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:
- Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)
- Developmental Synaptopathies Consortium (DSC)
- Inherited Neuropathy Consortium (INC)
- Myasthenia Gravis Rare Disease Network (MGNet)
- North American Mitochondrial Disease Consortium (NAMDC)
Listen to these summaries on the Rare Research Report podcast.
Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)
Exploring the Underlying Causes of Symptom Severity in Eosinophilic Esophagitis
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 can include difficulty swallowing, food getting stuck in the throat, vomiting, reflux, malnourishment, and poor appetite. Not much is known about the underlying causes of variation in EoE symptoms.
In this study, researchers explored the underlying causes of symptom severity in EoE. First, the team compared a validated patient-reported outcome metric with a set of transcripts expressed in the esophagus of 146 patients with EoE. Next, the team used single-cell RNA sequencing data to identify the cellular source of EoE genes and further analyzed patients with mild and severe symptoms.
Results reveal that EoE symptoms are correlated with nonepithelial esophageal gene expression. Authors note that these findings provide evidence that nonepithelial cells likely contribute to symptom severity.
Kim S, Ben-Baruch Morgenstern N, Osonoi K, Aceves SS, Arva NC, Chehade M, Collins MH, Dellon ES, Falk GW, Furuta GT, Gonsalves NP, Gupta SK, Hirano I, Hiremath G, Katzka DA, Khoury P, Leung J, Pesek R, Peterson KA, Pletneva MA, Spergel JM, Wechsler JB, Yang GY, Rothenberg ME, Shoda T. Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis. J Allergy Clin Immunol Pract. 2024 Dec;12(12):3346-3355.e1. doi: 10.1016/j.jaip.2024.05.015. Epub 2024 May 18. PMID: 38768900; PMCID: PMC11570700.
Developmental Synaptopathies Consortium (DSC)
Evaluating Remote Monitoring of Social Attention in Neurodevelopmental Genetic Syndromes
Neurodevelopmental genetic syndromes are conditions that affect the development of brain function. Many individuals with these syndromes experience altered social attention that can impact their ability to accurately perceive social information in their world.
In this study, researchers evaluated remote monitoring of social attention in children, adolescents, and adults with a wide range of neurodevelopmental outcomes. Participants included individuals with three genetic syndromes (PTEN hamartoma tumor syndrome, Malan syndrome, and SYNGAP1-related disorder), a mixed group of other neurodevelopmental genetic syndromes, and individuals with a range of idiopathic neurodevelopmental disorders, as well as neurotypical siblings and unrelated controls. Each participant completed a four-minute social attention paradigm via webcam.
Results show that social attention measures had good scale and test-retest reliability, with the exception of measures of non-social preference and face-specific processing. Findings demonstrate that remote monitoring of social attention may be useful for characterizing phenotypic profiles and tracking the natural history of distinct neurodevelopmental genetic syndromes and idiopathic neurodevelopmental disorders, as well as identifying autism spectrum disorder in patients with neurodevelopmental genetic syndromes. Authors note that global social attention and several distinct social attention measures may also be useful outcomes for future clinical trials.
Frazier TW, Busch RM, Klaas P, Lachlan K, Jeste S, Kolevzon A, Loth E, Harris J, Pepper T, Anthony K, Graglia JM, Helde K, Delagrammatikas C, Bedrosian-Sermone S, Smith-Hicks C, Sahin M, Youngstrom EA, Eng C, Chetcuti L, Hardan AY, Uljarevic M. Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability. Autism Res. 2024 Dec 6. doi: 10.1002/aur.3290. Epub ahead of print. PMID: 39643599.
Inherited Neuropathy Consortium (INC)
Investigating Patient Perspectives on Disease Burden Over Time in Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) is a group of disorders that affect the peripheral nerves of the feet and hands, leading to neuropathy. Symptoms may include weakness, sensory loss, muscle atrophy, balance problems, and foot deformities.
In this study, researchers investigated patient perspectives on disease burden over time in CMT. As part of an international clinical trial readiness study, 215 individuals with CMT type 1A participated in clinical outcome assessments (including the CMT Health Index) to capture changes in patient-reported disease burden over 12 months.
