Brain Vascular Malformation Consortium

Join the RDCRN for Rare Disease Day at NIH on February 27, 2026

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Join the RDCRN for Rare Disease Day at NIH on February 27, 2026 admin Wed, 02/04/2026 - 17:01

December 19 2025

Don’t miss the in-person and virtual celebration of Rare Disease Day at NIH on Friday, February 27, 2026, from 9 am to 5 pm EST. Each year, the NIH’s National Center for Advancing Translational Sciences (NCATS) sponsors the event as part of the global Rare Disease Day observance. Goals include raising awareness about rare diseases, the people they affect, and NIH collaborations that address scientific challenges and advance research for new treatments.

The event will be held in person at NIH Main Campus (Natcher Conference Center). There also will be a virtual livestream via NIH VideoCast with the event archived for replay afterward. The agenda will feature panel discussions, rare diseases stories, in-person exhibitors and scientific posters, and an art exhibition.

The RDCRN will host a booth during the event. You can visit our booth at any time to learn more about the RDCRN.

Rare Disease Day at NIH is free and open to the public, including patients, patient advocates, health care providers, researchers, trainees, students, industry representatives, and government employees. Register in advance here. We hope to see you there!

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Rare Disease Day at NIH. February 27, 2026. #RDDNIH. ncats.nih.gov/rdd

Rare Research Report: November 2025

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Rare Research Report: November 2025 admin Wed, 02/04/2026 - 17:01

November 25 2025

Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.

Jump to:

Brain Vascular Malformation Consortium (BVMC)
Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)
Myasthenia Gravis Rare Disease Network (MGNet)

Listen to these summaries on the Rare Research Report podcast.

Brain Vascular Malformation Consortium (BVMC)

Assessing Disparities in Access to Clinical Care and Research for Patients with Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of the blood vessels that can cause excessive bleeding. Patients with rare diseases like HHT are more likely to experience increased health outcome disparities due to inequitable healthcare.

In this study, researchers assessed disparities in access to clinical care and research for patients with HHT. First, the team collected race data from BVMC study recruits at HHT clinics in Toronto and San Francisco. Next, they compared the racial differences between HHT patients recruited for research and HHT patients in the general population.

Results reveal preliminary evidence of racial differences between HHT center clinic patients and surrounding populations. Findings also show an association between race and enrollment to HHT research studies. Authors note that this study lays the foundation for beginning to address disparities in HHT care and research.

_{Scott G, Agundiz A, Nelson J, Hetts S, Clancy M, Kim H, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. Assessing racial differences in North American hereditary hemorrhagic telangiectasia study recruitment and care. Orphanet J Rare Dis. 2025 Aug 28;20(1):461. doi: 10.1186/s13023-025-03883-1. PMID: 40877917; PMCID: PMC12392467.}

Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)

Working with Caregivers to Capture Lived Experiences of Children with Multiple Sulfatase Deficiency

Rare diseases deeply affect children and families, but their experiences are only incompletely understood—especially for extremely rare conditions like multiple sulfatase deficiency (MSD), a leukodystrophy.

In this study, researchers worked directly with caregivers to capture lived experiences of children with MSD. Nineteen caregivers shared information about their child’s daily skills, emotional health, and overall quality of life, as well as their own well-being. The team used several established questionnaires to measure these areas and compared the results to data from metachromatic leukodystrophy (MLD), a related rare disorder.

Results showed that although children with MSD face significant challenges with daily activities, caregivers reported that emotional well-being was a strength, underscoring the incredible resiliency of the rare disease community. When the team used caregiver-centered tools, they captured a richer picture of what matters most to families, such as coordination of care and emotional support. Caregivers themselves experienced major emotional and practical strain, often feeling grief and isolation, similar to those caring for children with MLD.

Authors note that these insights show why including patient and caregiver perspectives in research is critical. Their input helps identify meaningful outcomes, improves the design of clinical trials, and ensures that future treatments focus on what truly matters to families.

_{Gavazzi F, Yu E, Tashnim Z, Woidill S, Sevagamoorthy A, Arnold K, Ammann-Schnell L, Groeschel S, Krägeloh-Mann I, Breitling V, Schlotawa L, Ahrens-Nicklas R, Adang LA. Exploration Into Lived Experiences of Multiple Sulfatase Deficiency-Affected Individuals and Their Families. J Child Neurol. 2025 Nov;40(10):852-861. doi: 10.1177/08830738251339848. Epub 2025 May 14. PMID: 40368343; PMCID: PMC12240456.}

Myasthenia Gravis Rare Disease Network (MGNet)

Evaluating the Therapeutic Potential of Immunoglobin G- and Immunoglobin M-Specific Proteases in Acetylcholine Receptor-Positive Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder in which antibodies targeting the acetylcholine receptor (AChR) cause muscle weakness. Current therapies help many patients, but some remain refractory, underscoring the need for more personalized approaches.

In this study, researchers evaluated the therapeutic potential of S-1117, a pan-IgG–specific protease engineered to selectively cleave the Fcγ region of pathogenic AChR-IgG. Using live cell-based assays with monoclonal autoantibodies and patient serum, the team showed that S-1117 effectively impaired IgG-mediated complement activation on AChR-expressing cells.

Importantly, the work uncovered a previously unrecognized MG subset driven by pathogenic AChR-IgM, which either amplified IgG-mediated injury or served as the primary source of complement activation. An IgM-specific protease fully suppressed IgM-driven pathogenicity, and combining IgG- and IgM-targeted enzymes achieved broader inhibition.

These findings reveal critical disease heterogeneity in MG and highlight Ig-specific proteases as a promising precision-medicine strategy to improve treatment for patients with antibody-mediated weakness.

_{Bayer AC, Sanmarco LM, Pellerin A, Masi G, Plasencia A, Anderson JM, Nowak RJ, Damato V, Massacesi L, Pham MC, Khani-Habibabadi F, Vital H, Higginson-Scott N, Otipoby KL, Xing Y, Mascanfroni ID, O'Connor KC. Therapeutic IgG- and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology. Proc Natl Acad Sci U S A. 2025 Oct 28;122(43):e2505984122. doi: 10.1073/pnas.2505984122. Epub 2025 Oct 21. PMID: 41118207.}

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, and the Office of Dietary Supplements.

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NIH Announces Funding to Establish and Strengthen Rare Disease Research Groups

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NIH Announces Funding to Establish and Strengthen Rare Disease Research Groups admin Wed, 02/04/2026 - 17:01

October 29 2025

The National Institutes of Health (NIH) has awarded approximately $26 million in grants in the fiscal year 2025 to begin the fifth cycle of funding for the Rare Diseases Clinical Research Network (RDCRN). This national network brings together scientists, clinicians, patients, families, and patient advocates to study a wide range of rare diseases.

Today, the network consists of 21 research consortia, including 10 that are joining the network for the first time, five that were active in the previous cycle and have been awarded a five-year renewal, and six Cycle 4 consortia that are continuing through a one-year extension of their previous award. An additional $5.6 million has been awarded to a separate Data Management and Coordinating Center hosted at Cincinnati Children’s Hospital Medical Center to support these research efforts.

Addressing the Challenges of Rare Diseases

About one in every nine Americans is affected by a rare disease. Of the approximately 10,000 known rare diseases, only around five percent have US Food and Drug Administration (FDA)-approved treatments. To get a drug from discovery to market, it can take as long as 10 to 15 years and cost up to $2.6 billion. And because most rare diseases are genetic, they often affect infants and children.

To advance rare disease research, Congress passed a law in 2002 authorizing several agencies within the NIH to launch the RDCRN. Each of the 21 consortia that make up the network study at least three different rare diseases.

