As a result, patients living with rare diseases often encounter serious challenges such as delays in diagnosis or incorrect diagnosis despite scientific advancements. Another major challenge is the shortage of available treatment options. Less than 5% of rare diseases have an available treatment, and only ~30% of patients have access to pharmacotherapy.2,3
Diagnostic complexities
Diagnosing a rare disease is extremely complex. To date, more than 7000 rare diseases have been identified of which ~70% have an onset during childhood, and ~72% are of genetic origin.2,3
Collectively, rare diseases affected ~300 million individuals globally. This translates to ~3.5%-5.9% of the global population. Rare cancers make up the bulk of rare diseases with others caused by infections, allergens, or other environmental factors. It is therefore apparent that, when considered collectively, rare diseases are indeed quite widespread, according to the International Rare Diseases Research Consortium Working Group.2
Physical and psychological impact of delayed diagnosis
Parents of children living with a rare disease describe the period from the onset of initial symptoms to the eventual diagnosis as having a profound physically and psychologically impact. During this time, parents and their children shoulder a considerable burden – causing excessive stress and anxiety.3
The lack of information provided by healthcare professionals further exacerbate the situation, resulting in feelings of frustration, anger and disappointment among families and patients. Furthermore, the absence of sufficient healthcare support amplifies feelings of isolation.3
Schools are often ill-equipped and underfunded to accommodate children with rare diseases, leading families to grapple with the challenge of finding inclusive environments designed to seamlessly integrate their children into educational and social settings enjoyed by their peers.3
Despite the expansion of screening and genetic testing, substantial disparities persist in newborn screening practices among countries, with the high costs of these tests posing a significant barrier to equitable access for every patient.3
What are the most well-known rare diseases?
The most well-known rare diseases are Ehlers Danlos syndrome (EDS), sickle cell disease (SCD), cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), and haemophilia.3
Ehlers Danlos syndrome
EDS comprises hereditary connective tissue disorders characterised by clinical manifestations such as hyper-elastic skin, joint hypermobility, atrophic scarring, and fragile blood vessels.4
Clinical diagnosis is relatively straight-forward, but identifying the specific collagen gene or associated proteins is crucial for determining the EDS type. Accurate identification guides appropriate management and counselling for individuals living with EDS.4
A multi-disciplinary approach is recommended to treat and manage patients living with EDS. Preventing disease progression and subsequent complications should be the focus as there is no cure yet for the disease.4
Sickle cell disease
SCD is a prevalent multisystem disorder. The aetiology of SCD remains incompletely understood, with environmental factors, genetic subtypes, and foetal haemoglobin levels influencing disease manifestation.5
Clinical presentations vary, impacting multiple systems and generally reducing life expectancy. Overall, the management of SCD involves a comprehensive approach tailored to the individual's needs and the specific complications encountered.5
Cystic fibrosis
CF is an autosomal recessive inherited disease that exerts systemic effects on various body systems. Poorly controlled, it significantly impacts both the quality and duration of life.6
As such, treatment strategies aim to optimise function and prevent acute illness events. Key priorities include preserving lung function through proactive management of respiratory infections and mucus clearance, enhancing nutritional status using pancreatic enzyme supplements and multivitamins, and addressing any additional health complications that may arise.6
Duchenne muscular dystrophy
DMD is a severe form of inherited muscular dystrophy and the most common hereditary neuromuscular disease, affecting boys more frequently than girls due to its X-linked recessive inheritance.7
The estimated incidence is one in 3600 male live-born infants. Unfortunately, there is no known treatment to halt the disease's progression, and available options are palliative, with affected individuals typically succumbing to respiratory muscle weakness or cardiomyopathy in their twenties.7
DMD is characterised by mutations in the dystrophin gene, leading to progressive muscle fibre degeneration and weakness. DMD poses a complex set of physical and cognitive challenges, making comprehensive management crucial for improving the quality of life for those affected.7
Symptoms manifest between two- and three-years, starting with difficulty in ambulation and progressing to the point where patients can no longer carry out daily activities without the aid of wheelchairs.7
Physical manifestations include pseudohypertrophy of the calves, lumbar lordosis, scoliosis, and muscle contractures. Respiratory compromise due to scoliosis may occur, along with intellectual impairment observed in all patients, though only 20%-30% have an IQ <70. Cardiomyopathy symptoms emerge in the early teens and affect almost all patients in their twenties.7
