Rare diseases
Rare diseases affect small populations individually, but together create a substantial burden of delayed diagnosis, limited treatment options and unmet care needs.
Definitions and terminology
Definitions of rarity vary by jurisdiction. A March 2025 overview of orphan applications gave the EU threshold as fewer than 5 affected people per 10,000. A clinical-trial overview published at the same time used no more than 5 per 10,000. These accounts gave the US threshold as fewer than 200,000 affected people and the Japanese threshold as fewer than 50,000. The clinical-trial overview defined ultra-rare diseases as affecting fewer than 1 in 50,000 people. National prevalence thresholds have ranged from 5 to 80 per 100,000 people.
“Orphan disease” can describe a condition neglected because treatment development is not considered profitable; not every orphan disease is rare. Rare diseases can be neglected because their patient populations are small. Drugs intended to treat rare diseases are commonly called orphan drugs.
The zebra symbol comes from a saying attributed to Theodore Woodward: “When you hear hoofbeats, think horses, not zebras.” It encourages considering common diagnoses first, but can also obscure the fact that rare diagnoses occur. Within rare-disease communities, the zebra represents thinking beyond the obvious diagnosis. Rare Disease Day is observed on the last day of February.
Numbers and their scope
Published estimates of the number of rare diseases and people affected differ. March 2025 accounts included the following estimates.
| Scope | Estimate cited in March 2025 |
|---|---|
| Number of rare diseases | More than 6,000. |
| Number of rare diseases | More than 7,000. |
| Number of rare diseases | 6,000–8,000. |
| Number of rare diseases | 7,000–10,000. |
| People affected worldwide | More than 260 million. |
| People affected worldwide | Around 300 million. |
| People affected worldwide | More than 350 million. |
| People affected worldwide | Around 400 million. |
| People affected worldwide | More than 400 million. |
| People affected in Europe | More than 20 million. |
| People affected in Europe | Roughly 30 million. |
| People affected in Europe | About 36 million. |
The age-related figures also describe different things. One 2025 estimate put childhood onset at 70% of rare diseases, while other accounts said about half of diseases affect children or that children represent more than half of patients. Approximately 80% of rare diseases were estimated to have a genetic cause, while one account gave a separate estimate of 50%–70% for genetic causes among rare diseases affecting children.
New conditions continue to be described: one March 2025 overview cited an estimate of five newly described rare diseases each month. A 2020 US account estimated that roughly 1 in 10 Americans had a rare disease.
The diagnostic odyssey
Low prevalence and limited professional knowledge can leave people facing a long, frustrating journey to diagnosis, often with several misdiagnoses. This diagnostic odyssey consumes time and can impose emotional and financial costs. A 2020 account reported an average of eight physicians seen and two or three misdiagnoses before the correct diagnosis; a regulatory practitioner's account published in 2025 put the average delay at seven years.
A Rare Barometer survey conducted from 17 March to 15 June 2022 collected responses from 10,453 people with rare diseases and close family members in 42 European countries, covering 1,675 diseases. It found an average of five years between first symptoms and confirmed diagnosis. Forty per cent had not been referred to a specialist centre, and 25% had eight or more consultations with a healthcare professional before diagnosis. Referral to a centre of expertise was associated with a shorter diagnostic journey. Women waited an average of 5.4 years compared with 3.7 years for men, and children and adolescents waited longer than adults, at 8.8 and 10.4 years respectively.
Delays can arise while common diagnoses are ruled out, and specialised confirmatory tests are not available to everyone worldwide. By March 2025, medical-school and continuing-development initiatives were beginning to emphasise consideration of rare diagnoses.
Newborn screening can improve early diagnosis. A Rare Barometer survey found that 95% of respondents supported testing for rare diseases at birth. A March 2025 account described substantial European variation in screening availability and coverage, from no programme in some countries to 48 conditions in Italy, with pilot programmes seeking improvements.
Treatment gaps and variation between patients
March 2025 estimates put the proportion of rare diseases without approved treatments at about 95%, while another estimate put the share with an FDA-approved drug at around 5%. Many rare diseases are life-limiting, and only a few families may have a confirmed ultra-rare diagnosis. Off-label prescribing is common where approved treatments are lacking. Five interrelated barriers contribute to the treatment gap.
- High development costs and limited returns from small markets.
- Long development timelines because recruitment in small populations takes time.
- Limited understanding of disease mechanisms and natural history.
- Difficulty obtaining confirmatory evidence with traditional trial designs in small, heterogeneous populations, creating a need for innovative designs and endpoints.
- Limited collaboration and data sharing through registries, networks and databases.
Genetic treatment strategies have traditionally managed signs and symptoms rather than targeted the underlying mutation; by 2025, disease-modifying approaches such as nucleic acid-based therapies were under development. Parents of children with conditions such as giant axonal neuropathy and Canavan disease have raised funds and advocated for research where rarity discouraged interest.
Patients with the same rare disease can differ because a genetic change causes complete loss of function in some and partial function in others. Other genomic influences, diet and living conditions can also contribute to variation.
European organisations and research initiatives
In March 2025, EURORDIS reported representing more than 1,000 rare-disease patient organisations in 74 countries across Europe and beyond. Its work spanned rare diseases, including rare cancers, through advocacy with European institutions, training and mentoring for self-advocacy, and partnerships with other stakeholders. Its aims included equal rights and timely diagnoses for people with rare diseases.
The European Rare Diseases Research Alliance, ERDERA, launched in September 2024 as a seven-year EU and member-state initiative with around 180 partners from 37 countries and a €380 million budget from Horizon Europe, member states and public and private partners. It supported patient-driven research aligned with the International Rare Disease Research Consortium, established by the European Commission and US NIH in 2011. Its stated aims were diagnosis within six months of seeing a medical specialist, approval of 1,000 new therapies, and better understanding of the impact on patients, families and healthcare systems to inform policy.
ERDERA's 25 work packages covered research funding, education, data collection, integration, analysis and sharing. Plans described in 2025 included patient and young-researcher training, a master's degree in rare diseases, and clinical-research coordination of regulatory, outcome-assessment and data work before trials. A further component supported national mirror groups and countries underrepresented in Horizon Europe, including Portugal, Lithuania and Croatia.
Brexit affected five or six European reference networks coordinated from the UK, with some coordinators relocating to EU countries and UK centres no longer assured of network partnership. In March 2025, EURORDIS reported continuing collaboration with UK groups and UK association with Horizon Europe. It was advocating an EU Action Plan for rare diseases, while Rare Diseases International was campaigning for a World Health Assembly resolution in 2025.