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)
- Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
- Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) and Lysosomal Disease Network (LDN)
- Inherited Neuropathy Consortium (INC)
- Nephrotic Syndrome Study Network (NEPTUNE)
- Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium
- Urea Cycle Disorders Consortium (UCDC)
Listen to these summaries on the Rare Research Report podcast.
Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)
Exploring Clinical and Molecular Features Associated with the Index of Severity for Eosinophilic Esophagitis
Eosinophilic esophagitis (EoE) is a disorder in which eosinophils (white blood cells of the immune system) build up in the esophagus, in association with esophageal damage. The severity of EoE can be classified using a new clinical tool called the Index of Severity for Eosinophilic Esophagitis (I-SEE).
In this study, researchers explored the clinical and molecular features associated with the index of severity for EoE. Among 318 patients with EoE, the team assessed the associations between I-SEE scores, symptoms, and molecular activity.
Results show that I-SEE scores are associated with select clinical features across severity categories, as well as EoE molecular features for nonsevere categories. Authors note that these results warrant further validation.
Sato H, Dellon ES, Aceves SS, Arva NC, Chehade M, Collins MH, Davis CM, Falk GW, Furuta GT, Gonsalves NP, Gupta SK, Hirano I, Hiremath G, Katzka DA, Khoury P, Leung J, Menard-Katcher P, Pesek R, Peterson KA, Pletneva MA, Spergel JM, Wechsler JB, Yang GY, Rothenberg ME, Shoda T. Clinical and molecular correlates of the Index of Severity for Eosinophilic Esophagitis. J Allergy Clin Immunol. 2024 Aug;154(2):375-386.e4. doi: 10.1016/j.jaci.2024.04.025. Epub 2024 May 13. PMID: 38750825; PMCID: PMC11305930.
Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
Estimating the Global Prevalence of Primary Ciliary Dyskinesia
Primary ciliary dyskinesia (PCD) is an inherited multisystem disease involving dysfunctional motile cilia that can impact mucociliary clearance, fertility, and organogenesis. Although PCD is considered the second-most common inherited airway disease after cystic fibrosis, it is not well-recognized globally due to its nonspecific clinical features and the lack of gold standard diagnostic testing.
In this article, the authors conducted a scoping review (using PRISMA-ScR methodology) of the current PCD literature to better understand the global prevalence of PCD. Authors also identify key considerations of different study designs and inform the reader about the potential unmet health service needs in PCD.
Results found that the current best estimate for PCD global prevalence is one in 7,554, which was based on a genomic approach. Although this estimate is still considered conservative, this finding suggests that PCD is much more prevalent than previously thought and that there is an urgent need for more healthcare policies to accelerate improvements in PCD care, as well as expand services to underserved populations.
Wee WB, Gatt D, Seidl E, Santyr G, To T, Dell SD. Estimates of primary ciliary dyskinesia prevalence: a scoping review. ERJ Open Res. 2024 Aug 5;10(4):00989-2023. doi: 10.1183/23120541.00989-2023. PMID: 39104959; PMCID: PMC11299005.
Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) and Lysosomal Disease Network (LDN)
Exploring the Relationship Between Early Development Delay and Neurologic Regression in Metachromatic Leukodystrophy
Metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder caused by a missing or abnormal enzyme that cannot break down sulfatides (complex, fat-sugar molecules containing a sulfate group). Since therapies are most effective before patients begin experiencing symptoms, there is a critical need to define this window early in the disease course.
In this study, researchers explored the relationship between early development delay and neurologic regression in late-infantile MLD. The team studied medical records of 351 patients, including the specific ages of gain and loss of developmental milestones.
Results show that early developmental delay precedes regression in a subset of children affected by late-infantile MLD, defining an earlier onset of neurologic dysfunction than previously understood. As real-world data prior to diagnosis revealed early differences from typical development, authors note that close monitoring for early development delay in presymptomatic individuals may help with earlier diagnosis, leading to improved treatment decisions.
Adang LA, Groeschel S, Grzyb C, D'Aiello R, Gavazzi F, Sherbini O, Bronner N, Patel A, Vincent A, Sevagamoorthy A, Mutua S, Muirhead K, Schmidt J, Pizzino A, Yu E, Jin D, Eichler F, Fraser JL, Emrick L, Van Haren K, Boulanger JM, Ruzhnikov M, Sylvain M, Nguyen CÉ, Potic A, Keller S, Fatemi A, Uebergang E, Poe M, Yazdani PA, Bernat J, Lindstrom K, Bonkowsky JL, Bernard G, Stutterd CA, Orchard P, Gupta AO, Ljungberg M, Groenborg S, Zambon A, Locatelli S, Fumagalli F, Elguen S, Kehrer C, Krägeloh-Mann I, Shults J, Vanderver A, Escolar ML. Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy. Mol Genet Metab. 2024 Aug;142(4):108521. doi: 10.1016/j.ymgme.2024.108521. Epub 2024 Jun 29. PMID: 38964050; PMCID: PMC11348664.
Inherited Neuropathy Consortium (INC)
Exploring the Long-Term Outcomes of High-Dose Oral Riboflavin in Children with Riboflavin Transporter Deficiency
Riboflavin transporter deficiency (RTD) is a progressive neurodegenerative disease characterized by paralysis of the cranial nerves, sensorineural deafness, and signs of damage to other nerves. Without treatment, children with RTD can experience life-threatening respiratory failure. The only known effective treatment is high-dose oral riboflavin. To provide accurate prognosis information to newly diagnosed families and learn if additional treatments are required, more data is needed about the long-term effects of oral riboflavin supplementation.
In this study, researchers explored the long-term outcomes of children with RTD who were supplemented with high-dose oral riboflavin. The team assessed disease progression in 11 children with RTD, following up each year until they transitioned to adult services.
