Rare diseases revealed: Explaining, understanding, and raising awareness on rare disease day

Rare Disease Day is a global awareness day held annually to raise awareness of all rare diseases. It was first celebrated in 2008, on the rarest day – February 29. Since then, it is celebrated each year on the last day of February. It is a day to spread awareness about rare diseases, and receive support from the public that is invaluable in bridging health and social care. Although individual diseases may be rare and the number of people affected by each disease may be few, the total number of patients affected by rare diseases globally is estimated to be between 300 and 400 million – more than cancer and AIDS combined [1, 2, 3]. Despite this, many of us are unfamiliar with rare diseases, so on rare disease day, we ask what are rare diseases, what causes them, and why do we know so little about them?

What is a rare disease?

In Europe, a disease is termed rare if it occurs in less than 1 in 2,000 people [4]. In the US, a disease is called rare if fewer than 200,000 Americans are affected by it at any time [2]. Accordingly, there is a very broad frequency range of rare diseases. For example, trisomy 18, with a 1 in 5,000 incidence is considered rare [5], and so is Hutchinson-Gilford progeria that has a 1 in 4 million reported incidence [6].

Epidemiological prevalence of rare diseases is also interesting. B-thalassemia has a global incidence of 1 in 100,000, yet its incidence in the European population is 1 in 10,000 [7]. Likewise, Tay-Sachs disease is very rare in the general population, with a prevalence of 1 in 320,000 [8], yet it affects 1 in 3,500 Ashkenazi Jews [9].

Regardless of the official definition of a rare disease and the small numbers of people affected by each disease, the global impact of rare disease is huge, with up to 5.9% of the population affected [3].

How many rare diseases are there?

Worldwide, there are over 7,000 rare diseases [2]. Rare diseases are diverse with a wide variety of symptoms that differ not only between diseases, but also sometimes between patients with the same disease. Furthermore, demographic differences, diseases that overlap genetically and/or in presentation, confusions surrounding disease definitions (including cause and inheritance), and the continuous research and subsequent new information, make clearly separating rare diseases problematic. Consequently, the exact number of rare diseases is difficult to pinpoint, and an official ‘rare list’ naming and recording the frequency of each disease does not yet exist. Despite this, several comprehensive databases (Orphanet and GARD database) provide valuable information about known rare diseases.

What causes rare diseases?

Up to 80% of rare diseases have genetic origins [1] and are caused by single genes, chromosomal changes or have multifactorial causes. Rare genetic disorders can either be inherited or occur spontaneously. Although it can be difficult to separate rare genetic diseases into groups according to cause or inheritance, some examples are given below. See our infographics for more information about the types of genetic disorders or inheritance of rare diseases.

Rare diseases can also be non-genetic, with infectious or environmental causes, or classified as rare due to healthcare advances–smallpox and polio are now rare diseases due to successful vaccination programs.

Examples of rare disease by cause

• Inherited genetic cause: Spinal muscular atrophy (SMA) is characterized by the irreversible loss of motor nerve cells, leading to gradual weakening. It is caused by changes in one of the survival muscular atrophy genes, SMN1 and SMN2, which result in extremely low amounts of a protein with a vital role in the function and maintenance of motor neurons. It affects approximately 1 in 10,000 live births [10].

• Inherited rare diseases caused by changes to a single gene: Examples include Duchenne muscular dystrophy DMD), which is caused by mutations in the DMD gene, the largest gene in the human body (see here for more information); cystic fibrosis, which is caused by changes in the CFTR gene; and Huntington disease, which is caused by changes in the HTT gene.

• Spontaneously occurring genetic cause: Many rare genetic diseases can be inherited or occur spontaneously due to new mutations. Fibrodysplasia ossificans progressiva is an example of a rare disease that usually occurs spontaneously. This very rare genetic disease is characterized by the development of bone to replace muscle and soft tissue that leads to stiffness, limited movement and immobilization. It occurs in 1 in one million people worldwide [11].

• Chromosomal changes: Most rare chromosomal disorders occur spontaneously. Examples include trisomy 18 (Edwards syndrome), which occurs in around 1 in 5,000 births [5], Wolf-Hirschhorn syndrome, which occurs in 1 in 50,000 births [12], and DiGeorge syndrome, which has a prevalence of around 1 in 4,000 [13]. However, in rare cases Wolf-Hirschhorn and DiGeorge syndrome can be inherited.

