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Rare diseases: What rheumatologists need to know?
Advances in Rheumatology volume 64, Article number: 74 (2024)
Abstract
Although the terms “rare diseases” (RD) and “orphan diseases” (OD) are often used interchangeably, specific nuances in definitions should be noted to avoid misconception. RD are characterized by a low prevalence within the population, whereas OD are those inadequately recognized or even neglected by the medical community and drug companies. Despite their rarity, as our ability on discovering novel clinical phenotypes and improving diagnostic tools expand, RD will continue posing a real challenge for rheumatologists. Over the last decade, there has been a growing interest on elucidating mechanisms of rare autoimmune and autoinflammatory rheumatic diseases, allowing a better understanding of the role played by immune dysregulation on granulomatous, histiocytic, and hypereosinophilic disorders, just to name a few. This initiative enabled the rise of innovative targeted therapies for rheumatic RD. In this review, we explore the state-of-the art of rare RD and the critical role played by rheumatologists in healthcare. We also describe the challenges rheumatologists may face in the coming decades.
Introduction
Over the past five centuries, interest in the approach of disorders with low prevalence has slowly increased. The concept of rare diseases (RD) is discussed as far as 1581 by Rembert Dodoens, a Flemish physician author of “Medicinalium Observationum Exempla Rara, Recognita et Aucta”, in which an extensive list of 200 RD is described [1]. However, over the centuries, the distinction between RD and orphan diseases (OD) remains unclear and may have different definitions.
The National Institute for Health Orphan Drug Act has defined RD as a disease or condition that affects fewer than 200,000 people in the United States in 1983, representing a prevalence of 86 cases/100,000 citizens at that time [2]. European Union currently considers RD those affecting fewer than 1 in 2000 citizens (or 50 in 100,000 people), and the World Health Organization (WHO) suggested a frequency of less than 65 per 100,000 people [3]. Although the terms RD and OD are often used interchangeably, OD are defined as those underappreciated or neglected by the medical community and drug companies, for which research on diagnosis and effective treatment is sparse. Therefore, RD and OD are not synonymous, as some low-income countries prevalent diseases without commercial interest of research may still be orphan [4]. Although controversial, the National Institute for Health and Care Excellence for Drugs has introduced a novel subcategory of ultra-rare diseases, representing any illness with a prevalence lower than 1 per 50,000 individuals [5].
Despite the increasing burden of RD over time, reliable epidemiologic data are still lacking [6]. A total of 7000 RD affecting 20.5 million people in the United States and 46.5 million in Europe have been identified. Although individually rare, they collectively affect almost 10% of the global population, and this number is continuously growing as an estimated 250 new RD are being described yearly [5, 6]. Although awareness of RD has increased over the last decades, underdiagnosis is still a reality, and a long avenue to improve the unmet demands of the area is open. In this review, we explore the field of RD and how rheumatologists can play a critical role in their healthcare.
Epidemiological aspects
Although literature is laconic on unquestionable studies determining the real prevalence of RD worldwide, Wakap et al. [7] recently estimated that 3.5–5.9% of the world’s population (263–446 million people) might carry any RD. As 71.9% of these diseases have a genetic etiology and, therefore commonly manifest early in life, 69.9% of them are exclusive to the pediatric age group. Nevertheless, genetic inheritance also contributes to the understanding that certain rare diseases are more prevalent in smaller ethnicities or populations with a high rate of consanguinity (e.g., Gaucher disease and cystic fibrosis in Ashkenazi Jews), or in other subpopulations where the presence of a specific condition represents a biological survival advantage against other environmental challenges (e.g., sickle cell anemia in regions of Africa with a high prevalence of malaria) [7].
Moreover, up to 80.7% of these studied patients were concentrated in only 4.2% of the 6000 considered RD, all of which had a prevalence of 10–50/100,000 individuals, thus falling into the more “common” epidemiological stratum within the realm of reality [7]. Could this discovery truly be attributed to the higher frequency of these diseases? Or is it secondary to a greater number of diagnoses provided by physicians, given that, unlike lesser-known conditions, these clinical entities are at least discussed during their medical training? Despite the absence of a definite answer for this question, the financial burden of having a rare disease in the United States is significant and has a direct impact on public health. According to the National Organization for Rare Disorders (NORD) 2019 survey, 76% of respondents reported experiencing financial challenges due to their own or their family member’s rare diagnosis. Furthermore, certain support resources are not being fully utilized due to the lack of clinical data on unmet financial resources, direct and indirect costs of treatments, patient disability, or lack of benefits for caregivers [8].
