Rare Diseases: Everything You Need to Know About Challenges and Advances

Rare diseases present unique and significant challenges to public health, reflecting their complexity in diagnosis, treatment, and research.  

Genetic, phenotypic, and environmental characteristics that define these conditions are not always well established in different populations, making it difficult to standardize diagnoses and therapeutic approaches. Additionally, the lack of knowledge and consensus about these diseases contributes to neglect, delays in care, and limitations in resources available to patients. 

Although each rare disease affects a small number of people, it is estimated that, collectively, they impact about 400 million individuals worldwide, approximately 3.5% to 5.9% of the global population, highlighting the importance of strategies to improve recognition, care, and research in this area. 

In the face of these challenges, better understanding rare diseases and the advancements in healthcare is essential to improving patients’ quality of life and expanding access to diagnostics and treatments. 

In this article, we explore what rare diseases are, how many have been identified, how diagnosis occurs, and what treatments are available. Enjoy reading! 

What is a rare disease? 

 Rare diseases are those that affect a small portion of the population, with their definition varying according to the geographic region (1).  

International health organizations have sought to establish that a disease is considered rare when there is an abnormal condition, damage, or changes in an individual’s health status. Thus, it is understood that they do not occur with extreme frequency compared to more common diseases. 

In the United States, a rare disease is defined as a disorder that affects fewer than 200,000 people. In Europe, this classification applies to diseases that affect fewer than 1 in 2,000 individuals (2).  

In Brazil, a condition is considered rare if it affects fewer than 65 people per 100,000 inhabitants, with an estimated 13 million Brazilians living with one of these diseases. This number represents approximately 6% of the national population, according to the Special Subcommittee on Rare Diseases (3). 

Most rare diseases are chronic, often associated with high morbidity, reduced life expectancy, and impact on reproductive capacity (2). A striking fact is that one in four deaths in neonatal intensive care units is linked to rare genetic disorders.  

Additionally, patients with these conditions represent 10% of hospital discharges and, on average, have longer hospital stays than the general population (4, 5). These factors highlight the growing importance of rare diseases as a public health priority. 

How many rare diseases are there?  

Currently, between 6,000 and 8,000 rare diseases have been identified, and new conditions continue to be described in the literature. Although between 40% and 72% of these diseases are classified as genetic (1, 6), only a small portion of patients are correctly diagnosed, while many remain undiagnosed or receive incorrect diagnoses. 

Even those who manage to obtain an etiological diagnosis face significant challenges throughout the process. This journey, often called the “diagnostic odyssey,” can last for years, involving consultations with various specialists, invasive exploratory exams, and a series of laboratory and diagnostic investigations (7).  

Although there are incentives, such as the designation of orphan drugs, to date, only about 5% of these rare diseases have licensed treatments (8). 

The lack of knowledge about rare diseases has consequences: delayed diagnosis, which can take several years; psychological stress for the patient and their family; reduced family income due to leaving work in search of the cause of unexplained symptoms, as well as the emergence of irreversible complications and late treatment (9). 

What are the types of rare diseases?  

Rare diseases can be categorized based on their clinical prominence and relevance to public health, with causes associated with genetic, environmental, infectious, immunological factors, among others. 

Genetic and Hereditary Diseases 

• Cystic Fibrosis: affects the lungs and digestive system, caused by mutations in the CFTR gene.
• Duchenne Muscular Dystrophy: a progressive condition affecting muscles, linked to the X chromosome.
• Fanconi Anemia: a hereditary disease causing bone marrow failure and increased cancer risk.
• Rett Syndrome: mainly affects girls, causing regression of motor and cognitive development. 

Neurological and Neurodegenerative Diseases 

• Amyotrophic Lateral Sclerosis (ALS): characterized by the degeneration of motor neurons.
• Huntington’s Disease: hereditary and progressive, affecting motor and cognitive functions.
• Prader-Willi Syndrome: involves hypotonia, obesity, and intellectual disability, linked to genetic changes on chromosome 15. 

Metabolic Diseases 

• Phenylketonuria: a disorder in the metabolism of phenylalanine, treatable with a restrictive diet.
• Gaucher Disease: caused by a deficiency of the enzyme beta-glucocerebrosidase, leading to lipid accumulation in cells and organs.
• Fabry Disease: related to the accumulation of sphingolipids due to a deficiency of the enzyme alpha-galactosidase. 