• Multifactorial causes: Other factors such as lifestyle, environmental exposure and preexisting illness can interact with genetic risk factors in the formation of genetic disorders. Congenital heart defects have a multifactorial cause.

• Infections cause: Guillain-Barré syndrome is often preceded by a bacterial or viral infection. It is very rare, affecting 6 to 40 cases per 1 million people [14]. Whipple disease is a rare disease affecting the small intestine that is caused by the rod-shaped bacterium Tropheryma whippeli [15].

• Environmental cause: Mesothelioma is a rare type of cancer that is associated with exposure to asbestos in 80% of cases [16].

When do rare diseases start?

Around 70% of rare disease start in childhood [17], such as SMA, DMD or Rett syndrome, which are present from birth, and rare pediatric cancers. However, some rare diseases start or only produce noticeable symptoms later in life. Examples include the blue-black discoloration of connective tissue indicative of alkaptonuria, a rare disease affecting between 1 in 250,000 to 1 million people worldwide, that is usually seen around the age of 30 [18], and the uncontrolled movements of Huntington disease, which usually start between 35 to 44 years [19].

Examples of rare diseases

Some of the most common rare diseases are relatively well known, e.g., Huntington disease, Ehlers- Danlos syndrome, sickle cell disease, cystic fibrosis, DMD, and hemophilia [20]; however most are less well known. With around 7,000 known rare diseases, it is impossible to describe them all in this article; instead, several are described at the end to of this article to highlight further the diversity of rare diseases.

How are rare diseases diagnosed?

Diagnosis of rare diseases is challenging due to the diversity and variability of symptoms among diseases and patients. On average, an accurate diagnosis takes 4-5 years[1, 20]. Diagnosis is complicated by the fact that rare diseases often affect multiple organs and body systems, leading to visits to numerous medical specialists, and patients may receive several wrong diagnoses before a final one. Successful diagnosis requires the information from many specialties to be considered together. Moreover, doctors can only diagnose what they know about, and due to their rare nature, many physicians lack adequate knowledge of many rare diseases [21].

How are rare diseases treated?

Medically and socially, there is lack of information on the rarest diseases, which can be challenging. As a result, management of symptoms and treatment choices are limited for most rare diseases, with 95% of them not having an FDA-approved treatment [1]. Furthermore, treatments for rare diseases are often more expensive than treatments for common diseases [22]. It is an unfortunate fact that the high cost of drug development and the relatively small number of patients with each disease means that developing a drug for a rare disease is not always considered a financially viable option or a priority for many pharmaceutical companies [21]. In fact, rare diseases are also called ‘orphan diseases’ due to the drug companies’ lack of interest in developing treatments for them. However, where treatment is available, it can improve quality of life and even life expectancy.

It is not all bad news, however. The number of orphan medicinal products to treat rare diseases is increasing every year [23]. Moreover, there are many clinical trials in progress looking at treatments and outcomes for a wide range of rare diseases, and specialists can often help their patients to access applicable ones.

In some cases, support groups and online platforms for patients and family members can offer advice and knowledge on management, clinical trials and experts in the field.

Why do we know so little about rare diseases?

One reason we know so little about rare diseases in general is because there are so many of them, with new diseases or new genetic causes being described frequently [4], added to this, many of them may not be subject to scientific research [22]. Furthermore, with so few people globally having each disease, there is a lack of clinical evidence for researchers to evaluate [24]. In order to overcome this hurdle, clinical research trials need to be international to attract enough participants, which increases both cost and difficulty [21].

Modern technologies allow genetic research that was previously not possible, paving the way for continued breakthroughs in our knowledge of rare diseases [24].

The impact of rare diseases

The impact of the length of the diagnostic journey and the mental, emotional and financial costs of caring for someone with a rare disease cannot be underestimated. A survey of over 3,000 people by Eurordis found that 7 in 10 people with a rare disease or carer for someone with a rare disease were unable to work and that they were more likely to be unhappy or depressed than people in the general population [25]. Support groups are an essential management tool for those affected by a rare disease and there are many hard-working advocacy groups with the goals of raising awareness, educating and supporting people and families affected by rare diseases. Even so, as many as 50% of rare diseases do not have an active research or support group [1], leaving many patients and their families less well supported and highlighting the continued importance of raising rare disease awareness.

