“When you see hoof prints, look for horses, not zebras.” The message warns young doctors that most clinical findings can be accounted for by common diseases. Nonetheless, physicians must understand that zebras, unlike unicorns and griffins, actually exist (Jules J. Berman, 2014)... and this awareness is also needed by biomedical and life scientists.
Rare diseases are defined in the first instance because of their low prevalence, determined in the European Union to be less than 5 people affected per 10,000 inhabitants. Although this is a necessary concept, it is not enough to recognize as a whole what are the peculiarities of these diseases and health conditions, especially when we compare them with common diseases, much more known by the population and to which more resources are allocated in both healthcare and research. Rare diseases are seen from different, although complementary, points of view by different interested social groups. Physicians are interested in facing and solving the questions related to the diagnosis, treatment and management of the patient. Scientists raise questions about why and how the disease occurs, determine new diagnostic biomarkers and therapeutic targets and demonstrate whether a new compound can have therapeutic efficacy through research of clinical trials. Patients and associations of patients and relatives live the disease and its consequences from a global perspective, combining in their interests the medical, health, scientific, social, and political aspects. At the level of public life, the politicians and the administration of governments are fundamental actors, and many of the demands of the interested parties are addressed to them, especially from the patients but also the doctors and the researchers. We must not forget the importance of the biopharmaceutical industry to this field, whose investment in the development of new drugs and therapies for rare diseases is fundamental, although it contrasts with the actions developed in common diseases. We can say that the number of stakeholders that are involved and interact in the field of rare diseases is very broad. Here I will focus, above all, on different aspects of interest in the healthcare and biomedical science of the rare diseases.
If low prevalence is a necessary but not sufficient characteristic, what, then, are the other characteristics that underlie the concept of rare diseases? Among them we can consider the following: (i) the great majority of these diseases have a much lower prevalence than 5 per 10,000; they are ultra-rare diseases, with frequencies that are well below that reference rate; (ii) in many cases the disease begins at the pediatric age, and not infrequently, from birth, so affecting the complete biography of the person; (iii) rare diseases are chronic disorders, which make the person someone who lives with the disease or condition; (iv) rare diseases are many and very diverse, and they are usually systemic and affect several organs, which requires a management that combines the multidisciplinary approach and the deep knowledge shared by different specialists; (v) many of these diseases are genetic, having as a first cause a gene mutation or in a region of the genome, which means not only concern and care for the sick person but also for the consequences and risks in other members of the family, with a requirement to contemplate genetic counseling in the global plan of the patient and his family. The incorporation of these aspects to the 'definition' of what we understand as a rare disease has as a consequence the need to incorporate into the health system two fundamental aspects for the correct clinical and preventive management of these disorders: on the one hand, multidisciplinary and integrated healthcare, and on the other hand, clinical genetic services that integrate genetic diagnosis and counseling.
In the area of biomedical research, rare diseases offer a very wide field of action for the researcher and, especially, for the young researcher who wants to start a scientific career that combines curiosity and knowledge with repercussions on public health. On April 11, 2018 we can talk about 6000 disorders or traits that are genetically conditioned. The Orphanet portal (www.orpha.net) currently recognizes 5856 rare diseases, while in OMIM (www.omim.org), the online catalog of human genes and genetic disorders, 5146 single gene disorders are recognized, although the total of phenotypes for which the molecular basis is known is 6190. It is tempting to hypothesize that each human gene may be associated with a disease, trait or condition. If this were the case, there are still many disorders and phenotypes of a different nature to be discovered that have an impact on health. In any case, the translation between the genotype and the phenotype offers a first-order opportunity to investigate in depth the human pathophysiology, the biological pathways that are affected in the disease, and the molecules that intervene. This not only represents a vast field to get into to further scientific knowledge but also to apply science to the development of diagnosis and to the determination of new therapeutic molecular targets. A challenge... and a beautiful service of health sciences to society.