Since its establishment, the RDCRN has supported hundreds of studies at over 300 clinical sites around the world. These efforts have resulted in over 3,000 publications with topics ranging from natural history studies and case reports to practice guidelines and clinical trials of new treatments. Findings from these studies have contributed to the approval of 11 treatments for rare diseases by the FDA.

Expanding the Focus to New Diseases

The new consortia include:

Advancing Craniosynostosis Treatment (ACT) Rare Diseases Consortium
- Lead institution: Children's Hospital of Philadelphia
Advancing Rare Disorders: Vascular mAlformation Research Network with CaNVAS (ARDVARC)
- Lead institution: Children's Hospital of Philadelphia
Autoimmunity, Rasmussen’s, Inflammation & Status Epilepticus research Network (ARISEN)
- Lead institution: Emory School of Medicine
Batten Disease Clinical Research Consortium (BDCRC)
- Lead institution: Kennedy Krieger Institute
Initiation of a cohort to define pathogenic Mechanisms, Precision diagnosis And Complications of Thrombotic Microangiopathies: The IMPACT Study (IMPACT)
- Lead institution: Johns Hopkins Medicine
Network for Advancing Sex Chromosome Aneuploidy Research Readiness (NASCARR)
- Lead institution: Children's Hospital Colorado Anschutz Medical Campus
Pediatric Fungal Network STudy of Rare Invasive Fungal DisEases in Immunocompromised Pediatric Patients (PFN-STRIDE)
- Lead institution: Children's Hospital of Philadelphia
Rare Bronchiectatic Diseases Consortium (RBDC)
- Lead institution: University of North Carolina at Chapel Hill
Rare Organic Acidemias Research Consortium (ROAR)
- Lead institution: Baylor College of Medicine
Spastic Paraplegia Centers of Excellence Research Network (SP-CERN)
- Lead institution: Boston Children's Hospital

Supporting New Opportunities for Continuing Groups

The consortia returning for Cycle 5 include:

Brittle Bone Disorders Consortium (BBDC)
- Lead institution: Baylor College of Medicine
Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium
- Lead institution: University of Miami
Developmental Synaptopathies Consortium (DSC)
- Lead institution: Boston Children's Hospital
Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)
- Lead institution: Children's Hospital of Philadelphia
Myasthenia Gravis Rare Disease Network (MGNet)
- Lead institution: George Washington University

The consortia receiving a no-cost extension for Cycle 4 include:

Brain Vascular Malformation Consortium (BVMC)
- Lead institution: University of California, San Francisco
Congenital and Perinatal Infections Consortium (CPIC)
- Lead institution: University of Alabama at Birmingham
Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)
- Lead institution: Cincinnati Children's Hospital Medical Center
North American Mitochondrial Disease Consortium (NAMDC)
- Lead institution: Columbia University Medical Center
Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium
- Lead institution: Oregon Health & Science University
Urea Cycle Disorders Consortium (UCDC)
- Lead institution: Children's National Medical Center

Learn more about the RDCRN and the 21 consortia.

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Rare Research Report: September 2025

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Rare Research Report: September 2025 admin Wed, 02/04/2026 - 17:01

September 22 2025

Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.

Jump to:

Brain Vascular Malformation Consortium (BVMC)
Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)
Myasthenia Gravis Rare Disease Network (MGNet)

Listen to these summaries on the Rare Research Report podcast.

Brain Vascular Malformation Consortium (BVMC)

Comparing Circulating microRNAs in Neurovascular Disorders

Familial cerebral cavernous malformations (FCCM), Sturge-Weber syndrome (SWS), and hereditary hemorrhagic telangiectasia (HHT) are neurovascular disorders caused by genetic mutations that can lead to brain bleeding. Cerebral microbleeds (CMBs) are another type of neurovascular disorder that causes brain bleeding. However, CMBs are more often associated with the aging process than genetic factors.

In this study, researchers compared circulating microRNAs in these four neurovascular disorders. First, the team identified differentially expressed plasma microRNAs from patients with FCCM, SWS, HHT, and CMB. Next, they used analysis techniques to identify gene targets of the differentially expressed microRNAs and their associated pathways.

Results revealed both similarities and differences in microRNAs. Among all four disorders, dysregulated microRNAs targeted the PI3K-Akt and ROBO SLIT signaling pathways. Authors note that these findings reveal shared mechanistic pathways underlying vascular dysmorphism and bleeding, highlighting their potential use for disease monitoring and therapeutic intervention.

_{Koskimäki J, Jhaveri A, Srinath A, Bindal A, Vera Cruz D, Priyanka Yeradoddi G, Lightle R, Lee J, Stadnik A, Iqbal J, Alcazar-Felix R, Hage S, Romanos S, Shenkar R, Loeb J, Faughnan ME, Weinsheimer S, Kim H, Girard R, Awad IA. Common and distinct circulating microRNAs in four neurovascular disorders. Biochem Biophys Rep. 2025 Aug 2;43:102189. doi: 10.1016/j.bbrep.2025.102189. PMID: 40800603; PMCID: PMC12341739.}

Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)

Examining the Molecular Mechanisms of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a neurodegenerative disorder that affects the white matter of the brain. ALSP is caused by mutations in the CSF1R gene, which provides instructions for making a protein called the colony-stimulating factor 1 receptor (CSF1R). This protein plays a crucial role in the growth and survival of immune cells in the brain called microglia.

In this study, researchers examined the molecular mechanisms of ALSP. The team performed single-nucleus RNA sequencing on brain specimens with and without ALSP.

Results revealed distinctive characteristics of ALSP brains, including significantly lower amounts of microglia and impaired maintenance of brain white matter. Authors note that these findings highlight potential therapeutic strategies for ALSP and other genetically caused microgliopathies.

_{Du S, Zhou Y, Li D, Lier J, Cella M, Tada M, Hamasaki H, Wu J, Cai Z, Orthmann-Murphy JL, Kakita A, Kipnis J, Bergner CG, Colonna M. Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity. Nat Immunol. 2025 Jul;26(7):1198-1211. doi: 10.1038/s41590-025-02195-7. Epub 2025 Jun 26. PMID: 40571738.}

Myasthenia Gravis Rare Disease Network (MGNet)

Exploring the Effect of Atypical B Cells on Immune Response in Myasthenia Gravis

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors (AChR) in muscles, causing disabling weakness. Subtypes of MG—AChR-positive MG and muscle-specific kinase (MuSK)-positive MG—have different immune responses that may be caused by atypical B cells, an emerging subset of immune cells implicated in autoimmunity.

In this study, researchers explored the effect of atypical B cells on immune response in MG. The team used spectral flow cytometry to analyze atypical B cells in individuals with AChR-MG and MuSK-MG as well as healthy controls.

Results revealed that MG subtypes show distinct atypical B cell profiles that are linked to immunopathology and disease onset. Authors note that these findings highlight the potential for atypical B cells as therapeutic targets in both immunoglobin G1-3- and immunoglobin G4-mediated autoimmunity.

_{Sikorski PM, Kaminski HJ, Vincent A, Bauman T, Jacobson L, Kusner LL. Subtype-specific atypical B cell profiles in myasthenia gravis reveal distinct immunopathological pathways. Front Immunol. 2025 Jun 18;16:1608160. doi: 10.3389/fimmu.2025.1608160. PMID: 40607384; PMCID: PMC12213399.}

Investigating Pathogenic Properties of Acetylcholine Receptor Autoantibodies in Myasthenia Gravis

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages the neuromuscular junction in muscles, causing disabling weakness with characteristic fluctuation in severity over time. The most common form of MG is caused by acetylcholine receptor (AChR) autoantibodies, which either block the AChR, increase their removal from the muscle surface, or block complement.