Conclusion

The 350 million people affected by rare diseases are patients that deserve proper diagnosis, care and treatment. The public, decision-makers and the healthcare industry can drive action that will benefit patients. On a political level, the ‘Orphan Drug Act’ US Congress enforced in 1983 provided financial incentives to pharmaceutical companies to encourage them to research and develop drugs for rare diseases. Also in Europe, there are regulations that offer incentives for the research, development and marketing of orphan medicinal products, as well as multinational research projects in the field of rare diseases supported by the European Union. European Reference Networks established in 2017 are virtual networks that bring together medical specialists in rare diseases from across the member states, with the aim to advise on patient care, develop clinical guidelines, and share research and knowledge, thus supporting those affected by rare disease in Europe [26].

On a scientific level, international research, linking experts and combining knowledge and funds across the world can have a positive impact on patients’ lives, and research into rare diseases could unlock information applicable to our understanding and the treatment of other more common conditions.

Examples of rare diseases

Fanconi anemia

Fanconi anemia (FA) is a rare, hereditary disease that has a frequency rate of around 1 in 136,000 and is more common among Ashkenazi Jews, Spanish Roma, and Black South Africans [27]. Manifesting in childhood–where more than half of the diagnoses are made–symptoms vary from physical abnormalities, like small head and skin pigmentation, to bone marrow failure. Changes (mutations) in at least 18 genes are thought to cause FA. These genes are responsible for repairing DNA damage; as the changes in them prevent them from performing their normal actions, DNA damage accumulates. In turn, this disrupts the normal functions of the bone marrow, upsets the production of platelets, white and red blood cells, and ultimately raises the patients’ risk of excessive bleeding and bruising, anemia, and certain types of cancers. FA is usually inherited in an autosomal recessive manner, which means both parents need to carry a copy of the gene mutation for it to be inherited by the child. In less than 1% of cases, a change in a gene on the X chromosome causes FA and inheritance is X-lined recessive [27].

Gracile syndrome

Gracile syndrome is a rare, inherited metabolic disease. Its name stands for the disease symptoms and characteristics – growth retardation; aminoaciduria (an increased amount of amino acids in urine); cholestasis (the decreased flow of bile that causes indigestion); iron overload; lactacidosis (the build-up of lactate that affects the liver and kidneys); and early death. It is almost exclusively found in Finland, occurring in 1 in 50,000 individuals, with the worldwide prevalence being less than 1 in 1,000,000. Affected newborns are smaller than average, fail to thrive and exhibit serious liver and kidney problems within the early months of life. It is caused by a change in the BCS1L gene that prevents the gene from converting energy from food sources into a form that cells can use, resulting in a loss of energy. Gracile syndrome follows an autosomal recessive pattern, meaning both parents need to be carriers for the baby to be affected. Unfortunately, there is no cure for Gracile Syndrome, and most babies die by 4 months of age [28]. Early diagnosis–which can be achieved by certain NIPTs and subsequent confirmatory testing–is invaluable for managing clinical care and symptomatic treatment, and improving quality of life.

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) takes its name from the sweet odor of affected infants’ urine. It is a rare, autosomal recessive disorder occurring in less than 1 in 185,000 individuals globally. Symptoms vary depending on disease severity, and can appear within the first days of life. They include failure to thrive, drowsiness, progressive lethargy, and when left untreated, brain damage, eventually leading to coma and respiratory failure within the first months of life. This time-sensitive disorder can be detected prenatally via certain NIPTs, ensuring prompt clinical management of symptoms that may be lifesaving; however, episodes of metabolic crises triggered by infection, injury, fasting, or stress can occur despite treatment. MSUD is caused by mutations in one of three genes that result in decreased activity of enzymes involved in breaking down amino acids and toxic byproducts. As a result, they accumulate in the body and disturb the body’s metabolic processes [29].

Hemophilia

Hemophilia A and B are examples of hereditary rare diseases that are more common in men than in women. Hemophilia is an X-linked disorder: it is caused by changes to genes located on the X chromosome (F8 gene for hemophilia A and F9 gene for hemophilia B), and is inherited in a recessive manner, which means that two copies of the variant are usually required to cause the disease. However, men have only one X chromosome and if this carries the variant, they have symptoms of the disease. Women have two X chromosomes and in most cases, both need to carry the variant gene for them to have the disease.