Rare Autoimmune and Inflammatory Diseases 

• Systemic Lupus Erythematosus (SLE): although not rare in all populations, some variants are extremely specific.
• Behçet’s Syndrome: an inflammatory condition affecting multiple systems.
• Systemic Scleroderma: affects the skin and internal organs, with specific variants. 

Hematological Diseases 

• Thalassemias: hereditary diseases affecting hemoglobin production.
• Hemophilia: a blood clotting disorder, usually linked to the X chromosome.
• Diamond-Blackfan Syndrome: insufficiency in the production of red blood cells. 

Rare Ophthalmological and Auditory Diseases 

• Retinitis Pigmentosa: a progressive condition that can lead to blindness.
• Usher Syndrome: a combination of hearing loss and retinitis pigmentosa. 

Rare Infectious or Environmental Diseases 

• Familial Mediterranean Fever: recurrent inflammation due to a genetic mutation.
• Morgellons Syndrome: a controversial condition associated with the perception of filaments emerging from the skin. 

What are the main rare diseases?  

Rare diseases encompass a wide range of conditions that can affect various body systems, presenting varied and often challenging clinical manifestations for diagnosis and treatment.  

Despite their low individual prevalence, these conditions, when considered together, represent a significant impact on public health and demand personalized care strategies.  

Examples such as Huntington’s disease, osteogenesis imperfecta, neurofibromatosis, and Gaucher disease demonstrate the diversity of these pathologies, which include neurological, metabolic, structural, and genetic disorders. 

Although many rare diseases predominantly affect children, they can manifest at different stages of life, compromising development and causing disabilities of varying degrees of severity.  

Some have a limited impact on quality of life, while others can be severe or even fatal. The similarity of their symptoms to those of common diseases often delays diagnosis, reinforcing the need for a multidisciplinary and agile approach for proper management (10).  

Among these diseases, we can mention: 

• Huntington’s Disease: a genetic neurodegenerative condition causing progressive deterioration of motor, cognitive, and behavioral functions. Caused by mutations in the HTT gene (11).
• Gaucher Disease: a metabolic condition caused by a deficiency of an enzyme (glucocerebrosidase), leading to the accumulation of fatty substances in organs such as the spleen, liver, and bones. Caused by mutations in the GBA1 gene (12).
• Rett Syndrome: a rare genetic disorder affecting neurological development, mainly in girls, causing loss of motor and communication skills after an initial period of normal development. Mainly caused by mutations in the MECP2 gene (13).
• Neurofibromatosis: a group of genetic conditions characterized by the growth of benign tumors along the nerves, which can cause skin changes, bone problems, and, in severe cases, neurological complications. Associated with mutations in the FN1 and FN2 genes (14).

How is the diagnosis of rare diseases made?  

Traditionally, genetic investigations in individuals with rare diseases aimed to confirm clinical suspicions of Mendelian disorders or chromosomal syndromes, guide genetic counseling, and enable prenatal or pre-implantation testing for couples at high risk of recurrence.  

Currently, molecular diagnosis has become essential in precision medicine, allowing personalized treatments, surveillance strategies, and, in some cases, targeted therapies. The use of genomic sequencing as a first-line tool significantly reduces the time to diagnosis, mitigating the so-called “diagnostic odyssey” (15). 

The discovery and understanding of rare diseases have evolved significantly over the past decades, driven by technological advances such as Sanger sequencing, PCR, and positional cloning.  

Chromosomal microarray brought new perspectives on structural variants and copy number in the genome, especially in children with developmental delays and/or congenital malformations (16).  

In 2023, the Online Mendelian Inheritance in Man (OMIM) catalog listed 7,352 phenotypes with known molecular causes, more than 5,000 of which have been molecularly characterized in the last 20 years (17). 

• Next-Generation Sequencing (NGS) 

Next-generation sequencing (NGS), based on short DNA reads, has the main advantage of being able to simultaneously investigate multiple genomic regions. This makes it ideal for diagnosing Mendelian diseases with genetic heterogeneity (similar phenotypes, different genotypes) (18). 