Policy panorama and main limitations for RD research
Since its creation in 1983, the Orphan Drug Act has designated over 5000 drugs and biologics for OD in the United States [9]. Despite considerable progress in product approvals, the majority of the estimated 7000 known RD remains unaddressed [10]. Analysis of an internal Food and Drug Administration (FDA) database reveals that only 19% of the 199 drugs designated for OD from 1983 to 2019 have been approved [9].
Several caveats on RD-related scientific research challenges new orphan drugs approval and clinical trials conduction, including (but not restricted to): (1) unclear pathophysiology mechanisms, which make it difficult to identify potential therapeutic targets; (2) limited patient population, hardening recognition and recruitment of individuals; (3) heterogeneous manifestations, making it difficult to homogenize populational samples; (4) lack of well-established diagnostic criteria and reliable biomarkers for robust statistical data; (5) higher prevalence in children, which challenges ethics committees approval; (6) post-marketing safety concerns; and (7) lack of follow-up metrics and geographic dispersion of RD patients, which preclude regular blood draws and sequential evaluations in studies [11].
Approximately one in 13 people currently live with an undiagnosed condition, which makes them prone to being overlooked. The Undiagnosed Diseases Network (UDN) was created in 2014 to improve the level of diagnosis and care of undiagnosed diseases, facilitate research, and create an integrated and collaborative database community to improve patient management. The UDN was funded by the National Institutes of Health (NIH) and aims to solve unsolved cases worldwide (https://undiagnosed.hms.harvard.edu) [12]. The integration of novel technologies, including Ribonucleic acid (RNA) sequencing, long-read sequencing, and periodic reanalysis of whole exome sequencing (WES) and whole genome sequencing (WGS), has played a crucial role in driving advancements in diagnostic rates in UDN [13].
In Brazil, the Ministry of Health issued Ordinance 199 on January 30, 2014, aiming to reduce morbidity and mortality while enhancing the quality of life for patients with RD by instituting the National Policy for Comprehensive Care of People with Rare Diseases [14]. This initiative laid the groundwork for the establishment of the Brazilian Rare Diseases Network (RARAS-BRDN), comprised of 40 voluntary reference institutions across the country. Although data in this field are still emerging in Brazil, this group published in 2022 the first epidemiological survey of diagnoses for 13 rare diseases, providing a reliable estimate based on the Brazilian public health database: approximately 55,000 individuals. However, extrapolating Wakap et al. [7] results, the estimate of Brazilian RD patients would be approximately 7.2–12.2 million [7, 15]. Despite the remarkable work conducted by the authors, it is numerically evident that there remains a tremendous challenge ahead to identify and support millions of other affected individuals.
In December 2020, Brazilian interministerial committee was initiated by decree 10,558, tasked with the formulation, coordination, and execution of projects, policies, programs, and initiatives directed at safeguarding of RD patients [16]. Physical and mental well-being, as well as advancing and defending the rights of individuals with RD were also encompassed. Concurrently, in September 2023, the Mixed Parliamentary Front for Innovation and Technologies in Rare Diseases emerged, comprising senators and deputies. Additionally, analogous efforts at the state level, exemplified by the Legislative Chamber of the Federal District, share a common purpose: deliberating, advocating, and proposing measures to enhance the support for RD patients. On December 29, 2023, the official gov.br website reported the recommendation by the National Committee for Health Technology Incorporation (CONITEC) for the assimilation of technologies tailored to RD. These assimilations serve as pivotal components in shaping public healthcare policies and are integral for potential inclusion within the National Agency of Supplementary Health (ANS) coverage, thereby influencing forthcoming healthcare programs. The website publication delineates explicit recommendations, encompassing interventions such as Trikafta® for cystic fibrosis, agalsidase beta for Fabry disease, neonatal screening, and others. This underscores an elevated receptiveness of CONITEC towards incorporating state-of-the-art medical technologies since the establishment of the interministerial committee [16].
Another pivotal policy against disinformation regarding RD is to dedicate a day in the year to raise awareness for rare diseases. Since 2008, Rare Disease Day has been commemorated on February 29, precisely because it is a “rare” date. In non-leap years, this day is celebrated on February 28, yet maintaining its purpose: a time to celebrate progress in research and advocacy efforts, and to reflect on ongoing challenges (https://www.rarediseaseday.org/) [17].