Both hemophilia A and B are bleeding disorders. A lack of clotting factor in the blood means that patients experience prolonged bleeding after injury, as the clot formation essential to stop the bleeding is impaired. In severe cases, bleeding can occur without obvious injury and can develop in the joints, organs or brain. Hemophilia A is the most common type, occurring in 1 in 4,000 to 1 in 5,000 males worldwide, while hemophilia B is found in approximately 1 in 20,000 males worldwide [30].

Rett syndrome

In contrast to hemophilia, Rett syndrome occurs almost exclusively in females. This rare disease affects 1 in 9,000 to 10,000 females and usually occurs due to spontaneous new mutations in the MECP2 gene rather than being inherited. Children with this brain disorder develop normally for 6 to 18 months before developing language and communication difficulties and losing meaningful hand control. As well as delayed growth and a small head, there are a range of other symptoms, including seizures and scoliosis [31].

Pseudomyxoma peritonei

Pseudomyxoma peritonei is a rare cancer caused by a growth (polyp) in the appendix that perforates through the appendix and spreads into the abdomen and pelvic cavity, causing swelling, intestinal obstruction and life-threatening complications. There are thought to be approximately 2 cases per million people. This rare cancer of the appendix does not have any known genetic or environmental causes [32]. It is one of more than 500 types of rare cancer [2].

References

[1] “Rare Disease Facts” Global Genes, https://globalgenes.org/rare-disease-facts/. Accessed 5 Feb. 2024.

[2] “Rare Disease Facts & Statistics | NORD.” NORD (National Organization for Rare Disorders), Rarediseases.org, https://rarediseases.org/understanding-rare-disease/rare-disease-facts-and-statistics/. Accessed 5 Feb. 2024.

[3] What Is a Rare Disease? – Rare Disease Day, https://www.rarediseaseday.org/what-is-a-rare-disease/. Accessed 5 Feb. 2024.

[4] “Rare Diseases.” Research-And-Innovation.ec.europa.eu, https://research-and-innovation.ec.europa.eu/research-area/health/rare-diseases_en. Accessed 5 Feb. 2024.

‌[5] MedlinePlus. “Trisomy 18: MedlinePlus Genetics.” Medlineplus.gov, 16 Feb. 2021, https://medlineplus.gov/genetics/condition/trisomy-18/. Accessed 5 Feb. 2024.

[6] Hutchinson-Gilford Progeria Syndrome: MedlinePlus Genetics.” Medlineplus.gov, 1 May 2016, https://medlineplus.gov/genetics/condition/hutchinson-gilford-progeria-syndrome/. Accessed 5 Feb. 2024.

[7] Galanello, Renzo, and Raffaella Origa. “Beta-thalassemia.” Orphanet journal of rare diseases vol. 5 11. 21 May. 2010, doi:10.1186/1750-1172-5-11, https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-11.

[8] “Orphanet: Tay-Sachs Disease.” www.orpha.net, https://www.orpha.net/en/disease/detail/845. Accessed 5 Feb. 2024.

[9] Rozenberg, R, and L da V Pereira. “The frequency of Tay-Sachs disease causing mutations in the Brazilian Jewish population justifies a carrier screening program.” Sao Paulo medical journal = Revista paulista de medicina vol. 119,4 (2001): 146-9. doi:10.1590/s1516-31802001000400007 https://www.scielo.br/j/spmj/a/HLkR8z3f9wnw3tQQM3P35wn/?lang=en.

[10] “Spinal muscular atrophy | NORD.” NORD (National Organization for Rare Disorders), 12 Jan. 2022, https://rarediseases.org/rare-diseases/spinal-muscular-atrophy/. Accessed 21 Feb. 2024.

[11] “Fibrodysplasia ossificans progressiva: MedlinePlus Genetics.” Medlineplus.gov,” 15 Jul. 2022, https://medlineplus.gov/genetics/condition/fibrodysplasia-ossificans-progressiva/. Accessed 21 Feb. 2024.

[12] “Wolf Hirschhorn syndrome: MedlinePlus Genetics.” Medlineplus.gov,” 22 May 2023, https://medlineplus.gov/genetics/condition/wolf-hirschhorn-syndrome/. Accessed 21 Feb. 2024.