NGS can be applied in different ways, the most common being targeted panels, exome sequencing, and genome sequencing. The main advantage of genome sequencing over targeted approaches, such as gene panels and exome sequencing, is its ability to detect single nucleotide variants (SNVs) and structural variants (SVs), including balanced rearrangements and short tandem repeats (19-21).  

Additionally, although exome sequencing captures all coding regions of the genome, genome sequencing is superior even in detecting coding SNVs due to its more uniform coverage (22). 

• Chromosomal Array 

Chromosomal arrays allow the detection of alterations in small chromosomal segments that are not identified by traditional methods. These techniques enable the identification of copy number variations (CNVs), uniparental disomy, and loss of heterozygosity, characteristics present in microdeletion, microduplication syndromes, and complex chromosomal rearrangements. 

This method is especially useful in investigating patients with neuropsychomotor developmental delays, intellectual disabilities, autism spectrum disorder, seizure disorders, and congenital malformations (23). 

Thus, chromosomal arrays have emerged as a powerful tool in the investigation of rare diseases, providing faster and more accurate diagnoses. This precision is essential for identifying genetic syndromes, allowing appropriate therapeutic interventions and more efficient genetic counseling. 

What is the most comprehensive genetic test?  

There is no single test or genetic examination that can be considered complete for the diagnosis of rare diseases, as each method has specific purposes and technical limitations. 

However, different approaches are often used complementarily to enhance diagnostic accuracy. For example, next-generation sequencing (NGS) allows the simultaneous analysis of multiple genes associated with certain conditions, while karyotyping or comparative genomic hybridization (CGH-array) are more suitable for detecting larger structural alterations in the genome.  

In some cases, methods such as PCR, Sanger sequencing, or functional analysis techniques are incorporated to validate specific variants or explore underlying molecular mechanisms. 

Thus, the choice of diagnostic strategy should be personalized, considering the patient’s clinical picture, family history, and initial laboratory findings. 

How are rare diseases treated?  

Most rare diseases have no cure, and the available treatments are largely aimed at reducing symptoms, preventing complications, and improving quality of life. 

These conditions, often chronic and complex, require multidisciplinary approaches involving professionals such as doctors from various specialties, nurses, nutritionists, physiotherapists, psychologists, among others. 

The Ministry of Health develops Clinical Protocols and Therapeutic Guidelines (PCDTs) to guide the management of these diseases, currently totaling 62 documents focused on rare conditions.  

However, many diseases still lack specific protocols and are treated based on the general guidelines of the Unified Health System (SUS) and guidance from specialized outpatient clinics or reference services (10). 

Rare diseases, often without effective treatments, find a promising solution in gene therapy due to its ability to correct specific genetic alterations. 

Gene Therapy and Rare Diseases 

Originally conceived as a means to alleviate or cure diseases by correcting defective genes, gene therapy has evolved to encompass various therapeutic interventions, being considered an innovative approach that treats or cures diseases by modifying the patient’s genetic material.  

It can be performed in vivo (directly in the body) or ex vivo (cells modified outside the body and reintroduced). Methods include viral vectors, such as AAV and lentivirus, and technologies like CRISPR and antisense oligonucleotides (24). 

Notable examples in rare diseases are Luxturna, which treats Leber congenital amaurosis type 2, restoring vision in patients, and Strimvelis for severe combined immunodeficiency associated with ADA deficiency (24). 

These advances show how gene therapy can improve the quality of life for patients with difficult-to-treat diseases, despite challenges such as high costs and technical complexity. Moreover, these treatments offer hope for patients who previously had no viable therapeutic alternatives. 

Advances and Challenges in the Global Rare Diseases Landscape  

In recent years, research and investment in rare diseases have advanced significantly. A report by the organization Global Genes revealed that in 2021, drug developers allocated $22.9 billion to research in this field, a 28% increase from the previous year (25).  

This evolution reflects a growing awareness of the importance of these conditions, highlighted annually on Rare Disease Day, celebrated on February 28. 

Despite the advances, many challenges remain. Access to diagnostics and treatments of rare diseases remains unequal. While patients in developed countries are more likely to receive adequate care, the limitations are much greater in developing countries.  

