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Rare diseases are no longer just a curiosity
Rare diseases evolved from anomalies to recognized conditions, with key advances in genetics, treatment, and global initiatives.
Early observations on rare diseases
The history of rare diseases is deeply linked to the evolution of medicine and scientific philosophy. For several centuries, rare diseases were simply considered singular anomalies, isolated events without a specific classification. The first written evidence dates back to ancient times, when Herodotus described a case of albinism in an African population and Pliny the Elder noted the presence of individuals with particular physical characteristics. Galen and Avicenna, although with different approaches, spoke of uncommon diseases as curiosities of nature, without ever attempting to fit them into a coherent diagnostic system.
During the Scientific Revolution, from the 16th century onwards, clinical observations became more systematic. In 1581, Rembert Dodoens (1517-1585) wrote the “Medicinalium observationum exempla rara, recognita et aucta”, a book in Latin on the diagnosis and treatment of disorders with a low prevalence. This text is a collection of 53 medical observations of rare and unusual clinical cases that Dodoens had encountered during his medical practice. The work is structured systematically, following a “a capite ad pedes” (from head to toe) order. It begins with cases involving head injuries and concludes with a case of gangrene that led to the loss of a young patient's feet. Many consider this the first book on rare diseases.
“Medicinalium observationum exempla rara, recognita et aucta” cover (photocredit: Google Books)
The progress of pathological anatomy led to greater attention being paid to less frequent diseases. Giovanni Battista Morgagni (1672-1771), in his “De sedibus et causis morborum per anatomen indagatis” of 1761, demonstrated that diseases had a precise anatomical basis, paving the way for the discovery of many previously neglected pathologies. During the same period, medical classification was refined. Carl von Linné (1707-1778) also attempted to catalogue abnormalities, while William Cullen (1710-1790) included some rare diseases in his taxonomies. Jean Cruveilhier (1791-1874) published an atlas (“Anatomie du système nerveux de l'homme”, 1845) in which he described numerous uncommon neurological pathologies, providing a first attempt at a scientific organisation of the phenomenon.
Advances in Medical Genetics and the identification of rare diseases
A significant leap forward came with the rise of medical genetics. John Langdon Down (1828-1896), in 1866, first described the syndrome that bears his name and recognised its specific clinical features. Archibald Garrod (1857-1936), at the beginning of the 20th century, introduced the concept of “congenital errors of metabolism”, paving the way for the study of rare diseases of genetic origin. With the discovery of the structure of DNA in 1953, research into rare diseases accelerated. A few years later, Jérôme Lejeune (1926-1994) identified trisomy 21 as the cause of Down syndrome, marking a fundamental breakthrough in the understanding of chromosomal abnormalities. Advances in cytogenetics then led to the discovery of other conditions such as Turner syndrome and Klinefelter syndrome.
Despite these discoveries, rare diseases remained a marginal area of medicine for a long time. The very concept of “rare disease” was absent, and uncommon conditions were only studied in relation to individual clinical cases. It was only at the end of the last century that rare diseases emerged as an entity worthy of their own label.
Global initiatives and remaining challenges
In the United States, in 1983, the government approved the Orphan Drug Act (ODA), a law aimed at stimulating research and drug development for conditions neglected by pharmaceutical companies, creating a regulatory framework to facilitate the introduction of new therapies. At that time, a clear definition for rare diseases was established: a rare disease was considered as such if it affected less than 200.000 people in the United States. Prior to ODA approval in 1983, only ten orphan disease drugs were commercially accessible for patient use. As of 2015, the FDA had approved more than 550 orphan drugs and granted more than 3,600 orphan drug designations targeting 277 rare diseases. In addition to changing the drug development landscape in the United States, the enactment of the ODA inspired similar changes internationally in regions such as Europe, Australia, Singapore, and Japan.
1982: Demonstrators in favour of the Orphan Drug Bill (photocredit: Abbey Meyers)
In Europe, in 1999, as part of the Community Action Programme on Rare Diseases 1999-2003, rare diseases were qualified as life-threatening or chronically debilitating, mostly hereditary conditions, with a prevalence threshold of no more than 5 patients per 10.000.
In recent years, the issue has gradually entered the global health agenda, leading to the creation of international research networks and the promotion of awareness days such as Rare Disease Day, established in 2008.
In the 21st century, research on rare diseases has benefited from advances in genomics and precision medicine. The completion of human genome sequencing in 2003 made it possible to more rapidly identify the genetic basis of many rare diseases, improving diagnosis and opening up new therapeutic perspectives. Gene therapy, thanks to technologies such as CRISPR, is offering real hope for some of these conditions, with the first treatments already approved for diseases such as Leber congenital amaurosis and Duchenne muscular dystrophy. In parallel, the use of artificial intelligence and big data is making earlier diagnosis possible, reducing waiting times for patients.
Today, the management of rare diseases is no longer a problem confined to individual physicians or specialised research centres, but a global challenge. The creation of the European Reference Networks in 2017 was a decisive step towards more collaborative medicine, allowing patients to access specialists regardless of their geographical location. Despite progress, however, many challenges remain: late diagnosis, lack of therapies for most rare diseases and difficulties in accessing innovative drugs are still unresolved problems.
Rare Disease Day on 28 February 2025
Since 2008, the Rare Disease Day has been celebrated worldwide at the end of February. esanum covers the day and reports not only on current topics, but also on possible symptom complexes, diagnostics, therapeutic approaches and orphan drugs for the treatment of rare diseases.