In this study, researchers investigated the pathogenic properties of AChR autoantibodies in MG and whether they varied over time in relationship to severity of disease. The team analyzed serum specimens from 50 patients with MG collected every six months for two years. Next, they used live cell-based assays to measure AChR autoantibody isotypes, immunoglobulin G subclasses, and the nature of the pathogenic mechanisms.

Results showed that the pathogenic mechanisms of the antibodies fluctuated over time and were generally not associated with disease severity. Authors concluded that additional studies of autoantibody pathogenicity should be incorporated into MG clinical trials to assess differential treatment responses.

_{Khani-Habibabadi F, Roy B, Pham MC, Obaid AH, Filipek B, Nowak RJ, O'Connor KC. AChR Autoantibody Pathogenic Properties Are Heterogeneously Distributed and Undergo Temporal Changes Among Patients With Myasthenia Gravis. Neurol Neuroimmunol Neuroinflamm. 2025 Sep;12(5):e200436. doi: 10.1212/NXI.0000000000200436. Epub 2025 Jul 18. PMID: 40680247; PMCID: PMC12275905.}

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$27M Grant Renews Cincinnati Children’s as Coordinating Center for the Rare Diseases Clinical Research Network

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$27M Grant Renews Cincinnati Children’s as Coordinating Center for the Rare Diseases Clinical Research Network admin Wed, 02/04/2026 - 17:01

August 12 2025

The federal agency that oversees a large network of research centers seeking cures for hundreds of rare, disabling, and often fatal diseases has renewed Cincinnati Children’s as its data management and coordinating center.

In 2019, Cincinnati Children’s received a five-year grant from the National Center for Advancing Translational Sciences (NCATS) to establish the center. Now, a $27 million grant from NCATS continues this designation for another five years.

The funds will be used to support the Rare Diseases Clinical Research Network (RDCRN)’s mission of working toward faster diagnosis and better treatments for people living with rare diseases. The Coordinating Center facilitates studies involving thousands of scientists—both in the US and internationally—by collecting, organizing, sharing, and analyzing large amounts of data about rare diseases.

The center is led by two senior scientists at Cincinnati Children’s: Maurizio Macaluso, MD, DPH, Director, Division of Biostatistics and Epidemiology; and Michael Wagner, PhD, Associate Professor, Division of Biomedical Informatics.

What are the challenges of rare disease research?

In the US, a disease or disorder is defined as “rare” by the Centers for Disease Control and Prevention (CDC) when it affects fewer than 200,000 people—but collectively, rare diseases are not rare. It is estimated that about one in every nine Americans is affected by one of more than 10,000 rare diseases.

However, treatments for rare diseases are rare. Fewer than five percent of rare diseases have a treatment approved by the US Food and Drug Administration (FDA). To get a drug from discovery to market, it can take as long as 10 to 15 years and cost up to $2.6 billion. And because most rare diseases are genetic, they often affect infants and children.

Although there are many different types of rare diseases, people who live with rare diseases face common challenges. Arriving to the correct diagnosis may take years, and the “diagnostic odyssey” may delay proper clinical management. Lack of well-collected and organized patient data, diagnostic criteria, and genetic information contributes to the problem. Well-designed studies are expensive and difficult to conduct because enrolling patients is a major challenge. Developing new treatments and bringing them to approval requires large investments—and industry commits to making investments only after enough evidence is available. This means that many families face a difficult journey through many challenges, which for too many does not result in a better quality of life.

What is the Rare Diseases Clinical Research Network?

In 2002, Congress passed a law authorizing several agencies within the National Institutes of Health to launch the RDCRN. The network is currently made up of 19 consortia, each studying at least three different rare diseases. Each consortium includes scientists, clinicians, patients, and advocates collaborating to advance rare disease research.

Since its establishment, the RDCRN has supported hundreds of studies at over 300 qualified clinical sites around the world. These efforts have resulted in over 3,000 publications with topics ranging from natural history studies and case reports to practice guidelines and clinical trials of new treatments. Findings from these studies have contributed to the approval of 11 treatments for rare diseases by the FDA.

What is Cincinnati Children’s role?

The Data Management and Coordinating Center (DMCC) at Cincinnati Children’s supports research consortia with designing studies and protocols, developing data collection instruments and databases that capture high-quality information, maintaining a centralized storage and tools for data analysis, and sharing data among the 19 groups. The DMCC also promotes the engagement of participants and patient advocates throughout the network and facilitates dissemination of information about ongoing studies and their results.

“The DMCC is responsible for providing state-of-the-art infrastructure for collaboratively implementing best practices that help consortia coordinate their research efforts,” says Wagner. “By ensuring reproducibility of results and making research data accessible, we help ensure that precious data from the limited numbers of patients eligible for and willing to participate in clinical trials is used as efficiently as possible.”

In this new grant cycle, the center’s goals include:

Supporting the RDCRN and advancing the methods and the practice of rare disease clinical research to promote clinical trial readiness.
Maintaining a leading-edge, cloud-based data ecosystem to facilitate the research done by the consortia and promote data sharing within the RDCRN and with other stakeholders.
Expanding research collaboration within the RDCRN and with other partners, disseminating the RDCRN research findings, and promoting the RDCRN globally.

“The DMCC at Cincinnati Children’s combines strong expertise with outstanding infrastructure, state-of-the-art technology, and institutional support,” says Macaluso. “We will help accelerate discovery and collaboration across the RDCRN, bring new treatment options to trial, and improve health and wellness for rare disease patients and their families.”

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Pre-Doc Preparatory Program (P³) in Translational Research

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Pre-Doc Preparatory Program (P³) in Translational Research admin Wed, 02/04/2026 - 17:01

June 23 2025

Do you have a rare disease research coordinator, genetic counseling assistant, or technician who may benefit from formal training in clinical and translational research? If so, we invite you to nominate them for the one-year Pre-Doc Preparatory Program (P³) in Translational Research from October 2025 through May 2026, offered by ITMAT Education at the University of Pennsylvania in partnership with the CHOP Leukodystrophy Center.

What are the goals of the program?

This program provides a foundation for careers in rare disease translational research through research seminars and advocacy group presentations, professional skills development workshops, research in progress presentations, and career pathway panels.

Who can join the program?

The program is open to anyone who is:

Currently a research coordinator, genetic counseling assistant, or research technician involved in rare disease research activities at your site. Exceptions may be made for other entry-level research staff who plan to pursue graduate or medical school education in the future.
Interested in growing a career in research and seeking professional development opportunities. The curriculum is targeting future leaders in translational research.
Able to attend and participate in the program every Friday from 11:00AM-1:00PM EST beginning October 2025 through May 2026. (Note that timing might shift for some in-person events.)
A US Citizen and Permanent Resident. Site Investigator support and approval of conditions of enrollment are also required.

What are the requirements?

P³ Scholars are expected to attend and actively participate in two hours of scheduled activities every Friday from 11:00AM-1:00PM EST. Most of the sessions will be held online via Zoom with opportunities to connect in person at program meetings and events.

Scholars will be invited to attend the ITMAT Symposium on October 13-14, 2025, in Philadelphia, PA. In addition, scholars may attend the ULF Scientific Symposium and Family Conference on June 25-27, 2026, in Chicago, IL. Travel support is provided by the program.

P³ is funded by NCATS (5R25TR005269) and is available at no cost to participants.

How does one apply?

Investigators may nominate 1-2 participants by submitting a Scholar Nomination and Conditions of Enrollment Form no later than Friday, July 18. If any members of your group are eligible and interested in participating, please speak with them before nominating them.

Once your nominations are submitted, your nominees must submit their own applications by Friday, August 1. You can encourage them to visit this page for instructions on how to do so. Detailed instructions are available under the ‘Applications’ header on the page.