Health policies have played a crucial role in reducing these disparities. In Europe, for example, the European Plan for Rare Diseases aims to improve diagnosis, treatment, and support for patients. 

Research is also gaining momentum. Technological advances, such as whole genome sequencing, have shown promise for diagnosing complex genetic diseases, such as myotonic dystrophy, Huntington’s disease, and hereditary ataxias. These technologies offer high sensitivity and specificity, allowing the identification of previously undiagnosed disorders. 

However, the challenges are numerous. The lack of knowledge among healthcare professionals, the high cost of orphan drugs, and the scarcity of effective treatments hinder progress. Additionally, more research and support networks for patients and families are essential to improve their quality of life. 

International efforts have also been highlighted. The International Rare Diseases Research Consortium (IRDiRC) has already surpassed some ambitious goals, such as approving 200 new therapies before 2020 (26). 

For the next decade, the consortium plans to ensure rapid diagnoses – within one year – for patients with suspected rare diseases, approve 1,000 new therapies, and develop methodologies to assess the impact of treatments on patients’ lives (27).  

Collaboration between various sectors is considered essential to achieve these goals and transform the global rare diseases landscape. 

February and Rare Disease Day: A Milestone for Awareness 

February was chosen as a symbol of awareness for rare diseases due to its peculiarity: in leap years, it gains an extra day, which alludes to the rarity of these conditions.  

Rare Disease Day is celebrated on the last day of February, whether on the 28th or the 29th, when applicable. 

Created in 2008 by the European Organization for Rare Diseases (EURORDIS), the date aims to raise awareness about these conditions, mobilize public opinion, and highlight the challenges faced by patients and their families.  

It is also an opportunity to promote advances in diagnosis, treatment, and social inclusion for those living with these conditions. 

What tests does SYNLAB offer for investigating rare diseases?  

SYNLAB offers a wide range of tests aimed at investigating rare diseases, meeting the specific needs of each clinical case.  

Among the available tests, the following stand out: 

• Whole Exome Sequencing: Analyzes all coding regions of the human genome, responsible for about 85% of known disease-causing mutations. It is indicated for patients with suspected Mendelian genetic conditions or complex clinical presentations.

• Exome Focused on Intellectual Disability and Autism: Aimed at investigating genetic causes associated with neurodevelopmental disorders, such as intellectual disability, autism spectrum disorder, and epilepsy. This test focuses on the coding regions most frequently associated with these conditions, providing a more targeted and efficient diagnosis.

• Whole Exome + Mitochondrial Genome: In addition to exploring the coding regions of the nuclear genome, it includes a detailed analysis of the mitochondrial genome, essential for investigating diseases related to energy metabolism and mitochondrial hereditary conditions.

• Postnatal Array: Uses chromosomal arrays to detect copy number variations (CNVs), uniparental disomy, and loss of heterozygosity, ideal for investigating cases of neuropsychomotor developmental delay, intellectual disability, autism, and congenital malformations.

• Next-Generation Sequencing Panels: Performed with targeted panels for specific diseases or custom panels with the choice of genes at the discretion of the requesting physician.

Get to know SYNLAB – A Leader in Medical Diagnostic Services! 

Accurate and up-to-date testing is essential for precise diagnoses and better treatment guidance. SYNLAB is here to help. 

We offer diagnostic solutions with rigorous quality control to the companies, patients, and healthcare providers we serve. Present in Brazil for over 10 years, we operate in 36 countries across three continents and are leaders in diagnostic services in Europe. 

Contact the SYNLAB team to learn about our available tests. 

References: 

1. Nguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28:165–73.

2. Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019;179:885–92.

3. BRASIL. Câmara Dos Deputados. Subcomissão especial de doenças raras: relatório final. Brasília, 2019. Disponível em: https://www.camara.leg.br/proposicoesWeb/prop_mostrarintegra?codteor=1839802& filenam e=Tramitacao-REL+1/2019+SUBRARAS.

4. Wojcik MH, Schwartz TS, Yamin I, Edward HL, Genetti CA, Towne MC, et al. Genetic disorders and mortality in infancy and early childhood: delayed diagnoses and missed opportunities. Genet Med. 2018;20:1396–404.