The disease also presents challenges like pharyngeal weakness, incontinence, and rare occurrences of malignant hyperthermia after anaesthesia. Current therapies involve glucocorticoids and physiotherapy to manage orthopaedic complications.7
Haemophilia
Haemophilia, characterised by a deficiency in clotting factors, is the most common severe hereditary haemorrhagic disorder. The disorder is often referred to as ‘the disease of the Kings’ due to its historical association with the lineage of Queen Victoria of England.8
Haemophilia A and B result from factor VIII and factor IX protein deficiency, respectively, leading to prolonged and excessive bleeding even after minor trauma or spontaneously. Haemophilia C, caused by factor XI deficiency, is rare. Acquired haemophilia, related to age or childbirth, is another variant that usually resolves with treatment.8
Typically inherited, haemophilia follows an X-linked recessive pattern, affecting males more frequently. The estimated frequency is one in 10 000 live births, with around 400 000 people worldwide living with haemophilia. Haemophilia A is more prevalent than B, presenting in one in 5 000 live male births, while haemophilia B occurs in one in 30 000 live male births.8
As mentioned, the pathophysiology involves a deficiency in clotting factors VIII and IX, disrupting the intrinsic pathway of blood clot formation. Symptoms range from mild to severe, with joint and muscle bleeding being characteristic.8
Severe cases may lead to life-threatening complications such as intracranial haemorrhage, iliopsoas muscle bleeds, and retropharyngeal bleeds, requiring prompt evaluation.8
Diagnosis combines familial history, clinical manifestations, and laboratory testing. Haemophilia is confirmed by assessing factor activity levels, with molecular genotyping used for confirmation and predicting disease severity. Factor inhibitors, antibodies against factor VIII, are also measured to guide treatment.8
Evaluation includes a thorough examination of bleeding symptoms, with laboratory tests such as complete blood count, prothrombin time, partial thromboplastin time, and bleeding time. Additionally, factor assays and molecular genotyping play a crucial role in confirming the diagnosis and predicting disease severity.8
Patients living with haemophilia may present with various bleeding patterns, including joint and muscle bleeding, intracranial and extracranial bleeds, abdominal and thoracic bleeds, and soft tissue contusions.8
How is haemophilia treated?
The haemophilia treatment strategy is divided into two main categories:8
- Management of acute bleeding: The primary goal is to achieve quick and aggressive haemostasis within two hours of symptom onset. Patients should be hospitalised, and high dose clotting factor concentrate (CFC) with factor VIII or IX is administered based on the severity of the bleed. Urgent surgery may be required in specific cases, with CFC replacement preceding or simultaneous to the procedure. Imaging studies determine bleeding sites, and specialty referrals are made accordingly. High-dose CFC continues even if bleeding slows down. Factor levels are monitored, and additional doses are given as needed. Pain management avoids acetylsalicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs).
- Prophylaxis in haemophilia: Prophylactic treatment aims to prevent bleeding episodes, reducing hemarthroses, cerebral and muscle bleeds, and hospitalizations. Primary prophylaxis starts <3-years of age, before osteochondral joint disease onset, while secondary prophylaxis follows the first joint bleed. Continuous or intermittent prophylaxis is categorized by treatment duration. The optimal regimen varies, with protocols like the Malmo and Utrecht protocols commonly used.
Factor VIII dosing calculations depend on body weight, and various schedules exist. Extended half-life products decrease infusion frequency, improving patient quality of life.8
Historically, plasma-derived products treated haemophilia, but in the 1980s, HIV and hepatitis infections prompted safer recombinant factor VIII development.8
Recombinant factor VIII has an extended half-life, minimising infusions. Ongoing research seeks to enhance factor VIII half-lives, reducing infusion frequency and inhibitor development.8
Other pharmacological options include desmopressin, TA, and epsilon aminocaproic acid (EAA) complement coagulation factor concentrates. Desmopressin aids mild or moderate haemophilia A treatment without factor concentrate, especially in haemophilia carriers. TA and EAA Tranexamic acid stabilise clots, primarily for mucocutaneous bleeds or dental surgery.8
Joint bleeding complications necessitate a comprehensive approach. Prophylaxis, initiated early, prevents joint bleeds and haemophilic arthropathy. Acute bleeding episodes require quick factor infusion for haemostasis.8
Pain management differentiates between acute and chronic pain. Acetaminophen is the first choice, followed by cyclooxygenase-2 inhibitors or opioids if necessary. ASA and NSAIDs should be avoided. Persistent pain might require corrective surgery or pain management interventions.8
