Rare diseases: Not such a rare problem

Written by Alice H. , Chloe Dodsworth , and Jessica Page-Campbell

What are rare diseases?

As the name suggests, rare diseases (RDs) are inherently uncommon, but just how infrequent does a disease have to be before it is considered ‘rare’? A disease is defined as ‘rare’ if it affects <1 in 2,000?people in Europe or <200,000 people in the United States (1). It is estimated that 3.5–5.9% of the world’s population have a diagnosis of one of 6,000 known RDs, with 250–280 new diseases described annually (1–3). According to research, the 5 rarest diseases are:

1. Perinatal hypophosphatasia (0.03/100,000 people): Characterised by an absence of bone calcification and vitamin B6-dependent seizures (4,5)
2. Congenital factor XIII deficiency (0.04/100,000 people): Patients experience prolonged bleeding episodes due to an inability to form stable blood clots (6)
3. Tyrosinemia type 1 (0.05/100,000 people): Patients are unable to break down the amino acid tyrosine causing elevated blood levels which can result in liver and kidney failure (7)
4. Dopa-responsive dystonia (DRD [0.05/100,000 people]): Symptoms include muscle contractions that cause abnormal, painful repetitive movements of the lower limbs (8)
5. Fibrodysplasia ossificans progressiva (0.08/100,000 people): Tendons and ligaments in the body become bone over time limiting movement (9)

What causes RDs?

Next-generation genomics and improved data sharing have enabled us to decipher the genetic origin of 80% of RDs, resulting from the faster discovery of causative genes (2,10). For example, in Sanfilippo syndrome subtype A (childhood dementia), variants in the SGSH gene cause heparan sulphate (a sugar) to accumulate causing cell death and dementia (11). RDs can be caused by disordered immunity, infections, allergies, disruption to development in the womb, and deterioration of body tissues and organs (10).

The long, winding road to a diagnosis

RDs are often difficult to diagnose as their symptoms can be unfamiliar and/or atypical to clinicians, preventing a timely diagnosis (1,12). For example, in Europe, 25% of patients waited 5–30 years from disease onset to a RD diagnosis (3). Therefore, it is vital to raise awareness of RDs to avoid misdiagnosis, one of the main aims of RD awareness day, held annually on February 28th (13).

Do you know why the zebra logo was chosen for RDs? Dr Theodore Woodward, a Nobel Prize nominee, once said when teaching about diagnosing patients: “When you hear the sound of hooves, think horses, not zebras.” (14,15). This metaphor expresses that clinicians should expect and accept the most common outcome, the horse, instead of the rarer outcome, the zebra (14,15). The zebra logo is used to remind healthcare professionals to consider the rarer outcome when making diagnoses as RDs are less uncommon than once thought (14,15).

Are there treatments?

Even when patients receive a diagnosis, <5% of diagnosed RDs have suitable treatment options (3,12). For example, DRD’s muscular symptoms can be treated successfully by a dopamine precursor (8). Where possible, patients should be treated at centres of expertise where there is access to a specialist multidisciplinary team. However, these are geographically widespread and few and far between, a problem which could be overcome by offering virtual appointments (12). Often when there is no disease-modifying treatment, the focus is on the clinical management of patients, which requires a multidisciplinary team of psychologists, physicians, and occupational therapists (12,16).

Sadly, more than 75% of RDs affect children and ~30% of these children die before their 5th birthday (10). Despite this urgent need for clinical research into RDs, it has largely been neglected due to a limited target market and profitability for pharmaceutical companies (17). Unfortunately, only ~6% of drugs in clinical trials for RDs are successful, mostly for rare forms of cancer (17). There is an imperative need for an improved understanding of the biology that underlies RDs (17). Due to the small and clinically diverse number of patients with each RD, proving a drug’s benefit in clinical trials is challenging (17). This may be overcome through the development of specific clinical measures for RD (17).

Despite this, clinical trials are making significant progress with RD research and therapies (18). The number of clinical trials for RDs has risen by 88% from 2006?2016, leading to 164 new treatments for around 90 RDs by 2018 (19,20). There is hope for the future as research and development into RDs is continuously pushing the boundaries of medical knowledge (18).

The individual and societal impact of RD

RDs have prompted changes to global public health policy due to RD-associated challenges (3). But, which challenges have catalysed this?

Treatments for RDs are typically more expensive and can be as much as 13.8 times more expensive than ‘conventional’ treatments (3). In Western Australia for example, only 2% of the population in 2010 was affected by 467 RDs, but this accounted for 10.5% of in-patient hospital costs (2). Although very few RDs have established treatments, where they do exist, they can be life-changing to patients living with a RD (10).

