Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.
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- Initiation of a cohort to define pathogenic Mechanisms, Precision diagnosis And Complications of Thrombotic Microangiopathies: The IMPACT Study (IMPACT)
- Myasthenia Gravis Rare Disease Network (MGNet)
- Network for Advancing Sex Chromosome Aneuploidy Research Readiness (NASCARR)
- Spastic Paraplegia Centers of Excellence Research Network (SP-CERN)
- Urea Cycle Disorders Consortium (UCDC)
Listen to these summaries on the Rare Research Report podcast.
Initiation of a cohort to define pathogenic Mechanisms, Precision diagnosis And Complications of Thrombotic Microangiopathies: The IMPACT Study (IMPACT)
Advancing Treatment in Congenital Thrombotic Thrombocytopenic Purpura
Congenital thrombotic thrombocytopenic purpura (cTTP) is a disorder in which blood clots form in the small blood vessels throughout the body. cTTP is caused by mutations in the ADAMTS-13 gene, leading to microvascular thrombosis (abnormal clotting), hemolytic anemia (destruction of red blood cells), and organ damage.
In this review, researchers summarize the clinical course, complications, and advances in treatment of cTTP. The team reviewed registry data, clinical studies, expert guidelines, and real-world patient experiences, including pregnancy management.
Results suggest that recombinant ADAMTS-13, a therapy that helps restore the ADAMTS13 enzyme, is more effective, safe, and convenient than the standard plasma therapy. Authors note that although recombinant ADAMTS-13 represents a major advance in cTTP management, more studies are needed to evaluate its long-term safety, particularly during pregnancy, and to optimize treatment strategies.
Glasner MF, Sukumar S, Cataland SR, Scully M, Chaturvedi S. Optimizing the management of congenital thrombotic thrombocytopenic purpura. Res Pract Thromb Haemost. 2026 Jan 20;9(Suppl 4):103270. doi: 10.1016/j.rpth.2025.103270. PMID: 41641186; PMCID: PMC12866082.
Myasthenia Gravis Rare Disease Network (MGNet)
Investigating the Impact of Demographic Trends on Disease Prognosis in Myasthenia Gravis
Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which compromises nerve muscle communication, causing disabling weakness. In the past 50 years, the epidemiology of MG—how often it occurs in different groups of people and why—has changed over time. However, not much is known about how these changes have impacted management of MG.
In this study, researchers investigated how demographic trends have affected disease prognosis in MG. The team assessed demographics, MG subtypes, and antibody status over 50 years in 1,023 patients with AChR-MG. In 517 patients, the team also evaluated treatment response and adverse events over 20 years.
Results show an increased rate of patients diagnosed with very late-onset MG. Authors note that patients with very late-onset MG may face an increased risk of long-term treatment exposure and adverse events, especially in elderly patients.
Falso S, Spagni G, Monte G, Marini S, Marini M, Alboini PE, Damato V, Evoli A, Iorio R. Half a century of change: demographic trends and their clinical impact in acetylcholine receptor antibody-positive myasthenia gravis. J Neurol. 2026 Mar 23;273(4):227. doi: 10.1007/s00415-026-13670-y. PMID: 41872575.
Network for Advancing Sex Chromosome Aneuploidy Research Readiness (NASCARR)
Creating a Patient Registry to Improve Health Outcomes for Individuals with Sex Chromosome Aneuploidies
Sex chromosome aneuploidies (SCAs) are a group of conditions in which an individual has either extra or missing X and/or Y chromosomes present in the cells of their body. Although SCAs are the most common chromosomal abnormality, they are often underdiagnosed. Research in SCAs has been limited by over-representation of more severely impacted individuals in clinical studies, as well as low geographic and demographic diversity.
In this study, researchers partnered with the SCA community to create a patient registry to improve health outcomes for individuals with SCAs. The Generating Advancements with Longitudinal Analysis in X and Y variations (GALAXY) Registry helps advance SCA research by collecting, storing, and analyzing clinical data from SCA patients.
To date, GALAXY includes hundreds of participants with a verified diagnosis of SCA. Next, researchers plan to recruit more individuals from underrepresented groups, extract medical record data into the registry, expand internationally, and continue to engage with the SCA community. Authors note that the GALAXY Registry is a powerful resource for future patient-centered clinical research.