Physical activity is crucial for maintaining physical fitness, muscle strength, and overall health in patients living with haemophilia. Activities are tailored to the patient's ability and interests. Contact sport should be avoided. Organised sports with appropriate supervision are recommended. Physical therapy before and after joint bleeds or surgery plays a vital role.8
Glanzmann's thrombasthenia
Glanzmann's thrombasthenia (GT), a congenital bleeding disorder first described in 1918, results from a defect or deficiency in the platelet integrin alpha IIb beta3, a crucial component for platelet aggregation and haemostasis.9
Most patients are diagnosed by 14-years, with symptoms improving in some cases by adulthood. The disorder poses lifelong challenges, requiring ongoing management and monitoring.9
GT is caused by mutations in the ITGA2B or ITGB3 genes on chromosome 17q21, following an autosomal recessive pattern. The prevalence is estimated at one in a million, with variations in consanguineous populations.9
The alpha IIb beta3 integrin, or GPIIb-IIIa, functions as the platelet's fibrinogen receptor, essential for clot formation. Platelets in GT lack efficient fibrinogen receptors, leading to spontaneous bleeding or bleeding after injury.9
The disorder affects primary and secondary haemostasis, as platelets in GT are less effective at generating thrombin, crucial for converting fibrinogen to fibrin.9
Symptoms manifest early, often within the first year of life, with bleeding episodes involving mucocutaneous membranes. Common manifestations include epistaxis, menorrhagia, and gingival bleeds.9
Diagnosis involves a bleeding and bruising history, family history, and laboratory tests, such as a complete blood count, activated partial thromboplastin time, and platelet function studies.9
The International Society on Thrombosis and Haemostasis recommends light transmission aggregometry and flow cytometry for definitive diagnosis, with genetic testing for cases that remain undiagnosed after initial evaluations.9
Physical examination focuses on identifying bleeding and its consequences, such as ecchymoses. Treatment aims to manage bleeding episodes, and while there is no cure, platelet transfusions or bone marrow transplantation may be considered in severe cases.9
For mild bleeding, local measures like pressure, cauterisation, sutures, or ice therapy are employed. Antifibrinolytic agents, such as tranexamic acid, can be used as a mouthwash for gingival bleeding.9
In cases unresponsive to local measures or during surgery, platelets and/or recombinant activated clotting factor VII (rFVIIa) may be necessary. Platelet transfusion is standard for surgical prophylaxis and treating moderate to severe bleeding.9
Female patients may require menorrhagia management, ranging from antifibrinolytics to surgical interventions. Pregnancy guidelines recommend prophylaxis for vaginal delivery and caesarean sections.9
While most patients find relief with preventative and symptomatic treatments, hematopoietic stem cell transplant offers a curative option for select cases, requiring careful risk-benefit assessment.9
Conclusion
The complexity of diagnosing and managing rare diseases underscores the need for early detection. Despite their rarity, rare diseases collectively affect a significant portion of the global population, presenting unique challenges in diagnosis and treatment. Delayed diagnoses impose profound physical and psychological burdens on patients and their families.
The scarcity of information exacerbates feelings of frustration and isolation, particularly in educational settings. Early identification of common rare diseases, such as EDS, SCD, CF, DMD, and haemophilia, allows for targeted management and improves the quality of life for affected individuals.
Timely intervention and comprehensive care, including innovative treatments like haematopoietic stem cell transplant, can mitigate the impact of rare diseases, emphasising the critical importance of early diagnosis in enhancing patient outcomes.
REFERENCES:
- Messinger H. In Neurogenetics, Hoofbeats Mean Zebras, Not Horses. Pen Medicine, 2019. [Internet]. Available from: https://www.pennmedicine.org/news/news-blog/2019/september/in-neurogenetics-hoofbeats-mean-zebras-not-horses#:~:text=%E2%80%9CDoctors%20are%20taught%20'when%20you,the%20zebras%2C%E2%80%9D%20Bardakjian%20said.
- Zanello G, Chan CH, Pearce DA, IRDiRC Working Group. Recommendations from the IRDiRC Working Group on methodologies to assess the impact of diagnoses and therapies on rare disease patients. Orphanet J Rare Dis, 2022.
- No author/s listed. Raising the voice for rare diseases: under the spotlight for equity. eClinicalMedicine (Lancet), 2023.
- Miklovic T, Sieg VC. Ehlers-Danlos Syndrome. [Updated 2023 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549814/
- Sedrak A, Kondamudi NP. Sickle Cell Disease. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482384/
- Yu E, Sharma S. Cystic Fibrosis. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493206/
- Venugopal V, Pavlakis S. Duchenne Muscular Dystrophy. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482346/
- Mehta P, Reddivari AKR. [Updated 2023 Jun 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551607/
- Krause KA, Graham BC. Glanzmann Thrombasthenia. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538270/