Rheumatologist as a bridge for RD
Patients with RD often face a “diagnostic odyssey” from the onset of the disease, resulting in an unbetterable therapeutic delay [18, 19]. In 2019, NORD found that only 36% of patients with RD were diagnosed within the first year, and 28% reported a delay of seven or more years, with 38% being misdiagnosed during their diagnostic journey [20, 21]. Rheumatologists routinely evaluate patients who have already been seen by multiple specialists and may play an important role on their “diagnostic odyssey.” Moreover, the area experienced a critical growth lately, as rheumatologists are increasingly adopting previously considered OD, such as Mikulicz syndrome and Riedel thyroiditis, which are now recognized fibroinflammatory conditions under the umbrella of IgG4-related disease (IgG4-RD) [22]. Therefore, IgG4-RD was compared to “a black crow flying through the dark night” as it passed unscathed upon the history of rheumatic diseases.
In addition, broad spectrum gene sequencing assays overcame unsolved rheumatic cases into novel RD, such as monogenic forms of relapsing polychondritis (VEXAS Syndrome - vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) or polyarteritis nodosa (deficiency of Adenosine deaminase 2) [21, 22]. Similarly, as the description of new inborn errors of immunity (IEI) exponentially increases, new entities previously classified as undifferentiated autoinflammatory diseases have been defined [23]. In the upcoming decades, the focus of the specialty should be on raising awareness of RD as a cornerstone of health care and research.
Red flags for RD in rheumatology
Given the wide clinical spectrum of RD, it is difficult to develop general clues and warning signs involving all RD of interest to the rheumatologist. Jeffrey Modell Foundation’s warning signs for primary immunodeficiencies diagnosis may help the identification of underlying IEI in patients with rheumatic conditions, such as recurrent, severe, persistent, or unusual infections, especially those unexplained by predisposing factors such as asplenia, malignancies or immunosuppressive treatment. Maybe even more presumptive is the coexistence of polyautoimmunity, life-threatening or treatment refractory rheumatic disorders, mainly in younger ages, which may represent a relevant sign of an IEI [24, 25].
“Red flags” suggesting an IEI may also be considered among those patients presenting with uncommon associations of rheumatic conditions, such as systemic lupus erythematosus (SLE) and Behçet disease in A20 haploinsufficiency or relapsing polychondritis and polyarteritis nodosa in VEXAS. Noteworthy, rheumatologists should be also attentive whenever IEI-associated manifestations, such as autoimmune cytopenia, sarcoid-like inflammation, benign or malignant lymphoproliferative (among other malignancies) are concurrent to rheumatic manifestations. Last, but not least, given the monogenic basis of IEI, a family history of primary immunodeficiency or immune dysregulation should be definitely valued for inherited underlying conditions as the etiology of a rheumatic disease [24, 25].
In an effort to suggest clinical and laboratory criteria for RD and OD screening, the Brazilian Society of Rheumatology has established a task force: the Rare Diseases Committee (RDC). RDC aims to lead scientific research, provide support for patients, and promote information about RD to rheumatologists and healthcare professionals involved in this field. Based on their own experience, the experts suggested 9 clinical and 6 laboratorial “red flags” that should trigger the suspicion of RD in the context of rheumatic manifestations (Table 1).
When dealing with multiorgan unexplained features, rheumatologists should always rule out infection, malignancy, and classic autoimmune diseases before proceeding with RD investigation. Due to the vast number and heterogeneity of RD, 11 subgroups of the most significant conditions for the rheumatologist were proposed, including: (1) autoinflammatory diseases (Table 2); (2) other primary immune regulatory disorders (PIRD) (Table 3); (3) granulomatous diseases (Table 4); (4) histiocytosis disorders (Table 5); (5) primary connective tissue diseases (Table 6); (6) storage diseases (Table 7); (7) metabolic bone diseases (Table 8); (8) rare vasculopathies (Table 9); (9) hypereosinophilic syndromes (Table 10); (10) adjuvant-induced rheumatic diseases (Table 11); and (11) rare infectious/parasitic diseases (Table 12).