Results show that patient-reported disease burden in CMT type 1A as measured by the CMT Health Index is associated with measures of neurologic impairment and physical functioning. Women reported a higher disease burden than men. Authors note that these data will inform the design of clinical trials in CMT type 1A.
Rehbein T, Purks J, Dilek N, Behrens-Spraggins S, Sowden JE, Eichinger KJ; ACT‐CMT Study Group; Burns J, Pareyson D, Scherer SS, Reilly MM, Shy ME, McDermott MP, Heatwole CR, Herrmann DN. Patient-reported disease burden in the Accelerate Clinical Trials in Charcot-Marie-Tooth Disease Study. J Peripher Nerv Syst. 2024 Dec;29(4):487-493. doi: 10.1111/jns.12662. Epub 2024 Oct 10. PMID: 39390667; PMCID: PMC11631656.
Myasthenia Gravis Rare Disease Network (MGNet)
Comparing the Accuracy of Radioimmunoassay and Fixed Cell-Based Assay for Diagnosis of Myasthenia Gravis
Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles, causing disabling weakness. Acetylcholine receptor antibody detection is crucial for MG diagnosis. Currently, radioimmunoassay is the gold-standard test used to measure the concentration of acetylcholine receptor antibodies. However, this test may detect false positives for nonpathogenic antibodies.
In this study, researchers compared the accuracy of radioimmunoassay and fixed cell-based assay for MG diagnosis. First, the team reviewed medical records of 605 patients who tested positive for acetylcholine receptor antibodies via radioimmunoassay and confirmed these results. Next, the team retested asymptomatic patients via fixed cell-based assay to determine whether this method would show higher accuracy in detecting pathogenic antibodies.
Results show that, in rare cases, fixed cell-based assay may be more specific than radioimmunoassay in detecting pathogenic antibodies. Authors note that fixed cell-based assay may be performed as an additional tool to increase diagnostic accuracy when clinical presentation and electrodiagnostic studies are found to be atypical for MG.
Falso S, Marini S, Carrozza C, Sabatelli E, Mascagna G, Marini M, Morroni J, Evoli A, Iorio R. Concordance between radioimmunoassay and fixed cell-based assay in subjects without myasthenia gravis: optimizing the diagnostic approach. Eur J Neurol. 2024 Dec;31(12):e16435. doi: 10.1111/ene.16435. Epub 2024 Aug 8. PMID: 39118440; PMCID: PMC11554847.
North American Mitochondrial Disease Consortium (NAMDC)
Exploring the Clinical Utility of Growth Differentiation Factor 15 as a Biomarker for Primary Mitochondrial Disorders
Primary mitochondrial disorders (PMD) are chronic, multisystemic disorders involving dysfunction of the mitochondria caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Due to the clinical and genetic diversity of PMD, recognition of these disorders in a clinical setting is often difficult.
In this study, researchers explored the clinical utility of growth differentiation factor 15 (GDF15) as a biomarker for PMD. First, the team reviewed medical records from 418 cases where GDF15 levels were obtained by clinicians at a tertiary care hospital. Next, they classified each case as PMD due to mtDNA-related defects (mtDNA deletions, mtDNA depletion, tRNA variants), PMD due to structural defects or other nuclear causes, and non-mitochondrial disease. Patients with liver disease or systemic critical illness were excluded. Finally, GDF15 was assayed in a clinical laboratory.
Results show that in a real-life clinical setting—after excluding abnormal liver function and critical illness—GDF15 had good clinical utility of increasing the odds at predicting mtDNA-related primary mitochondrial disorders by 14-fold. An elevated GDF15 had 40.8% odds of identifying an mtDNA-related mitochondrial disorder versus 2.7% if not elevated. However, GDF15 did not show good clinical utility as a biomarker for structural or other nuclear-encoded primary mitochondrial disorders.
Fernández AC, Estrella J, Oglesbee D, Larson AA, Van Hove JLK. The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders. J Inherit Metab Dis. 2024 Nov 24. doi: 10.1002/jimd.12821. Epub ahead of print. PMID: 39582258.
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.