Applications will be evaluated by P³ Leadership in consultation with the relevant consortium sites. Applicants will be notified by mid/late August regarding the selection committee’s decision.

To learn more or ask questions, please contact Associate Director Jessica German, MSEd, at jbgerman@upenn.edu or Program Director Laura Adang, MD, PhD, MSTR at adangl@chop.edu.

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Rare Research Report: December 2024

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Rare Research Report: December 2024 admin Wed, 02/04/2026 - 17:01

December 18 2024

Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.

Jump to:

Brain Vascular Malformation Consortium (BVMC)
Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)
Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC)
Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)
Myasthenia Gravis Rare Disease Network (MGNet)
Porphyrias Consortium (PC)

Listen to these summaries on the Rare Research Report podcast.

Brain Vascular Malformation Consortium (BVMC)

Determining Current Rescreening Practices for Brain and Lung Arteriovenous Malformations in Children and Adults with Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of the blood vessels that can cause excessive bleeding. Patients with HHT are at risk for organ vascular malformations, including arteriovenous malformations (AVMs) in the brain and lungs. Although HHT guidelines recommend initial screening in children and adults, rescreening is not consistently addressed.

In this study, researchers determined current rescreening practices for brain and lung AVMs in children and adults with HHT. The team surveyed 30 North American HHT Centers of Excellence on rescreening practices for new brain and lung AVMs in patients with initial negative screening.

Results show that most HHT Centers of Excellence routinely rescreen children for brain and lung AVMs and adults for lung AVMs when initial screening is negative. However, adults are infrequently rescreened for brain AVMs. Authors note that long-term data regarding risk for new brain and lung AVMs are required to establish practice guidelines for rescreening.

_{Beslow LA, Kim H, Hetts SW, Ratjen F, Clancy MS, Gossage JR, Faughnan ME. Brain and lung arteriovenous malformation rescreening practices for children and adults with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2024 Nov 9;19(1):421. doi: 10.1186/s13023-024-03402-8. PMID: 39522006; PMCID: PMC11549847.}

Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)

Comparing Parent and Child Patient-Reported Outcomes in Eosinophilic Esophagitis Over Time

Eosinophilic esophagitis (EoE) is a disorder in which eosinophils (white blood cells of the immune system) build up in the esophagus, causing tissue damage. Symptoms include difficulty swallowing, food getting stuck in the throat, vomiting, reflux, malnourishment, and poor appetite. Because young children are unable to report their own symptoms, parents must report on the child’s behalf. However, not much is known about the long-term alignment of symptoms reported by parents and child patients.

In this study, researchers compared parent and child patient-reported outcomes in EoE over time. A total of 292 parent-child respondents completed 723 questionnaires about symptoms over a 5-year period, which researchers used to track long-term changes and similarities in reported outcomes.

Results show that there is strong long-term alignment between parent and child patient-reported outcomes. Authors note that these findings provide evidence that parent-report by proxy is an accurate means to monitor symptoms, which provides a framework for monitoring pediatric patients in clinical trials.

_{Martin LJ, Zhang X, Chehade M, Davis CM, Dellon ES, Falk GW, Gupta SK, Hirano I, Hiremath GS, Katzka DA, Khoury P, Leung J, Menard-Katcher P, Gonsalves N, Pesek RD, Spergel JM, Wechsler JB, Kliewer K, Arva NC, Collins MH, Pletneva M, Yang GY, Furuta GT, Rothenberg ME, Aceves SS. Long-term durability between parent and child patient-reported outcomes in eosinophilic esophagitis. J Allergy Clin Immunol. 2024 Nov;154(5):1232-1240.e12. doi: 10.1016/j.jaci.2024.07.011. Epub 2024 Jul 25. PMID: 39059504.}

Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC)

Evaluating the Use of RNA Sequencing to Clarify Variants of Uncertain Significance in a Clinical Setting

RNA sequencing (RNA-seq) is a technique used to evaluate the sequence and quantity of messenger RNA, which can provide insights on gene expression. Although RNA-seq can help identify pathogenic variants in individuals with suspected genetic conditions, technological complexities and limited experience might affect its use in clinical practice.

In this study, researchers evaluated the use of RNA-seq to clarify variants of uncertain significance (VUS) in a clinical setting. The team developed a process to identify individuals who might benefit from clinical RNA-seq. Over a two-year period, genetics providers referred 26 cases for clinical RNA-seq, of which nine cases met the criteria for sequencing.

Results show that clinical RNA-seq was useful in clarifying uncertain results in about one-third of cases, including a new diagnosis of NGLY1 congenital disorder of deglycosylation. Authors note that demonstrating the clinical utility of RNA-seq may improve access to this new testing technique.

_{Marquez J, Cech JN, Paschal CR, Dingmann B, Scott AI, Thies JM, Mills MR, Albert CM, Beck AE, Beckman E, Bonkowski ES, Earl DL, Lam CT, Mefford HC, Merritt JL 2nd, Nelson Z, Ohlsen TJ, Taylor MR, Perlman SJ, Rudzinski ER, Sikes MC, Waligorski N, Wenger TL, Adam MP, Mirzaa GM, Bennett JT, Glass IA, Sternen DL, Miller DE. Clinical RNA sequencing clarifies variants of uncertain significance identified by prior testing. Genet Med Open. 2024;2:101886. doi: 10.1016/j.gimo.2024.101886. Epub 2024 Aug 9. PMID: 39484203; PMCID: PMC11526042.}

Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)

Characterizing Family Perspectives to Define Health Concepts in β-Propeller Protein–Associated Neurodegeneration

β-propeller protein–associated neurodegeneration (BPAN) is a progressive, neurodegenerative disease characterized by buildup of iron in the brain, leading to severe neurologic impairments. Future clinical trials are anticipated to identify new therapies for BPAN.

In this natural history study, researchers characterized family perspectives to define health concepts in BPAN. Among 42 caregivers of children diagnosed with BPAN, the team administered the Vineland Adaptive Behavior Scales, Third Edition—a tool which supports diagnosis of intellectual and developmental disabilities—along with health-related quality of life questionnaires.

Results highlight the effects of BPAN on both patient and caregiver quality of life. Key health concepts identified by families included overall health, comfort, and communication. Authors note that these health concepts will help inform future clinical outcome assessments.

_{Kotes E, Gavazzi F, Woidill S, Sevagamoorthy A, Yang E, Smith V, Dubbs H, Pierce SR, Pucci K, Vithayathil J, Thakur N, Adang LA. Determination of Health Concepts in β-Propeller Protein-Associated Neurodegeneration. J Child Neurol. 2024 Oct 8:8830738241283932. doi: 10.1177/08830738241283932. Epub ahead of print. PMID: 39376195.}

Myasthenia Gravis Rare Disease Network (MGNet)

Proposing an Artificial Intelligence-Powered Telemedicine Tool for Automatic Scoring of Neuromuscular Examinations in Patients with Myasthenia Gravis

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. Telemedicine is now being used more frequently to evaluate patients with MG. During these remote visits, symptoms are evaluated using the Myasthenia Gravis Core Exam (MG-CE) and Myasthenia Gravis Activities of Daily Living (MG-ADL) assessments. However, human subjectivity can limit the reliability of these examinations.

In this study, researchers propose an artificial intelligence-powered telemedicine tool for automatic scoring of neuromuscular examinations in patients with MG. The team used computer vision, deep learning, and natural language processing methods to automate a standard telemedicine video by segmenting it into clips corresponding with the MG-CE assessment.

Results show that this AI-powered solution improves scoring efficiency and quality in neuromuscular assessments. Authors note that the tool could potentially enhance patient participation in clinical trials for MG and other neurological diseases.

