervention?  How do we avoid the potential slippery slope of CRISPR becoming a powerful eugenic tool? Can we envision how routine genome editing will change our world?  Children – manufactured products? Would access to gene editing be limited to the privileged?

Rare diseases (RD) are an emerging group of diseases that pose special challenges to affected patients and their families, treating physicians, researchers, insurance companies and the government. Georgia is a small country with a population of 3.7 million people and awareness of rare diseases is still low among health professionals. Our aim was to raise awareness of RD in the country and enable diagnosis of RD patients. In 2018-2020, we were part of the biomarker clinical trial with Centogene, a Germany based biotech company (www.centogene.com) . Before enrolment in the trial, patients were offered a free genetic test. We also collaborated with Face2Gene to conduct several workshops on the application of artificial intelligence in the diagnosis of rare diseases for doctors and medical students. We initiated the “Rare diseases” section in one of the largest Georgian medical social media groups “MedCity”, where information about a specific rare disease is uploaded in Georgian language every week. We also collaborate with Unique (rarechromo.org) and provide translations of rare disease guides in Georgian language. As a result, over 3000 individuals were genetically tested over a 4-year period. Interestingly, WES had a diagnostic yield of up to 60% in a cohort of clinically well characterized patients with neurodevelopmental disorders, the majority of which were caused by novel de novo mutations. Based on these activities, awareness of RD among health professionals has increased significantly. Our goal for the future is to promote the education of doctors and students to recognize RD, support the formation of patient advocacy groups, negotiate with the government to support RD patients, and facilitate the improvement and expansion of the national NBS programme.

PNH results from an acquired mutation of the PIG-A gene resulting in sensitivity of red cells to undergo intravascular haemolysis with a number of life-threatening downstream effects such as anaemia, transfusion requirement and most importantly, thromboembolic phenomena. The introduction of anti-complement factor 5 (C5) therapy into clinical practice cover a decade ago, transformed the outlook of this disease with benefit to nearly all symptomatic patients.  The success of the original monoclonal antibody therapy, eculizumab, development of a longer acting form, ravulizumab has made treatment more reliable. And convenient for patients. During this decade new issues with suboptimal responses in some patients have been identified, particularly the issue of extravascular haemolysis. This has led to the development and eventual marketing of a more proximal inhibitor of complement at C3 which has shown effectiveness in this setting. A cornucopia of agents, both proximal and terminal are under development with a variety of routes of administration including oral, subcutaneous and intravenous. This may eventually result in a very unusual situation in an ultra-rare disease, of a huge array of treatment choices. With multiple treatments comes the need to develop an outcome registry beyond the single company-sponsored registry that has been in existence for 15 years. The International PNH Interest Group (IPIG) is close to finalising an academic registry with industry stakeholders participating and having the ability to develop product-specific silos of commercially sensitive data. This could be a model for sustainable registries in other rare diseases.

There are many disorders that involve the bones, the most common being osteoporosis.
We are going to describe other diseases that are for less common.
These disorders are about 500, whose over 100 are metabolic nature.
These disorders are taking off as new dedicated drugs are becoming available.
In this speach recent progresses in the field will be presented and discussed.