[13] “22q112 deletion syndrome: MedlinePlus Genetics.” Medlineplus.gov,” 01 Dec. 2019, https://medlineplus.gov/genetics/condition/22q112-deletion-syndrome/. Accessed 21 Feb. 2024.

[14] “Guillain-Barré syndrome: MedlinePlus Genetics.” Medlineplus.gov,” 01 Sep. 2011” https://medlineplus.gov/genetics/condition/guillain-barre-syndrome/. Accessed 21 Feb. 2024.

[15] “Whipple disease | NORD.” NORD (National Organization for Rare Disorders), 08 Apr. 2009, https://rarediseases.org/rare-diseases/whipple-disease/. Accessed 21 Feb. 2024.

[16] “Mesothelioma | NORD.” NORD (National Organization for Rare Disorders), 26 Oct. 2020, https://rarediseases.org/rare-diseases/mesothelioma/. Accessed 21 Feb. 2024.

[17] “What is a rare disease?” Eurordis.org, https://www.eurordis.org/information-support/what-is-a-rare-disease/. Accessed 21 Feb. 2024.

[18] “Alkaptonuria: MedlinePlus Genetics.” Medlineplus.gov,” 01 Nov. 2013, https://medlineplus.gov/genetics/condition/alkaptonuria/. Accessed 21 Feb. 2024.

[19] “Huntington disease| NORD.” NORD (National Organization for Rare Disorders), https://rarediseases.org/gard-rare-disease/huntington-disease/. Accessed 21 Feb. 2024.

[20] “Raising the voice for rare diseases: under the spotlight for equity.” eClinicalMedicine, Vol 57, 101941, Mar. 2023, https://www.thelancet.com/action/showPdf?pii=S2589-5370%2823%2900118-9.

[21] “Rare disease research.” Beacon for Rare Diseases, https://www.rarebeacon.org/research/rare-disease-research/. Accessed 5 Feb. 2024.

[22] “Rare Disease Day: Frequently Asked Questions.” https://rarediseases.org/wp-content/uploads/2019/01/RDD-FAQ-2019.pdf. Accessed 22 Feb. 2024.

[23] “RD Metrics – IRDiRC.” International rare diseases research consortium, https://irdirc.org/resources-2/rd-metrics/. Accessed 21 Feb. 2024.

[24] UCL. “Feature: Why Rare Diseases Are Key for Scientific Discovery.” UCL News, 28 Feb. 2023, https://www.ucl.ac.uk/news/2023/feb/feature-why-rare-diseases-are-key-scientific-discovery. Accessed 5 Feb. 2024.

[25] “Juggling care and daily life: the balancing act of the rare disease community.” Eurordis, https://download2.eurordis.org/rbv/juggling_care_and_daily_life.infographic__final.pdf. Accessed 21 Feb. 2024.

[26] European Commission. “Rare Diseases.” Health.ec.europa.eu, https://health.ec.europa.eu/european-reference-networks/rare-diseases_en?prefLang=de. Accessed 22 Feb. 2024.

[27] “Fanconi anemia| NORD.” NORD (National Organization for Rare Disorders), 14 May 2020, https://rarediseases.org/rare-diseases/fanconi-anemia/. Accessed 21 Feb. 2024.

[28] “Orphanet: GRACILE Syndrome.” www.orpha.net, https://www.orpha.net/en/disease/detail/53693?name=gracile&mode=name. Accessed 21 Feb. 2024.

[29] “Maple Syrup Urine Disease| NORD.” NORD (National Organization for Rare Disorders), 05 Jun 2020, https://rarediseases.org/rare-diseases/maple-syrup-urine-disease/. Accessed 21 Feb. 2024.

[30] “Hemophilia: MedlinePlus Genetics.” Medlineplus.gov,” 06 May 2022, https://medlineplus.gov/genetics/condition/hemophilia/. Accessed 22 Feb. 2024.

[31] “Rett syndrome: MedlinePlus Genetics.” Medlineplus.gov,” 01 Oct 2018, https://medlineplus.gov/genetics/condition/rett-syndrome/. Accessed 22 Feb. 2024.

[32] “Pseudomyxoma-peritonei | NORD.” NORD (National Organization for Rare Disorders), 25 Nov 2019, https://rarediseases.org/rare-diseases/pseudomyxoma-peritonei/. Accessed 21 Feb. 2024.