_{Lesport Q, Palmie D, Öztosun G, Kaminski HJ, Garbey M. AI-Powered Telemedicine for Automatic Scoring of Neuromuscular Examinations. Bioengineering (Basel). 2024 Sep 20;11(9):942. doi: 10.3390/bioengineering11090942. PMID: 39329684; PMCID: PMC11429301.}

Porphyrias Consortium (PC)

Developing a Wearable Light Dosimeter to Improve Quality of Life in Patients with Erythropoietic Protoporphyria

Erythropoietic protoporphyria (EPP) is a metabolic disorder characterized by the buildup of protoporphyrin, which is a light-sensitive substance. Individuals with EPP often experience severe pain from light exposure.

In this study, researchers developed a wearable light dosimeter both to improve quality of life in patients with EPP and to capture light exposure data for future EPP clinical trials. The dosimeters work by continuously capturing light doses of UVA, blue, and red wavelengths. The team tested the devices among five individuals with EPP, each wearing two light dosimeters—one as a watch, and one as a shirt clip—for three weeks.

Results show that wearable blue light dosimetry worn as a wristband is a promising method for measuring light exposure, as well as predicting and preventing symptoms in EPP.

_{Dickey AK, Berkovich J, Leaf RK, Jiang PY, Lopez-Galmiche G, Rebeiz L, Wheeden K, Kochevar I, Savage W, Zhao S, Campisi E, Heo SY, Trueb J, LaRochelle EPM, Rogers J, Banks A, Chang JK. Observational pilot study of multi-wavelength wearable light dosimetry for erythropoietic protoporphyria. Int J Dermatol. 2024 Nov;63(11):1584-1591. doi: 10.1111/ijd.17166. Epub 2024 Apr 11. PMID: 38602089; PMCID: PMC11467130.}

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 fourth 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, and the Office of Dietary Supplements.

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Rare Research Report: July 2024

admin — Wed, 04 Feb 2026 22:01:19 +0000

Rare Research Report: July 2024 admin Wed, 02/04/2026 - 17:01

July 26 2024

Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.

Jump to:

Brain Vascular Malformation Consortium (BVMC)
Developmental Synaptopathies Consortium (DSC)
Dystonia Coalition (DC)
Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)

Listen to these summaries on the Rare Research Report podcast.

Brain Vascular Malformation Consortium (BVMC)

Measuring the Angiographic Compactness Score for Brain Arteriovenous Malformations in Children with Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of the blood vessels that can cause chronic bleeding. People with HHT can experience brain arteriovenous malformations (BAVMs), which are tangles of blood vessels with abnormal connections between arteries and veins in the brain. In children with sporadic (non-HHT) BAVMs, angiography—an X-ray-based image of the blood vessels—can be used to assess the BAVM nidus compactness score, which helps predict BAVM recurrence after surgical removal.

In this study, researchers measured the angiographic compactness score for BAVMs in children with HHT. The team reviewed angiograms from 47 children with HHT in the Brain Vascular Malformation Consortium.

Results show that children with HHT have a range of compactness scores, suggesting the usefulness of these scores for future studies of BAVM recurrence and hemorrhage risk in children with HHT. The authors note that these studies could help direct BAVM treatment in the future.

_{Beslow LA, Vossough A, Kim H, Nelson J, Lawton MT, Pollak J, Lin DDM, Ratjen F, Hammill AM, Hetts SW, Gossage JR, Whitehead KJ, Faughnan ME, Krings T; Brain Vascular Malformation Consortium HHT Investigator Group. Brain AVM compactness score in children with hereditary hemorrhagic telangiectasia. Childs Nerv Syst. 2024 Jul;40(7):2101-2108. doi: 10.1007/s00381-024-06366-z. Epub 2024 Mar 22. PMID: 38517485; PMCID: PMC11179972.}

Developmental Synaptopathies Consortium (DSC)

Examining the Function of the Blood-Brain Barrier in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a genetic condition that affects many organs and can cause benign tumors in the skin, kidney, brain, heart, eyes, lungs, and other organs. The most severe symptoms—including seizures, intellectual disability, autism, and behavioral problems—result from complications in the central nervous system. Although these neurological complications are well-understood, less is known about how the genetic mutations that cause TSC might affect different components of the brain, including the blood-brain barrier.

In this study, researchers examined the function of the blood-brain barrier in TSC. The team created TSC patient-specific brain tissue models to explore how mutations in the TSC2 gene affect the blood-brain barrier.

Results show altered function of a blood-brain barrier generated from TSC2 mutant cells, which can improve with treatment of the drug rapamycin or replacement of mutant cells with astrocytes (glial cells in the brain) that do not carry the mutation. Authors note that these findings demonstrate the importance of their methods in ongoing research for TSC and other neurogenetic disorders.

This project was funded by the National Center for Advancing Translational Sciences (NCATS) Tissue Chips for Disease Modeling and Efficacy Testing Projects initiative.

_{Brown JA, Faley SL, Judge M, Ward P, Ihrie RA, Carson R, Armstrong L, Sahin M, Wikswo JP, Ess KC, Neely MD. Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit. J Neurodev Disord. 2024 May 23;16(1):27. doi: 10.1186/s11689-024-09543-y. PMID: 38783199; PMCID: PMC11112784.}

Dystonia Coalition (DC)

Exploring Factors and Mechanisms Underlying Differences Between Males and Females with Dystonia

Dystonia is a neurological disorder characterized by excessive muscle contractions leading to abnormal postures, movements, and pain. Previous studies have suggested that there are more female individuals with certain types of dystonia compared to male individuals. However, not much is known about the factors that impact these differences or the mechanisms behind them.

In this study, researchers explored the factors and mechanisms underlying differences between males and females with dystonia. The team analyzed data from two different sources, including 3,222 individuals from the Dystonia Coalition database and 1,377 individuals from the Movement Disorder Society Genetic mutation (MDSGene) database.

Results show that female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic (single-gene) dystonias, with females making up about two-thirds of all cases. In addition, these findings reveal that the ratio of females to males with dystonia depends on the type of dystonia, age, and underlying genetics.

_{Kilic-Berkmen G, Scorr LM, McKay L, Thayani M, Donsante Y, Perlmutter JS, Norris SA, Wright L, Klein C, Feuerstein JS, Mahajan A, Wagle-Shukla A, Malaty I, LeDoux MS, Pirio-Richardson S, Pantelyat A, Moukheiber E, Frank S, Ondo W, Saunders-Pullman R, Lohman K, Hess EJ, Jinnah HA. Sex Differences in Dystonia. Mov Disord Clin Pract. 2024 May 22. doi: 10.1002/mdc3.14059. Epub ahead of print. PMID: 38778444.}

Using Proteomics Methods to Identify Changes in Blood Plasma Proteins in Patients with Adult-Onset Focal Dystonias

Adult-onset focal dystonias are neurological disorders characterized by overactive muscles leading to involuntary, sometimes painful movements in one part of the body. In most cases, the cause and development of these disorders are unknown.

In this study, researchers used proteomics methods to identify potential changes in blood plasma proteins in patients with adult-onset focal dystonias. The team compared over 6,000 proteins in the blood plasma of participants with cervical dystonia, laryngeal dystonia, and blepharospasm, as well as healthy controls. Next, researchers identified relevant biological pathways and used protein changes to build a prediction model for dystonia.

Results show that 15 proteins were associated with adult-onset focal dystonia, with some proteins shared across multiple subgroups and others unique to just one. The top biological pathways involved changes in the immune system, metal ion transport, and reactive oxygen species. Finally, the prediction model showed high accuracy in discriminating control participants from those with dystonia. Authors note that this study provides new insights into the cause and development of dystonia, as well as new potential biomarkers.

