Scope of the project
While any rare disease (RD), by definition, affects < 1 in 2000 individuals, together RDs represent more than 8,000 disorders affecting more than 50 million patients in Europe and North America. The majority of RDs are genetic, presenting with highly varied clinical symptoms from the neonatal period to late adulthood. Mis-diagnosis is frequent, with many individuals having a poor prognosis and a very poor quality of life. These conditions have a significant impact on the ethical, psychological, social and economic status for affected individuals and their families. Accurate and timely diagnosis of RD is critical for proper treatment and qualified genetic counselling. A genetic cause has been identified in less than half of RDs. History has demonstrated that finding the genetic causes of RDs leads to remarkable insights about basic biological principles and pathophysiologic processes in humans and provides unique biological models that are relevant to the pathways involved in the etiology of many common diseases, making RDs a public-health and research priority world-wide.
Over the last 20 years, with significant institutional support from Charles University and extramural grants, we have developed a highly effective multidisciplinary platform for research, diagnostics, treatment and prevention of RDs. This platform is composed of a clinical framework, comprehensive genomic, genetic and biochemical analyses that are complemented by targeted molecular biology, and cell pathology characterization of identified causal genes and mutations. This approach enabled us to establish biochemical and genetic diagnoses in more than 3,000 families and has led to novel insights into the etiologies of numerous RDs, including inherited metabolic disorders, genetic syndromes, cardiomyopathies, kidney diseases, and ocular disorders. In many cases this process resulted in identification of disease biomarkers, development of novel diagnostic procedures, specific treatment regimens, and implementation of clinical studies.
The research also provided important insights into basic biological processes such as mitochondrial biogenesis, the detoxification-enhancing liver-blood shuttling loop, and de novo purine synthesis; (see CVs and publications).
In this project we proposed further continuation and expansion of our long-term efforts to identify the genetic causes and characterize causal biochemical and molecular defects, biological principles and pathophysiologic processes in patients and families with RDs across the broad spectrum of medical specialties, including pediatrics, internal medicine, ophthalmology, neurology and psychiatry. We will collect and develop unique biological materials (chemicals, recombinant enzymes, tissue biopsies, cell cultures, organoids, and model organisms) and develop appropriate bioanalytical methods that will be used by us and others in the study of rare and common diseases.