The impact of RDs extends to family members and caregivers, affecting approximately 1.05–1.4?billion people globally (3,10,12). The effects are far-reaching, including education, finance, stability, mobility, and mental health (10). Since RDs predominantly affect children, parents often face a significant care burden, requiring time off work to look after their children or attend appointments, which can impact their ability to hold full-time employment (2,10). Furthermore, patients living with a RD and their carers can also feel isolated and excluded from society because of social discrimination and limited RD awareness (3).

The importance of patient advocates

Patient advocates are a lifeline for patients with RDs, who have faced inadequate support from healthcare professionals and wider society (21). These groups can offer patients the medical information, understanding, and support required to make informed decisions about their health, including treatment choices (21). Patient advocacy groups also lead research projects, launch awareness campaigns, and advocate for the approval of treatments (21). Additionally, input from patient advocacy groups has been pivotal in deciding clinical trial outcomes (22).

Research into RDs doesn’t just help the small patient populations directly affected, it can also shine a light on more common health conditions (23). A brilliant illustration of this is the discovery of the regulation of a fatty substance known as cholesterol, through a type of receptor for fat transporters (low-density lipoprotein receptor[LDLR]) (23). In the 1970s, the American researchers Dr Michael Brown and Dr Joseph Goldstein began studying an RD known as familial hypercholesterolaemia, which affects the way the body processes cholesterol (23,24). They discovered that cholesterol was regulated through the LDL receptor, paving the way for the development of one of the world’s most prescribed class of drugs for cardiovascular disease: statins (23,24). What started as research into a RD ended up revolutionising the treatment of cardiovascular disease, the number one cause of death in the world (23).

Some top tips for living with or caring for a person with an RD include (25,26):

What steps are being taken in RD care?

Since individual RDs affect small numbers of people who are scattered globally, communities must work together to improve the lives of those living with RDs (2,10). This is where the International Rare Disease Research Consortium (IRDiRC) comes in (3). Established in 2011, the IRDiRC facilitates international collaboration between public and private sectors, patient advocacy groups, government research funding bodies, and academia (3). The IRDiRC aims to (3):

1. Develop new methods for RDs that assess diagnosis and the impact of treatment
2. Approve 1,000 new treatments for RDs (particularly for RDs without approved treatments)
3. Provide a diagnosis for all individuals with a suspected RD, within a year of that particular RD being reported in the literature

The UK Rare Diseases Framework have set out 4 priorities that have been identified from a National Conversation on Rare Diseases Survey, the results are illustrated in Figure 1. (10). The 4 priorities are (10):

1. Helping patients get a quick and accurate diagnosis
2. Raising awareness of RDs among healthcare professionals
3. Improved coordination between healthcare professionals and better support during the transition between paediatric and adulthood services
4. Utilising new digital tools to support the coordination of care e.g., holding virtual multidisciplinary team meetings or providing video appointments

?Figure 1: Challenges Faced By Patients With RDs (UK Rare Diseases Framework: National Conversation Survey (10)

Conclusion

RDs affect 300 million people worldwide, with hundreds of new RDs being described every year (1,2). The causes of RDs are numerous and diverse with advances in genomic techniques facilitating the discovery of those with genetic origin (2,10). However, RDs remain difficult to diagnose and can be life-threatening and life-limiting, impacting not only the person affected, but also generating a substantial societal burden (10,12). Therefore, raising awareness of RDs is vital to combat delays in diagnosis (10).

While a small number of RDs have established treatments, the therapies that do exist can be life?changing to patients living with RD (10). If you wish to learn more about RDs, be sure to keep an eye out for further blogs in Bham Pharma’s mini-blog series on RDs coming out this month.