5. Walker CE, Mahede T, Davis G, Miller LJ, Girschik J, Brameld K, et al. The collective impact of rare diseases in Western Australia: an estimate using a population-based cohort. Genet Med. 2017;19:546–52.

6. Souza IP; Androlage JS; Bellato R; Barsaglini RA. Ciênc. saúde coletiva. 2019;24(10). A qualitative approach to rare genetic diseases: an integrative review of the national and international literature. https://doi.org/10.1590/1413-812320182410.17822019

7. Molster C, Urwin D, Di Pietro L, Fookes M, Petrie D, Van Der Laan S, et al. Survey of healthcare experiences of Australian adults living with rare diseases. Orphanet J Rare Dis. 2016;11:30.

8. Bax BE. Biomarkers in Rare Diseases. Int. J. Mol. Sci. 2021,22, 673.

9. Lima, MAFD. As associações de pacientes com doenças raras e as mídias sociais. 2018. 167 f. Tese (Doutorado em Ciências) – Instituto Nacional da Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro, 2018. Pág 52. Disponível em: https://www.arca.fiocruz.br/bitstream/icict/40463/2/maria_lima_iff_dout_2018.pdf.

10. Ministério da Saúde: https://www.gov.br/saude/pt-br/composicao/saes/doencas-raras

11. McColgana P, Tabrizi SJ. Huntington’s disease: a clinical review. Eur Journal of Neurology 2018, 25: 24–34.

12. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int. J. Mol. Sci. 2017, 18, 441.

13. Vilvarajan S, McDonald M , Douglas L, Newham J, Kirkland R, Tzannes G, et al. Multidisciplinary Management of Rett Syndrome: Twenty Years’ Experience. Genes 2023, 14, 1607.

14. Weisman AG, McQuaid SW, Radtke HB, Stoll J, Brown B, Gomes A. Neurofibromatosis- and schwannomatosis-associated tumors: Approaches to genetic testing and counseling considerations. Am J Med Genet. 2023;191A:2467–2481.

15. Tesi B, Boileau C, Boycott KM, Canaud G, Caulfield M, Choukair D, et al. Precision medicine in rare diseases: What is next? J Intern Med.2023;294:397–412.

16. Speicher MR, Carter NP. The new cytogenetics: blurring the boundaries with molecular biology. Nat Rev Genet.2005;6:782–92.

17. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). https://omim.org/

18. Wright CF, Fitzpatrick DR, Firth HV. Paediatric genomics: diagnosing rare disease in children. Nat Rev Genet. 2018;19:253–68.

19. Lindstrand A, Eisfeldt J, Pettersson M, Carvalho CMB, Kvarnung M, Grigelioniene G, et al. From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of diseasecausing genetic variation underlying intellectual disability. Genome Med. 2019;11:68.

20. Eisfeldt J, Vezzi F, Olason P, Nilsson D, Lindstrand A. TIDDIT, an efficient and comprehensive structural variant caller for massive parallel sequencing data. F1000Res.2017;6:664.

21. Dolzhenko E, Van Vugt JJFA, Shaw RJ, Bekritsky MA, Van Blitterswijk M, Narzisi G, et al. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res. 2017;27:1895–903.

22. Belkadi A, Bolze A, Itan Y, Cobat A, Vincent QB, Antipenko A, et al. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. PNAS. 2015;112:5473–8.

23. Evangelidou P, Alexandrou A, Moutafi M, Ioannides M, Antoniou P, Koumbaris G, et al. Implementation of high resolution whole genome array CGH in the prenatal clinical setting: advantages, challenges, and review of the literatura. Biomed Res Int. 2013:2013:346762. doi: 10.1155/2013/346762. Epub 2013 Mar 4.

24. Papaioannou I, Owen JS, Yáñez-Muñoz RJ. Clinical applications of gene therapy for rare diseases: A review. Int J Exp Path. 2023;104:154–176.

25. Report from Global Genes https://www.businesswire.com/news/home/20220112005794/en/New-Report-Shows-28-Increasein-YoY-Funding-for-Rare-Disease-Drug-Developmentin-2021

26. Goal of the IRDiRC: https://irdirc.org/about-us/vision-goals/

27. Rare 2030 Foresight Study http://download2.eurordis.org/rare2030/Rare2030_recommendations.pdf