Novel tools for investigating RD in rheumatology
Numerous advancements in RD approach have impacted rheumatological practices lately, necessitating ongoing education regarding newly identified autoantibodies, cytokine signatures, imaging modalities, and enhanced accessibility to molecular diagnoses [19]. Rheumatologists now encounter novel autoantibodies in the field of myositis, which have facilitated the proposition of updated diagnostic classifications based on a better understanding of the pathophysiology of these conditions and more precise recognition of clinical phenotypes and prognoses [26].
The description of a subgroup of patients with lupus manifestations and type 1 interferon signature, currently identified as interferonopathies, provided insights into the molecular pathways involved in systemic lupus erythematosus and opened a significant avenue for targeted anti-interferon therapies [27, 28]. 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography has been progressively indicated for monitoring disease activity and assessing target organ damage at baseline. This promising tool has been applied to evaluate treatment responses and helps diagnosing multisystemic diseases such as sarcoidosis, IgG4-related disease, amyloidosis, and relapsing polychondritis [29, 30]. Whole-body magnetic resonance (WB-MR) imaging is now utilized in a multitude of rheumatic, bone, and muscle disorders, resulting in a robust and sophisticated tool for the detection, staging, and monitoring of various non-oncologic musculoskeletal conditions such as chronic recurrent multifocal osteomyelitis/chronic non-bacterial osteomyelitis (CRMO/CNO) [31, 32].
As a result of greater access to molecular diagnosis, an exponential increase in the discovery of new PIRD was observed in the last decade [23]. Interestingly, in the immune-mediated rheumatic diseases universe, different pathogenic variants in the same gene can lead to widely discordant phenotypes. As a result, identification of a defect in a PIRD-associated gene should be considered based on its immunologic function and not discounted solely on previously described phenotype with that gene. VEXAS syndrome is a good example, as it disrupts the paradigm by utilizing a genotype-first approach, where a large genetic database is analyzed for commonalities among patients with minimal consideration of clinical phenotypes [33, 34]. By broadening the phenotype, we have discovered that RD may be more prevalent than previously thought, with new evidence indicating that Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) pathogenic variants are present in 1 in 13,591 individuals [35].
Since 2010, the number of pathogenic variants discovered each year has increased rapidly, due to advances in Deoxyribonucleic acid (DNA) sequencing technologies and big data analysis. As of May 2017, Orphanet lists 3573 RD-linked genes. Many relatively low-cost phenotype-driven commercial and customizable gene sequencing panels are available. Exome sequencing has become more cost-effective, offering new opportunities for Mendelian disease diagnosis and research [36]. The field of multi-omics methodologies will transform disease discovery and diagnosis by utilizing advanced technologies beyond DNA sequencing, including metabolomics, epigenomics, RNA-Seq (transcriptomics), and proteomics [37].
Regrettably, several challenges are present in the “diagnostic odyssey” of patients with RD, and health policies must be implemented to encourage research. Additionally, more randomized controlled trials are urgently needed to address this significant unmet need [11]. A comprehensive understanding of current research efforts, knowledge/research gaps, and funding patterns is critical to systematically expedite the pace of research discovery in rare diseases [38].
Targeted therapy for rheumatological RD
Despite some progress in the last decades, only 5% out of the 7000 identified RD have an approved treatment. Improvement of this therapeutic gap may be multifaceted challenge impeded by factors such as limited access to medical expertise, diagnostic testing, and translational approaches [39, 40]. According to NORD, while only 29% of the patients with any RD had been authorized to use off-label FDA unapproved treatment for their medical condition, 61% were denied or faced delays in obtaining therapies that necessitated pre-approval from an insurance company [20, 21]. As RD constitute a heterogeneous group of illnesses, numerous therapeutic methods have been currently established, including enzyme replacement therapies (ERT), oligonucleotide therapies, monoclonal antibodies (mAb), gene therapies, cell therapies, anti-fibrotic agents, amongst others [41].
ERT involve low molecular weight compounds that regulate biological processes, typically administered as an infusion of a native or recombinant enzyme. ERT have long been a fundamental element in treating RD associated with an enzyme loss of function, such as lysosomal storage disorders [40]. Approved examples of ERT are agalsidase β and agalsidase α for Fabry disease; laronidase for Mucopolysaccharidosis type 1 and alglucosidase α for Pompe disease [40].