_{Timsina J, Dinasarapu A, Kilic-Berkmen G, Budde J, Sung YJ, Klein AM, Cruchaga C, Jinnah HA. Blood-Based Proteomics for Adult-Onset Focal Dystonias. Ann Neurol. 2024 Jul;96(1):110-120. doi: 10.1002/ana.26929. Epub 2024 Apr 5. PMID: 38578115; PMCID: PMC11186717.}

Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)

Describing the Latest Advancements in Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an inherited condition in which mucociliary clearance of the lungs is impaired, leading to accumulation of harmful particles and pathogens trapped within mucus. In the past two decades, research and international collaborations have led to a better understanding of PCD. However, PCD is still not well-known in clinical settings, with only a fraction of patients receiving an accurate diagnosis.

In this review paper, authors describe the latest advancements in PCD research. Topics include the range of clinical manifestations, cutting-edge diagnostic practices, new genotype-phenotype associations, and the latest management techniques for individuals with PCD.

Authors note that sharing these advancements will have important clinical impacts, including improved disease recognition, diagnostic testing, and management. Additionally, increased awareness of PCD could help boost enrollment in upcoming clinical trials for new therapies.

_{Wee WB, Kinghorn B, Davis SD, Ferkol TW, Shapiro AJ. Primary Ciliary Dyskinesia. Pediatrics. 2024 Jun 1;153(6):e2023063064. doi: 10.1542/peds.2023-063064. PMID: 38695103; PMCID: PMC11153322.}

Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)

Assessing Balance and Gait in Adults with Adrenoleukodystrophy Using Wearable Sensors

Adrenoleukodystrophy (ALD) is an X-linked disorder (on the X chromosome) characterized by the disruption in fat metabolism (break down) which leads to the accumulation of long-chain fatty acids throughout the nervous system, adrenal glands, and testes. Individuals with ALD experience a slowly progressive myeloneuropathy, which causes problems with balance and gait. Evaluating this progression can often be complicated due to the inconsistency of symptom patterns. However, wearable sensors could make it easier to collect more frequent information about balance and gait.

In this study, researchers assessed balance and gait in adults with ALD using wearable sensors. The team measured postural body sway and gait in 120 participants using a type of wearable device called an accelerometer. Researchers also measured disease severity, as well as falling frequency and quality of life in men.

Results show clinically meaningful relationships for sway and gait with use of an assistive device, falling frequency, and quality of life. Authors note that wearable accelerometers are a valid means to measure sway and gait in ALD, which could help improve clinical trial designs to assess myeloneuropathy and monitor disease progression.

_{Yska HAF, Turk BR, Fatemi A, Goodman J, Voermans M, Amos D, Amanat M, van de Stadt S, Engelen M, Smith-Fine A, Keller J. International validation of meaningfulness of postural sway and gait to assess myeloneuropathy in adults with adrenoleukodystrophy. J Inherit Metab Dis. 2024 May 25. doi: 10.1002/jimd.12753. Epub ahead of print. PMID: 38795020.}

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 fourth 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, and the Office of Dietary Supplements.

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Rare Research Report: June 2024

admin — Wed, 04 Feb 2026 22:01:19 +0000

Rare Research Report: June 2024 admin Wed, 02/04/2026 - 17:01

June 26 2024

Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.

Jump to:

Brain Vascular Malformation Consortium (BVMC)
Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)
Urea Cycle Disorders Consortium (UCDC)

Listen to these summaries on the Rare Research Report podcast.

Brain Vascular Malformation Consortium (BVMC)

Investigating the Formation of New Brain Vascular Malformations in Patients with Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of the blood vessels that can cause excessive bleeding. About 10% of individuals with HHT have brain vascular malformations, which occur when the blood vessels in the brain develop abnormally. Children with HHT are screened for brain vascular malformations upon initial diagnosis, and many North American centers rescreen children for brain vascular malformations at interval throughout childhood. However, not much is known about whether people with HHT can develop new brain vascular malformations over time.

In this study, researchers investigated the formation of new brain vascular malformations in patients with HHT. The team analyzed data from 1,909 patients enrolled in the Brain Vascular Malformation Consortium natural history study, searching for brain vascular malformations that were new since previous imaging was performed.

Results showed that 409 patients had brain vascular malformations, with three showing new malformations confirmed by neuroimaging review. These findings demonstrate that patients with HHT can form new brain vascular malformations over time, though this is probably a rare occurrence. Authors note that more information about the frequency of new brain vascular malformation formation is needed.

_{Beslow LA, Krings T, Kim H, Hetts SW, Lawton MT, Ratjen F, Whitehead KJ, Gossage JR, McCulloch CE, Clancy M, Bagheri N, Faughnan ME; Brain Vascular Malformation Consortium HHT Investigator Group. De Novo Brain Vascular Malformations in Hereditary Hemorrhagic Telangiectasia. Pediatr Neurol. 2024 Jun;155:120-125. doi: 10.1016/j.pediatrneurol.2024.03.013. Epub 2024 Mar 22. PMID: 38631080; PMCID: PMC11102835.}

Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)

Investigating Clinical Outcomes of Children with Primary Ciliary Dyskinesia and Situs Ambiguus

Primary ciliary dyskinesia (PCD) is a genetic disorder in which mucociliary clearance of the lungs is impaired. While most individuals with PCD have normal arrangement of organs in the abdomen and chest (situs solitus), some present with situs ambiguus (abnormal arrangement) or situs inversus totalis (mirror image of normal arrangement).

In this study, researchers compared the clinical outcomes of children with PCD and situs ambiguus to those with situs solitus or situs inversus totalis. The team categorized 397 participants with PCD aged 21 years or younger into situs groups, then evaluated markers of disease severity.

Results show that children with PCD and situs ambiguus have worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with situs solitus or situs inversus totalis combined. Authors also note that these outcomes are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both.

_{Kaspy KR, Dell SD, Davis SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla C, Olivier KN, Barber AT, Wee W, Lin FC, Li L, Rampakakis E, Zariwala MA, Knowles MR, Leigh MW, Shapiro AJ. Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia. Chest. 2024 May;165(5):1070-1081. doi: 10.1016/j.chest.2023.12.005. Epub 2023 Dec 9. PMID: 38072392.}

Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)

Describing Patients with TBL1XR1-Related Disorder Using a Caregiver Survey

TBL1XR1-related disorder is a group of neurodevelopmental disorders caused by variants in the TBL1XR1 gene. As these disorders are rare with a wide range of characteristics, not much is known about the developmental trajectory and progression of neurological symptoms over time.

In this study, researchers describe the largest group of patients to date with TBL1XR1-related disorder. The team surveyed caregivers of 41 patients with TBL1XR1-related disorder, focusing on the pregnancy and perinatal course, caregiver-reported developmental trajectory, associated symptoms and diagnoses, neurological progression over time, and genetic information.

Results reflect the spectrum of diverse traits in TBL1XR1-related disorder, including developmental delay and regression ranging in severity. Seizures were common, which could be related to language regression. Authors note that further study is needed to determine whether functional differences caused by different variants in the TBL1XR1 gene explain the range of characteristics in this disorder.

_{Nagy A, Molay F, Hargadon S, Brito Pires C, Grant N, De La Rosa Abreu L, Chen JY, D'Souza P, Macnamara E, Tifft C, Becker C, Melo De Gusmao C, Khurana V, Neumeyer AM, Eichler FS. The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects. Orphanet J Rare Dis. 2024 Feb 20;19(1):79. doi: 10.1186/s13023-024-03083-3. PMID: 38378692; PMCID: PMC10880200.}

Sharing a New Approach to Creating Longitudinal Natural History Studies for Rare Diseases

In rare diseases, natural history studies are essential to understanding disease progression over time. Prospective studies are limited by fewer available patients at a given time, impacting the timely collection of natural history data. These studies are also unlikely to capture pre-diagnostic clinical trajectories in conditions where diagnostic delays are common.