References

1. Li X, Wang Y, Wang D, Yuan W, Peng D, Mei Q. Improving rare disease classification using imperfect knowledge graph. BMC Medical Informatics and Decision Making. 2019;19(5):238.
2. Dawkins HJS, Draghia-Akli R, Lasko P, Lau LPL, Jonker AH, Cutillo CM, et al. Progress in Rare Diseases Research 2010–2016: An IRDiRC Perspective. Clinical and Translational Science. 2018;11(1):11–20.
3. Chung CCY, Chu ATW, Chung BHY. Rare disease emerging as a global public health priority. Front Public Health. 2022;10:1028545.
4. Euroridis, Orphanet. Rare diseases in numbers. 2021.
5. Oyachi M, Harada D, Sakamoto N, Ueyama K, Kondo K, Kishimoto K, et al. A case of perinatal hypophosphatasia with a novel mutation in the ALPL gene: clinical course and review of the literature. Clinical Pediatric Endocrinology. 2018;27(3):179.
6. Factor XIII Deficiency - National Organization for Rare Disorders [Internet]. [cited 2023 Jan 31]. Available from: https://rarediseases.org/rare-diseases/factor-xiii-deficiency/
7. Tyrosinemia Type 1 - National Organization for Rare Disorders [Internet]. [cited 2023 Jan 31]. Available from: https://rarediseases.org/rare-diseases/tyrosinemia-type-1/
8. Dopa-responsive dystonia [Internet]. Dystonia UK. 2020 [cited 2023 Jan 31]. Available from: https://www.dystonia.org.uk/pages/faqs/category/dopa-responsive-dystonia
9. Fibrodysplasia ossificans progressiva: MedlinePlus Genetics [Internet]. [cited 2023 Jan 31]. Available from: https://medlineplus.gov/genetics/condition/fibrodysplasia-ossificans-progressiva/
10. The UK Rare Diseases Framework [Internet]. GOV.UK. [cited 2023 Jan 30]. Available from: https://www.gov.uk/government/publications/uk-rare-diseases-framework/the-uk-rare-diseases-framework
11. Selemin J. What Is Sanfilippo Syndrome? [Internet]. WebMD. [cited 2023 Jan 24]. Available from: https://www.webmd.com/children/what-is-sanfilippo-syndrome
12. Long JC, Best S, Nic Giolla Easpaig B, Hatem S, Fehlberg Z, Christodoulou J, et al. Needs of people with rare diseases that can be supported by electronic resources: a scoping review. BMJ Open. 2022;12(9):e060394.
13. Rare Disease Day 2023 [Internet]. Rare Disease Day 2023. [cited 2023 Jan 31]. Available from: https://www.rarediseaseday.org/
14. Why the zebra? – The Ehlers-Danlos Support UK [Internet]. [cited 2023 Jan 31]. Available from: https://www.ehlers-danlos.org/about-us/charity-aims-and-focus/why-the-zebra/
15. Why the Zebra? [Internet]. CACP Research Foundation. [cited 2023 Jan 31]. Available from: https://www.cacpresearchfoundation.org/why-the-zebra
16. Muschol N, Giugliani R, Jones SA, Muenzer J, Smith NJC, Whitley CB, et al. Sanfilippo syndrome: consensus guidelines for clinical care. Orphanet J Rare Dis. 2022;17:391.
17. Rudebeck M, Scott C, Rhodes NP, van Kan C, Olsson B, Al-sbou M, et al. Clinical development innovation in rare diseases: lessons learned and best practices from the DevelopAKUre consortium. Orphanet Journal of Rare Diseases. 2021 Dec 14;16(1):510.
18. Mellerio JE. The challenges of clinical trials in rare diseases. Br J Dermatol. 2022 Oct;187(4):453–4.
19. European Medicines Agency. Orphan Medicinal Product Designation Overview 2000-2021. 2022.
20. Pugatch Consilium. BENCHMARKING SUCCESS Evaluating the Orphan Regulation and its impact on patients and rare disease R&D in the European Union. 2019.
21. What are patient advocacy groups? | Rare disease patient groups [Internet]. Beacon. [cited 2023 Jan 31]. Available from: https://www.rarebeacon.org/rare-diseases/why-patient-groups-matter/
22. How Patient Advocates Help Cancer Research: An Expert Q&A [Internet]. Cancer.Net. 2019 [cited 2023 Jan 31]. Available from: https://www.cancer.net/research-and-advocacy/introduction-cancer-research/how-patient-advocates-help-cancer-research-expert-qa
23. Megget K. How rare disease research benefits everyone [Internet]. Raconteur. 2022 [cited 2023 Feb 1]. Available from: https://www.raconteur.net/healthcare/rare-disease-research-benefits/
24. Goldstein JL, Brown MS. Familial Hypercholesterolemia: Identification of a Defect in the Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity Associated with Overproduction of Cholesterol. Proc Natl Acad Sci USA. 1973 Oct;70(10):2804–8.
25. Tips for Coping With a Rare Disease [Internet]. [cited 2023 Jan 30]. Available from: https://www.painscale.com/article/tips-for-coping-with-a-rare-disease
26. Raising children with rare diseases and conditions [Internet]. Raising Children Network. [cited 2023 Jan 30]. Available from: https://raisingchildren.net.au/disability/family-life/communicating-relationships/raising-children-with-rare-diseases