Oligonucleotide therapies are a promising strategy for intervening at the RNA level. Antisense oligonucleotides (ASO) and small interfering ribonucleic acid (siRNA) are the most extensively studied and can both prevent specific disease-associated protein translation by promoting degradation of its mRNA [40]. In 2018, patisiran became the first siRNA FDA approved therapy, shortly followed by the approval of the ASO inotersen [42]. Both drugs act by degrading mRNA encoding transthyretin (TTR) protein, which reduces tissue TTR deposits and clinically improves neurological manifestations of familial transthyretin amyloidosis [40].
Immunotherapies with mAb have been employed since 1983, using antibodies to specifically block immune targets, resulting in signaling pathways modulation, cell recruitment to specific sites, cytotoxins delivery, or circulating factors neutralization. Some mAb, such as canakinumab and rilonacept, have been authorized to address IL-1β inflammasome release in cryopyrin-associated periodic syndromes and other autoinflammatory syndromes, modifying the natural history of these diseases [43, 44].
Gene therapy is a therapeutic approach that involves nucleic acids delivery in cell nuclei, with the aim of replacing defective genes or inserting normal copies into the genome. This modality holds promise for treating monogenic diseases (138). Notably, ex vivo transfection utilizing lentivirus vectors has been employed in pioneering clinical trials for primary immune deficiency diseases such as adenosine deaminase deficiency, severe combined immunodeficiency (SCID), and Wiskott-Aldrich syndrome [45,46,47].
Cell therapy was originally developed for cancer treatment, with the introduction of chimeric antigen receptor (CAR) T-cells as an immunotherapeutic modality to combat the disease. Despite its early stage of development, CAR T-cell therapy is being explored as a potential option for treating autoimmune disorders such as refractory systemic lupus erythematosus, with successful outcomes reported and few severe adverse events such as cytokine release syndrome [48].
Antifibrotic agents, such as nintedanib and pirfenidone, exert their therapeutic effects by inhibiting tyrosine kinase activity, thus impeding the progression among fibrosing interstitial lung diseases (ILD) [49, 50]. Nintedanib has been shown to be efficacious in autoimmune [51] and systemic sclerosis associated ILD by mitigating the rate of forced vital capacity decrease [52]. Nevertheless, extensive research is necessary to fully elucidate the true benefits of these agents in the context of these heterogenous diseases.
As the understanding of RD progressively grows and novel translational therapies become available, it is imperative to share efforts among non-profit socially motivated organizations and the pharmaceutical industry to develop and improve access to more affordable orphan drugs. While global discussion relies on the equalization of profitable development of novel therapies and the available fundings to finance a lifelong treatment for a small number of citizens in a society, this approach would benefit not only patients but also national healthcare systems [53].
Non-governmental organizations and web-based resources in RD
As a multitude of domains within RD care remain unaddressed, therefore efforts to promote a reliable and comprehensible source of information through accessible platforms and tools are fundamental. Non-governmental organizations or philanthropic groups that advocate for a particular disease play a pivotal role in serving as a conduit to scientific medical societies or public and private resources. This comprehensive approach aims to overcome misperceptions and to shorten the “diagnostic odyssey” of individuals affected by RD [54].
Platforms like NORD (https://rarediseases.org/) and EURORDIS (European Organization for Rare Diseases - https://www.eurordis.org/) not only support patients and families affected by RD, but also guide patients, caregivers, healthcare professionals, and researchers in diagnosing and selecting specific treatments or participating in ongoing clinical trials for particular diseases [55, 56]. In Brazil, a similar initiative with information fully endorsed by the Brazilian Society of Medical Genetics (https://muitossomosraros.com.br) in partnership with a Federal Committee from the National Parliament (Mixed Parliamentary Front for Comprehensive Care for People with Rare Diseases) offers relevant content and facilitates patient access to reference centers.
As a crucial resource for genetic RD awareness, Online Mendelian Inheritance in Man (OMIM; http://www.omim.org/) provides a platform with a database of genetic syndromes, their phenotypes, inheritance patterns, and genetic variants, which helps physicians in determining diagnosis of RD all around the world. Additionally, Orphanet (http://www.orpha.net/) serves as a diagnostic aid and aims to disseminate information regarding novel treatment strategies available for RD [57]. Similarly, FindZebra (http://www.findzebra.com/) has been developed as an algorithm that employs freely available information to suggest suitable RD diagnoses for physicians and patients [58].
