Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.
- Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)
- Developmental Synaptopathies Consortium (DSC)
- Dystonia Coalition (DC)
- Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
- Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)
- Inherited Neuropathy Consortium (INC)
- Myasthenia Gravis Rare Disease Network (MGNet)
- Urea Cycle Disorders Consortium (UCDC)
Eosinophilic gastritis (EG) is a chronic inflammatory disease of the stomach that occurs when certain white blood cells known as eosinophils gather in large numbers in the stomach, causing injury and irritation.
In this study, researchers aimed to better understand the endoscopic manifestations of EG and develop a standardized instrument for investigations. Using data prospectively collected as part of CEGIR, the team evaluated endoscopic features of children and adults with EG recorded with the EG Endoscopic Reference System (EG-REFS).
Researchers identified a strong correlation between EG-REFS scores and physician global assessment of endoscopy severity. EG-REFS severity was significantly correlated with active histology and a tendency for the gastric antrum (lower portion of the stomach). The authors note that further development of EG-REFS should improve its utility in clinical studies.
Eosinphilic colitis (EoC) has been a poorly understood condition with uncertainty whether it is a distinct disease or a manifestation of eosinophilic gastrointestinal disease or inflammatory bowel disease. Researchers from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) seeking to better understand the condition analyzed samples from more than 60 people treated at multiple medical centers v. controls to compare this rare disease to other conditions. They identified and analyzed 987 differentially expressed genes, established EoC transcriptomic profiles, identified mechanistic pathways, and compared findings with related conditions. They concluded that EoC is a distinct disease, establishing a basis for improved diagnosis and treatment. Read more about this paper.
Eosinophilic esophagitis (EoE) is an allergic condition characterized by inflammation in the esophagus that causes a range of symptoms. Patients can have symptoms of esophageal dysfunction without meeting the classical diagnostic criteria. To characterize and classify the range of variants, an international team of researchers studied 69 patients with EoE variants. They identified and described three histological subtypes. Study authors concluded that EoE variants appear to be part of a disease spectrum, with classical EoE as the most common and apparent phenotype.
Neurodevelopmental neuropsychiatric disorders—such as autism spectrum disorder and schizophrenia—have strong genetic risk components, but researchers are still deciphering the underlying mechanisms. Rare variants could help us better understand the biological mechanisms for more common idiopathic diseases and reveal new therapeutic targets. This review summarizes insights from the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants.” Experts describe progress in genomic discovery and human phenotyping, as well as raise consistent issues.
Blepharospasm (BSP) is a form of focal dystonia that manifests with eyelid spasms, involuntary eyelid closures, and spontaneous blinking. To date, there are no widely accepted criteria to diagnose BSP. In this study, researchers validate the use of new diagnostic criteria for BSP in a diverse international population.
“This was a huge, multicenter effort aimed at establishing internationally acceptable diagnostic criteria for BSP,” says H. A. Jinnah, MD, PhD, principal investigator of the DC. “Such criteria did not exist before. What we do in the USA with RDCRN funding must ultimately go to the rest of the world.”
Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the movement of cilia, tiny hair-like structures on airway cells that beat rhythmically to move mucus out of the airways. Defects in cilia structure or function result in chronic upper and lower respiratory disease. Mutations in the ODAD1 gene result in a failure to assemble outer dynein arms (ODAs), the molecular motors that provide the force for ciliary beating. In the absence of ODAD1, cilia are mostly immotile cilia, and subjects suffer from a typical PCD phenotype.
In this study, researchers identified a patient with an unusually mild phenotype and a mutation in ODAD1. To investigate the mechanisms behind this unusual phenotype, they performed molecular and functional studies of cultured nasal epithelial cells.
Their findings indicate that the mutant protein retains partial function, allowing for the assembly of some ODAs and a significant level of ciliary activity that may result in the unusually mild phenotype. These findings also suggest that partial restoration of ciliary function by therapeutic agents could lead to significant improvement of PCD symptoms.
Leukodystrophies are a group of rare neurological disorders affecting the white matter of the brain that are characterized by severe neuromotor disability. Research on the functional status of people with leukodystrophy is limited by the need for in-person mobility assessments.
The Gross Motor Function Measure-88 (GMFM-88) is an assessment tool used to measure change in gross motor function over time. In this study, researchers assessed the reliability of the GMFM-88 using telemedicine compared with standard in-person assessments in patients with leukodystrophy. They found that remote application of the GMFM-88 is a feasible and reliable approach. The authors note that this approach may be of particular value in rare diseases and those with severe neurologic disability that impacts travel ability.
Charcot-Marie-Tooth (CMT) is a group of inherited, degenerative disorders affecting the nerves that travel to the feet and hands, causing muscle weakness, problems with balance and sensation as well as other symptoms.
Axonal transport (a process essential for nerve development, function, and survival) mediated by the KIF1A gene is driven by interaction cycles between the kinesin (motor protein)’s motor and neck domains.
In this study, researchers characterized a KIF1A mutant identified in a family with axonal-type CMT and other cases of human neuropathies. This characterization reveals that dynamic dissociation of the motor-neck interaction via the β7 (integrin protein) domain is essential for neuronal function.
SARM1 is a protein with critical NAD-glycohydrolase (NADase) activity. This protein drives axon (nerve fiber) degeneration, a characteristic of many neurodegenerative diseases.
In this study, researchers screened patient data for mutations associated with amyotrophic lateral sclerosis (ALS). They discovered disease-associated variant alleles that alter SARM1 function, hyperactivating the NADase activity that drives degeneration. The authors conclude that these may represent risk alleles for ALS and other motor nerve diseases.
These findings highlight the role of axonal degeneration in motor neuron diseases. The study also provides a rationale for SARM1-directed therapeutic intervention.
Henry Kaminski, MD, principal investigator of the Myasthenia Gravis Rare Disease Network (MGNet), and his colleagues have published a review of the present-day therapy for the autoimmune disease myasthenia gravis (MG). Despite there being only 120,000 patients with MG in the US, the well-understood pathophysiology provides a testing ground for drug development to reduce pathogenic antibody in circulation and for B cell depletion to target autoreactive cells. This review paper discusses a new class of agent, FcRn inhibitors, as well as complement inhibitors, which have recently been approved by the US Food and Drug Administration for use in MG. Challenges remain as a cure remains an elusive goal.
This new review paper highlights the evolving knowledge about the impact of urea cycle disorders (UCD) and hyperammonemia (HA) in particular on neurological injury and recovery. It discusses the use of electroencephalography (EEG) and magnetic resonance imaging (MRI) to study and evaluate prognostic factors for risk and recovery. It recognizes the work of others and discusses the UCDC's prior work and future research priorities, as well as lessons learned over 15 years of neuroimaging research.
Key learnings include the identification of the insular cortex as the area most vulnerable to hyperammonemia in UCD. Elevated glutamine and decreased myoinosital have been identified as key brain biomarkers on proton magnetic resonance spectroscopy (MRS), with decreased choline seen over time in patients with repeat HA episodes. Slow recovery of brain glutamine after recovery from hyperammonemia is common.
Researchers have found that 1H-MRS, a non-invasive technique that enables the detection, identification, and quantification of biochemical compounds or metabolites in the brain tissue, is most sensitive for proximal UCD and is often abnormal with elevated glutamine, before routine T1 and T2 sequences on MRI show abnormalities. In addition, our work demonstrates that more than one-third of female carriers of OTCD have the biochemical phenotype of UCD on MRS including mildly elevated glutamine and lower than normal myoinositol. 1H-MRS should be added to the clinical routine in patients with known and suspected metabolic conditions.
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.