In this study, researchers shared a new approach to creating real-world data-based longitudinal natural history studies for rare diseases. The team outlined various strategies developed by the Global Leukodystrophy Initiative Clinical Trials Network. Strategies include use of standard operating procedures and rigorous processes for staff training, data extraction, source documentation, and data management.

Authors note that these strategies will complement prospective studies by enabling the use of existing medical records to collect natural history data on large numbers of patients in a short time and map complete disease trajectory, including the time period before diagnosis.

_{Adang LA, Sevagamoorthy A, Sherbini O, Fraser JL, Bonkowsky JL, Gavazzi F, D'Aiello R, Modesti NB, Yu E, Mutua S, Kotes E, Shults J, Vincent A, Emrick LT, Keller S, Van Haren KP, Woidill S, Barcelos I, Pizzino A, Schmidt JL, Eichler F, Fatemi A, Vanderver A. Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach. Mol Genet Metab. 2024 May;142(1):108453. doi: 10.1016/j.ymgme.2024.108453. Epub 2024 Mar 18. PMID: 38522179.}

Urea Cycle Disorders Consortium (UCDC)

Exploring Risk Factors in Asymptomatic Females with Ornithine Transcarbamylase Deficiency

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). Because OTCD is caused by an X-linked mutation in the OTC gene, the majority of patients with severe presentation of OTC deficiency are male, as they have only one X chromosome. Although 80% of females with OTCD are typically thought to remain asymptomatic, not much is known about their clinical characteristics and long-term health vulnerabilities.

In this study, researchers explored the factors that might predict development of defined complications and serious illness in apparent asymptomatic females with OTCD. The team reviewed data from 302 females enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history study. Researchers also performed several types of neuroimaging studies in a female patient with OTCD.

Results show that these patients can experience neuropsychiatric and behavioral symptoms as well as an increased risk of hyperammonemia later in life, demonstrating that asymptomatic females with OTCD are not always asymptomatic. Authors note that these findings can aid in the development of a risk calculator and improve guidelines for management of these patients, paving the way for potential new therapies.

_{Sen K, Izem R, Long Y, Jiang J, Konczal LL, McCarter RJ; Members of the Urea Cycle Disorders Consortium (UCDC); Gropman AL, Bedoyan JK. Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database. Mol Genet Genomic Med. 2024 Apr;12(4):e2443. doi: 10.1002/mgg3.2443. PMID: 38634223; PMCID: PMC11024633.}

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 fourth 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, and the Office of Dietary Supplements.

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Rare Research Report: April 2024

admin — Wed, 04 Feb 2026 22:01:19 +0000

Rare Research Report: April 2024 admin Wed, 02/04/2026 - 17:01

April 24 2024

Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.

Jump to:

Brain Vascular Malformation Consortium (BVMC)
Brittle Bone Disorders Consortium (BBDC)
Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC)
Inherited Neuropathy Consortium (INC)
Myasthenia Gravis Rare Disease Network (MGNet)
Primary Immune Deficiency Treatment Consortium (PIDTC)
Urea Cycle Disorders Consortium (UCDC)

Listen to these summaries on the Rare Research Report podcast.

Brain Vascular Malformation Consortium (BVMC)

Developing a Quantitative Approach to Measure Deep Medullary Vein Volumes in Patients with Sturge-Weber Syndrome

Sturge-Weber syndrome (SWS) is a condition resulting in abnormal blood vessel formation in the brain, eyes, and skin at birth. In patients with SWS, enlarged deep medullary veins—mostly located in the white matter in the brain—may form early and can expand during the first years of life to provide compensatory collateral venous drainage of brain regions affected by leptomeningeal venous malformations localized on the brain surface.

The extent of enlarged deep veins during the early SWS disease course could be an imaging marker of this deep venous remodeling in an attempt to compensate for impaired brain surface venous blood flow. In this prospective imaging study, researchers used brain magnetic resonance imaging (MRI) to develop and optimize a quantitative approach to measure deep vein volumes in the affected brain of young patients with SWS and compare the findings to those of their healthy siblings.

 By combining two types of MRI (susceptibility-weighted imaging and volumetric T1 images), the authors were able to measure the volumes of deep veins, which were 10-12 fold higher than venous volumes in their healthy siblings. Greater deep vein volumes were associated with lower cortical surface area of the affected hemisphere, a measure of cortical atrophy. This new analytic approach of brain MRI can provide an objective way to assess the extent of deep venous remodeling in SWS and other disorders affecting the medullary veins of the brain.

_{Jeong JW, Lee MH, Luat AF, Xuan Y, Haacke EM, Juhász C. Quantification of enlarged deep medullary vein volumes in Sturge-Weber syndrome. Quant Imaging Med Surg. 2024 Feb 1;14(2):1916-1929. doi: 10.21037/qims-23-1271. Epub 2024 Jan 23. PMID: 38415136; PMCID: PMC10895099.}

Brittle Bone Disorders Consortium (BBDC)

Summarizing Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a group of inherited connective tissue disorders associated with a wide range of symptoms, including fragile bones that break easily. Drugs to improve skeletal health—including those initially developed to treat osteoporosis as well as new bone-protective agents—are in various phases of clinical trials for adults with OI.

In this review article, researchers summarize current and developing pharmacologic agents for improving skeletal health in adults with OI. The team performed online database searches to review published studies and clinical trials.

Results include ongoing clinical trials for several therapeutics, including those that may be useful in improving bone mineral density. Authors note that clinical trials involving gene editing may be possible in the coming decade.

_{Liu W, Nicol L, Orwoll E. Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta. Calcif Tissue Int. 2024 Mar 12. doi: 10.1007/s00223-024-01188-2. Epub ahead of print. PMID: 38472351.}

Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC)

Exploring Proteomics and N-Glycoproteomics in ALG1-Congenital Disorder of Glycosylation

ALG1-congenital disorder of glycosylation (ALG1-CDG) is an inherited disorder caused by variants in the ALG1 gene. These variants affect N-glycosylation, which is the body’s process of creating, changing, and attaching sugar blocks to proteins and lipids. However, not much is known about how these variants affect the cellular proteome (proteins expressed in cells) and the process of glycosylation.

In this study, researchers explored proteomics and N-glycoproteomics in ALG1-CDG. The team studied fibroblasts (connective tissue cells) from three individuals with different ALG1 variants.

Results revealed altered protein levels and a reduction of mature forms of glycopeptides. Authors note that these results can help us understand the biology and molecular mechanisms of ALG1-CDG, differentiate CDG types, and identify potential biomarkers.

_{Budhraja R, Joshi N, Radenkovic S, Kozicz T, Morava E, Pandey A. Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts. Proteomics. 2024 Mar 12:e2400012. doi: 10.1002/pmic.202400012. Epub ahead of print. PMID: 38470198.}

Exploring the Neurological Characteristics of PMM2-Congenital Disorder of Glycosylation Using Human In Vitro Neural Models

PMM2-congenital disorder of glycosylation (PMM2-CDG) is an inherited condition caused by mutations in the PMM2 gene. Most individuals with PMM2-CDG experience neurological symptoms. However, not much is known about the specific brain-related changes caused by PMM2 deficiency.

In this study, researchers explored the neurological characteristics of PMM2-CDG using human in vitro neural models. The team created human induced pluripotent stem cell (hiPSC)-derived neural models to observe changes in neural function and metabolic dynamics.

Results revealed disrupted functioning of PMM2-deficient neuronal networks, as well as widespread changes in metabolite composition, RNA expression, protein abundance, and protein glycosylation. Authors note that these findings introduce potentially critical factors contributing to the early neural issues in patients with PMM2-CDG, paving the way for exploring innovative treatment approaches.