Future perspectives
The “diagnostic odyssey” involving misdiagnoses, lack of specialists, and lack of access to an acceptable molecular diagnosis culminating in therapeutic delays, is an unmet demand that needs to be addressed in the upcoming decades. Artificial intelligence (AI) with deep learning technology holds great promise for RD. Big data software could gather various sources (multi-omics, patient registries, clinical trials) to overcome RD barriers (low diagnostic rates, reduced number of patients, geographical dispersion). AI is expected to create accessible algorithms able to integrate data among patients and health providers, improving diagnostic approaches, prognosis scoring, disease stratification, decision support, and health records [59,60,61].
Despite all the above-described efforts, there is no approved drug for 94% of all RD. A novel precision medicine-based approach can drive good discriminator assays designed to targeted therapy testing to predict its potential benefit individually. With a better understanding of molecular and environmental mechanisms causing RD, we will be able to deliver not only symptomatic treatment but also curative personalized medicine [53].
The challenges for the next decades are multiple, including case identification, medical education, investment in infrastructure, and optimization of financial resources for specific centers trained in RD. As a guide to improve the “diagnostic odyssey” of RD patients, European institutions and Member States have created a rare 2030 action campaign with eight recommendations: 1- a roadmap for RD long-term policies; 2- integrated European and national plans and strategies; 3- earlier, faster, and more accurate diagnosis; 4- access to high-quality healthcare; 5- integrated and person-centered care in partnership with patients; 6- innovative and need-led research development; 7- optimizing data for patient and societal benefit; 8- available, accessible, and affordable treatments [62].
Conclusion
While individually rare, the aggregated number of individuals with RD or OD represents a significant health burden. Rheumatologists will increasingly face unsolved cases in the next decades and play a cornerstone role in RD healthcare. The specialty’s efforts should focus on promoting awareness that these diseases may be rare, but patients cannot be orphans. Recognizing zebras among the horses requires paradigm shifts which drive into a famous speech by Sherlock Holmes: “How often have I said to you that when you have eliminated the impossible, what remains, however improbable, must be the truth?” [63].
Data availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Abbreviations
- ASO:
-
Antisense Oligonucleotides
- ANS:
-
National Agency of Supplementary Health
- CAR:
-
Chimeric Antigen Receptor
- CONITEC:
-
National Committee for Health Technology Incorporation
- CNO:
-
Chronic Non-Bacterial Osteomyelitis
- CRMO:
-
Chronic Recurrent Multifocal Osteomyelitis
- DNA:
-
Deoxyribonucleic Acid
- ERT:
-
Enzyme Replacement Therapies
- EURORDIS:
-
European Organization for Rare Diseases
- FDA:
-
Food and Drug Administration
- IgG4-RD:
-
Immunoglobulin IgG4-Related Disease
- IEI:
-
Inborn Errors of Immunity
- ILD:
-
Interstitial Lung Diseases
- IL-1β:
-
Interleukin-1 Beta
- mAb:
-
Monoclonal Antibodies
- NORD:
-
National Organization for Rare Disorders
- NIH:
-
National Institutes of Health
- OD:
-
Orphan Diseases
- OMIM:
-
Online Mendelian Inheritance in Man
- PIRD:
-
Primary Immune Regulatory Disorders
- RARAS-BRDN:
-
Brazilian Rare Diseases Network
- RD:
-
Rare Diseases
- RDC:
-
Rare Diseases Committee
- RNA:
-
Ribonucleic Acid
- SLE:
-
Systemic Lupus Erythematosus
- SCID:
-
Severe Combined Immunodeficiency
- siRNA:
-
Small Interfering Ribonucleic Acid
- TTR:
-
Transthyretin
- UBA1:
-
Ubiquitin Like Modifier Activating Enzyme 1
- UDN:
-
Undiagnosed Diseases Network
- WES:
-
Whole Exome Sequencing
- WGS:
-
Whole Genome Sequencing
- WHO:
-
World Health Organization
- WB-MR:
-
Whole-Body Magnetic Resonance
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do Nascimento, R.R.N.R., Piotto, D.G.P., Freire, E.A.M. et al. Rare diseases: What rheumatologists need to know?. Adv Rheumatol 64, 74 (2024). https://doi.org/10.1186/s42358-024-00407-6
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DOI: https://doi.org/10.1186/s42358-024-00407-6