A disease is considered rare when its low incidence becomes a problem to be added, making more difficult its accurate diagnosis and decreasing the interest in its research and the development of drugs for its treatment. According to the definition provided by the European Union, rare diseases are those with prevalence values lesser than 5/10,000 and leading patients to higher risk of death or chronic disability. Although it is difficult to estimate the exact number of rare diseases, most probably this number is within the range 6000–8000. More than 2000 rare diseases have already one or more genes assigned; see (http://www.rdplatform.org) and . The greatest database on the subject, Orphanet (http://www.orpha.net/consor/cgi-bin/index.php) contains information on almost 6000 rare diseases. Therefore, although each rare disease is infrequent, altogether rare diseases affect to 6–8% of total population in developed countries. Currently, more than 30 millions of European citizens suffer from some kind of rare disease and are exposed to discriminatory medical care benefits. Different projects have been financed under the Programme for Community Action on Rare Diseases in 1999–2003; the EU Public Health Programme 2003–2007 and the second EU Health Programme 2008–2013 (http://ec.europa.eu/health/rare_diseases/projects/cooperation/index_en.htm).
A fundamental question arises: how to get access to this highly specialized and very reduced knowledge area where each described rare disease becomes an isolated particularity? A reasonable option could be the comparative study of analogies among different rare diseases (http://www.orpha.net/consor/cgi-bin/Education_Home.php?lng=EN). However, the low prevalence (the fact of being rare) is the only descriptor that—by definition—can be applied in any methodology for the systemic study of all or a group of rare diseases. This description based on low prevalence is crucial for the integration of medical policies in the framework of rare diseases, but on the other hand it contributes nothing to the molecular description of rare diseases and the physio-pathological relationships they could share. This is the current situation, in spite of the fact that next-generation sequencing technologies and exome analysis are making possible to identify molecular markers for some rare diseases .
The specification of classification systems able to order the collected information on a disease according to coherent categories and criteria plays an essential role in biomedical sciences. In particular, this is of paramount importance for the description and diagnosis of rare diseases and for the adoption of decisions concerning health care, clinical and therapeutical indications and derivation of patients to specialists. In this context, Orphanet and WHO (World Health Organization) are currently making important efforts for the future specification of the international classification of diseases ICD11 (http://www.who.int/classifications/icd/revisionnews/en/), which will include rare diseases for the first time . Unfortunately, there is still a lack of a clinical identification accredited for this kind of diseases. In consequence, the search for information on rare diseases remains complex and diffuse.
Specific problems also arise from the usual way in which the scientific literature is written. Unfortunately, scientific literature does not use to identify rare diseases as such and the identifiers for them proposed (i.e. ORPHA or OMIM IDs) are scarcely mentioned. In consequence, the search of information on rare diseases through the primary sources of scientific documentation is not an easy task. In fact, the finding of common relationships among diseases depends mainly on the reduced and specialized area of knowledge that dominates each rare disease, a fact that severely limits the visibility of these relationships.
Far beyond the epidemiological, clinical and molecular studies and decision making in public health, the adoption of wider and more general and holistic approaches could become a new way to access to new knowledge in this area. The implementation of informatics resources to extract data from scientific literature and to analyze and enrich this information is currently contributing to the advancement of knowledge in biomedicine. This could be a powerful strategy to establish emerging sources of knowledge also in the specific field of rare diseases.
A systematic review and collection of relevant information contained in diverse sources of scientific information and documentation could provide new valuable, emergent information concerning rare diseases. In the present work, we apply this systemic approach to get a deeper insight on the current knowledge of angiogenesis-related rare diseases (A-RDs).
Angiogenesis, the formation of new vessels from the pre-existing vasculature, is one main mechanism of vascularisation during normal and specific physiological processes, such as embryonic development, growth, regeneration, wound healing and formation of corpus luteum and endometrium. Angiogenesis attracted wide interest in the scientific community when the pioneering hypothesis of Judah Folkman in 1971 that tumor progression and metastasis are dependent on angiogenesis (and, as such, cancer could be therapeutically attacked by inhibiting angiogenesis) began to be confirmed by experimental studies since the eighties [4-6]. In fact, inhibition of this process has become a major challenge in the development of new anticancer agents, with more than 40,000 scientific papers published on this subject, and about a hundred anti-angiogenic compounds entered in clinical trials, and numerous others in preclinical development [7-9]. Currently, it is well established that a deregulated and persistent angiogenesis is one of the hallmarks of cancer [10, 11]. Furthermore, there is overwhelming evidence on the involvement of deregulated angiogenesis in many other pathological situations, which are currently described as angiogenesis-dependent diseases . The interest and impact of angiogenesis as a new therapeutical target from the treatment of non-oncological angiogenesis-dependent diseases is well represented by the recent concession of the Lasker-Debakey Clinical Medical Research Award 2010 to Dr. Napoleone Ferrara for the discovery of VEGF as a major mediator of angiogenesis and the development of an effective anti-VEGF therapy for wet macular degeneration, a leading cause of blindness in the elderly . This is a type of age-related macular degeneration, included as a rare disease in the Orphanet website with the Orpha number ORPHA279. Other two examples of A-RDs are POEMS syndrome (ORPHA2905) [14, 15] and Amyotrophic lateral sclerosis (ORPHA803) .
In fact, a number of the so far described rare diseases are infrequent types of neoplasia, most probably related to angiogenesis. Furthermore, many other rare diseases could be related to angiogenesis. However, there is a lack of an exhaustive and systematic review on the topic “angiogenesis related rare diseases”. To contribute to fill this gap is the main aim of the present review. To reach this goal, our group can make use or our previous experience in the management of databases and the implementation of bioinformatics tools [17-19]. As a research group integrated in the Spanish Network of Rare Disease Research (http://www.ciberer.es/index.php?lang=english), we are actively involved in the search of new sources of knowledge in this research area. In the present work, we aim to evaluate how much and what kind of information we are able to uncover in the context of A-RDs. Furthermore, we also evaluate what kind of information contained in Orphanet can be extracted within the frame of our systematic search.