_{Radenkovic S, Budhraja R, Klein-Gunnewiek T, King AT, Bhatia TN, Ligezka AN, Driesen K, Shah R, Ghesquière B, Pandey A, Kasri NN, Sloan SA, Morava E, Kozicz T. Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models. Cell Rep. 2024 Mar 1;43(3):113883. doi: 10.1016/j.celrep.2024.113883. Epub ahead of print. PMID: 38430517.}

Inherited Neuropathy Consortium (INC)

Reporting Cases of Intermediate Nerve Conduction Velocity in Patients with Charcot-Marie-Tooth Disease Type 1A

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of inherited peripheral neuropathy, is caused by duplication of the PMP22 gene. Individuals with CMT1A experience slow nerve conduction velocity (the speed of electrical impulses moving through nerves). Because most patients have nerve conduction rates below 38 meters per second, genetic testing for PMP22 duplication is not usually recommended for those with higher rates.

In this study, researchers report cases of intermediate nerve conduction velocity in two patients with CMT1A. Both individuals had upper limb motor nerve conduction velocities above 38 meters per second. These patients also presented with very mild forms of CMT1A.

Authors note that although these cases are very rare, they highlight the importance of testing PMP22 duplication in patients with intermediate conduction velocities.

_{Tomaselli PJ, Blake J, Polke JM, do Nascimento OJM, Reilly MM, Marques Júnior W, Laurá M. Intermediate conduction velocity in two cases of Charcot-Marie-Tooth disease type 1A. Eur J Neurol. 2024 Feb 26:e16199. doi: 10.1111/ene.16199. Epub ahead of print. PMID: 38409938.}

Myasthenia Gravis Rare Disease Network (MGNet)

Investigating the Characteristics of Natural Killer Cells in Patients with Autoantibody-Mediated Autoimmune Diseases

Neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein Ab disease, and autoimmune myasthenia gravis (MG) are autoantibody-mediated autoimmune diseases. Autoantibodies can cause a type of immune reaction called Ab-dependent cellular cytotoxicity (ADCC) involving natural killer (NK) cells. However, it is not known whether ADCC contributes to disease development in patients with these conditions.

In this study, researchers investigated the characteristics of circulating NK cells in patients with NMOSD, myelin oligodendrocyte glycoprotein Ab disease, and MG. The team used functional assays, phenotyping, and transcriptomics to explore the role of NK cells in these diseases.

Results show elevated subsets of NK cells in patients with NMOSD and MG. Authors note that this elevation suggests prior ADCC activity occurring in the affected tissues.

_{Yandamuri SS, Filipek B, Lele N, Cohen I, Bennett JL, Nowak RJ, Sotirchos ES, Longbrake EE, Mace EM, O'Connor KC. A Noncanonical CD56dimCD16dim/- NK Cell Subset Indicative of Prior Cytotoxic Activity Is Elevated in Patients with Autoantibody-Mediated Neurologic Diseases. J Immunol. 2024 Mar 1;212(5):785-800. doi: 10.4049/jimmunol.2300015. PMID: 38251887; PMCID: PMC10932911.}

Primary Immune Deficiency Treatment Consortium (PIDTC)

Investigating Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with P47phox Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is an inherited disorder characterized by granulocytes that cannot properly kill invading pathogenic organisms, making patients susceptible to severe infections. Although X-linked CGD is the most common form, autosomal recessive CGD caused by deficiency of the protein p47phox causes nearly a third of cases and was historically thought to be milder than X-linked CGD. Allogeneic hematopoietic cell transplantation (HCT) is often used to treat other forms of CGD recognized to be severe. However, not much is known about HCT in patients with p47phox CGD.

In this study, researchers investigated outcomes of allogeneic HCT in patients with p47phox CGD. The team analyzed data from 30 patients with p47phox CGD who received HCT at Primary Immune Deficiency Treatment Consortium (PIDTC) centers since 1995.

Results show that HCT can effectively alleviate the disease burden of patients with p47phox CGD. The authors note that HCT should be considered for patients with p47phox CGD.

_{Grunebaum E, Arnold DE, Logan B, Parikh S, Marsh RA, Griffith LM, Mallhi K, Chellapandian D, Lim SS, Deal CL, Kapoor N, Murguía-Favela L, Falcone EL, Prasad VK, Touzot F, Bleesing JJ, Chandrakasan S, Heimall JR, Bednarski JJ, Broglie LA, Chong HJ, Kapadia M, Prockop S, Dávila Saldaña BJ, Schaefer E, Bauchat AL, Teira P, Chandra S, Parta M, Cowan MJ, Dvorak CC, Haddad E, Kohn DB, Notarangelo LD, Pai SY, Puck JM, Pulsipher MA, Torgerson TR, Malech HL, Kang EM, Leiding JW. Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A Primary Immune Deficiency Treatment Consortium study. J Allergy Clin Immunol. 2024 Jan 28:S0091-6749(24)00081-2. doi: 10.1016/j.jaci.2024.01.013. Epub ahead of print. PMID: 38290608.}

Urea Cycle Disorders Consortium (UCDC)

Comparing the Effects of Liver Transplantation and Medical Management on Health-Related Outcomes in Patients with Urea Cycle Disorders

Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Patients with UCD may undergo liver transplantation when medical management is not enough to prevent hyperammonemia. However, not much is known about how the effects of transplant compare to medical management alone.

In this study, researchers classified patients into “severe” and “attenuated” categories based on genetic information and a novel enzyme activity test. Then, using data collected from longitudinal observational studies, they compared the health-related outcomes in patients who underwent liver transplantation vs medical management.

Results show that liver transplantation led to greater metabolic stability without the need for protein restriction or nitrogen-scavenging therapy. However, while transplantation led to more favorable growth outcomes, it was not associated with improved neurocognitive outcomes compared to long-term medical management.

_{Posset R, Garbade SF, Gleich F, Scharre S, Okun JG, Gropman AL, Nagamani SCS, Druck AC, Epp F, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders. Genet Med. 2023 Dec 3;26(4):101039. doi: 10.1016/j.gim.2023.101039. Epub ahead of print. PMID: 38054409.}

Investigating the Impact of Long-Term L-Citrulline or L-Arginine Supplementation After Liver Transplantation in Patients with Urea Cycle Disorders

Urea cycle disorders (UCDs) are genetic disorders that result in a deficiency of one of the six enzymes in the urea cycle, causing hyperammonemia (high blood ammonia levels). When medical management is not enough to prevent hyperammonemia, patients with UCDs may undergo liver transplantation. Both before and after transplant, these patients often receive L-citrulline or L-arginine supplements to help their bodies eliminate ammonia. However, not much is known about the impact of long-term supplementation.

In this pilot study, researchers investigated the effects of long-term L-citrulline or L-arginine supplementation in patients with UCDs who have undergone liver transplantation. The team used data collected from longitudinal observational studies to compare outcomes of 16 patients who received these supplements long-term with 36 patients who were not supplemented over the course of 4 or 5 years after transplant.

Results suggest that although supplementation with L-citrulline or L-arginine is often continued after transplant, in this pilot study, such supplementation was not associated with health-related outcomes or biochemical responses. Authors note that analyzing larger samples over longer observation periods will provide more insight into the usefulness of long-term supplementation.

_{Posset R, Garbade SF, Gleich F, Nagamani SCS, Gropman AL, Epp F, Ramdhouni N, Druck AC, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group. Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders. Mol Genet Metab. 2024 Mar;141(3):108112. doi: 10.1016/j.ymgme.2023.108112. Epub 2023 Dec 10. PMID: 38301530.}

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 fourth 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, and the Office of Dietary Supplements.

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