Carl A, Bothwell S, Swenson K, Bregante R, Cohen L, Cover V, Dawczyk A, Decker G, Gerken SB, Hong D, Howell S, Raznahan A, Rogol AD, Tartaglia N, Davis S. Generating Advancements in Longitudinal Analysis in X and Y Variations: Rationale, Methods, and Diagnostic Characteristics for the GALAXY Registry. Am J Med Genet A. 2026 Jan;200(1):23-34. doi: 10.1002/ajmg.a.64214. Epub 2025 Aug 13. PMID: 40799057.
Spastic Paraplegia Centers of Excellence Research Network (SP-CERN)
Characterizing the Spectrum of ATP1A3-Related Disorders
ATP1A3-related disorders are a group of neurological conditions caused by mutations in the ATP1A3 gene. Due to the broad spectrum of clinical features and disease-causing variants, it can be challenging to classify these disorders.
In this study, researchers characterized the spectrum of ATP1A3-related disorders. The team evaluated 88 individuals with pathogenic or likely pathogenic variants in ATP1A3. Researchers used these observations to explore symptoms and genotype–phenotype relationships, as well as build a video archive.
Results reveal that most individuals with ATP1A3-related disorders show overlapping or atypical features, including presentations with progressive spastic paraparesis, which is typical of hereditary spastic paraplegia. Authors note that these findings support a shift toward flexible clinical approaches based on symptoms rather than relying on rigid classifications.
Bernardi K, Zhou A, Yang K, Rong J, Quiroz V, Alecu JE, Agianda HAP, Schmidt HJD, Tam A, Carty S, Espasandin-Hueter N, Macaya A, Stamelou M, Pringsheim T, Means M, Lakhotia A, Blackburn J, Zea Vera A, Becker LF, Brüggemann N, Münchau A, Seliverstov Y, Vogt L, Gorodetsky C, Levine JM, Runco AD, Calame DG, Dai L, Ding C, Ebrahimi-Fakhari D. The Movement Disorder Spectrum of ATP1A3-Related Disorders: Cross-Sectional Analysis and Video Archive of 88 Patients. Mov Disord. 2026 Mar 18. doi: 10.1002/mds.70227. Epub ahead of print. PMID: 41850905.
Urea Cycle Disorders Consortium (UCDC)
Exploring the Impact of Ornithine Transcarbamylase Gene Variants in Asymptomatic Individuals
Ornithine transcarbamylase deficiency (OTCD) is a type of urea cycle disorder characterized by hyperammonemia (high blood ammonia levels) due to deficiency or absence of an enzyme needed to convert nitrogen from protein into urea (a waste product). As genetic testing becomes more widely utilized in a variety of clinical contexts, an increasing number of asymptomatic individuals with variants in the OTC gene are being identified incidentally. However, there is a lack of guidance for counseling and management of these individuals.
In this study, researchers explored the impact of OTC variants in asymptomatic individuals. The team reviewed medical records, the Urea Cycle Disorders Consortium database, and published reports to characterize two common OTC gene variants, p.(Arg40Cys) and p.(Phe354Cys). Researchers also tested the variants in a lab yeast model to measure enzyme activity.
Results revealed a risk of late-onset hyperammonemia for males with p.(Arg40Cys) and p.(Phe354Cys). Common triggers included fasting, illness, and high-protein diets. Authors note that these findings can help guide counseling of individuals with these variants, including the importance of knowing the signs and symptoms of hyperammonemia as well as potential triggering factors.
Lang SH, Lo RS, Cromie GA, Dudley AM, Mew NA, Simpson K, Sutton VR, Darilek S, Ali S, Snyder MT, Lee B, Marom R, Nagamani SCS, Burrage LC. Two commonly reported incidental variants in OTC are associated with late-onset disease. HGG Adv. 2026 Jan 15;7(1):100531. doi: 10.1016/j.xhgg.2025.100531. Epub 2025 Oct 16. PMID: 41108081; PMCID: PMC12615274.
The Rare Diseases Clinical Research Network (RDCRN) is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). Now in its fifth five-year funding cycle, RDCRN is a partnership with funding and programmatic support provided by Institutes, Centers, and Offices across NIH, including the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, the National Institute of Mental Health, the Office of Dietary Supplements, the National Institute on Aging, the National Human Genome Research Institute, the National Institute on Deafness and Other Communication Disorders, and the Office of Research on Women’s Health.