Results show that children with RTD who were treated early after symptom onset had better long-term outcomes. However, although treatment with riboflavin slowed disease progression, patients were left with residual disability. To track disease progression and treatment response over time, authors recommend regular surveillance using the RTD Pediatric Scale, as well as the provided list of clinical measures.
Fennessy JR, Cornett KMD, Donlevy GA, Mckay MJ, Burns J, Menezes MP. Long-term outcomes in children with riboflavin transporter deficiency and surveillance recommendations. Dev Med Child Neurol. 2024 Sep 9. doi: 10.1111/dmcn.16083. Epub ahead of print. PMID: 39252496.
Investigating the Impact of Whole-Genome Sequencing on the Diagnostic Rate of Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological diseases, with more than 130 disease-causing genes. Although whole-genome sequencing has improved diagnosis across genetic diseases, the impact in CMT has not yet been explored.
In this study, researchers investigated the impact of whole-genome sequencing on the diagnostic rate of CMT. The team reviewed diagnostic results from 1,515 patients with a clinical diagnosis of CMT and related disorders at a single specialist inherited neuropathy center.
Results show a 3.5% increase in the diagnostic rate of participants due to whole-genome sequencing. Although the center’s diagnostic rate is the highest reported, almost one-quarter of all cases are still unsolved. Authors note that a new reference genome and technologies will help to improve diagnosis.
Record CJ, Pipis M, Skorupinska M, Blake J, Poh R, Polke JM, Eggleton K, Nanji T, Zuchner S, Cortese A, Houlden H, Rossor AM, Laura M, Reilly MM. Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease. Brain. 2024 Sep 3;147(9):3144-3156. doi: 10.1093/brain/awae064. PMID: 38481354; PMCID: PMC11370804.
Nephrotic Syndrome Study Network (NEPTUNE)
Exploring How Residential Air Pollution Affects Disease Progression in Patients with Primary Glomerular Diseases
Primary glomerular diseases are a group of conditions that affect kidney function by attacking the glomeruli, which are kidney structures responsible for filtering the blood and removing waste in urine. Not much is known about how environmental factors contribute to the progression of primary glomerular diseases.
In this study, researchers explored how residential air pollution affects disease progression in patients with primary glomerular diseases. Among 228 patients from the Nephrotic Syndrome Study Network (NEPTUNE) and 697 patients from CureGlomerulonephropathy (CureGN), the team studied residential census data and two years or more of follow-up. Researchers examined the associations between air pollution—including particulate matter, black carbon, and sulfates—and molecular markers of disease progression.
Results show that elevated exposure to particulate matter and black carbon is associated with an increased risk of disease progression in patients with primary glomerular diseases. Authors note that by identifying air pollution as a potentially modifiable external risk factor for kidney disease progression, health outcomes could be improved for patients with primary glomerulopathies.
Troost JP, D'Souza J, Buxton M, Kshirsagar AV, Engel LS, O'Lenick CR, Smoyer WE, Klein J, Ju W, Eddy S, Helmuth M, Mariani LH, Kretzler M, Trachtman H. Elevated Exposure to Air Pollutants Accelerates Primary Glomerular Disease Progression. Kidney Int Rep. 2024 May 18;9(8):2527-2536. doi: 10.1016/j.ekir.2024.05.013. PMID: 39156153; PMCID: PMC11328569.
Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium
Sharing Patient Stories About the Early Years Following Newborn Screening for Phenylketonuria
Phenylketonuria (PKU) is a genetic metabolic disorder that increases the body's levels of the amino acid phenylalanine, which can build up to harmful levels if left untreated. Newborn screening for PKU began in 1963. Over the following decades, knowledge and treatment recommendations have evolved, with individual and family experiences varying widely.
In this essay, authors share patient stories about the early years following newborn screening for PKU. The team recorded interviews with patients born in the first 25 years after newborn screening for PKU began. While some of these patients were actively followed in the PKU clinic, others had been out of the clinic for many years.
The resulting stories describe different individual experiences, including diet discontinuation in childhood, changing treatment guidelines, and new treatments that have become available. Authors note that these stories highlight the challenges of the early years of newborn screening, when best practices were being discovered through trial and error.
Holmes BM, Hollander S, Sacharow S. Perspectives and Insights Into Phenylketonuria: Patient Narratives About the Early Years Following Newborn Screening. Am J Med Genet C Semin Med Genet. 2024 Sep 17:e32110. doi: 10.1002/ajmg.c.32110. Epub ahead of print. PMID: 39285733.
Urea Cycle Disorders Consortium (UCDC)
Investigating the Link Between Seizures and Hyperammonemic Crises in Individuals with Urea Cycle Disorders
Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Individuals with UCDs may experience symptoms including developmental delays, buildup of fluid around the brain, and seizures.
In this study, researchers investigated the link between seizures and hyperammonemic crises in individuals with UCDs. Among 85 UCD patients, the team reviewed medical records for evidence of seizures during hyperammonemic crises as well as initial levels of ammonia and glutamine.
Results showed that 66% of UCD patients experienced hyperammonemic crises, with 13% of these patients experiencing seizures. Findings also revealed that initial ammonia and glutamine levels can help determine the risk of seizures. Authors note that this study highlights the utility of electroencephalogram monitoring during crises for patients who present with clinical seizures or who have encephalopathy (brain disease) with high ammonia levels.
Chanvanichtrakool M, Schreiber JM, Chen WL, Barber J, Zhang A, Ah Mew N, Schulze A, Wilkening G, Nagamani SCS, Gropman A; Urea Cycle Disease Consortium. Unraveling the Link: Seizure Characteristics and Ammonia Levels in Urea Cycle Disorder During Hyperammonemic Crises. Pediatr Neurol. 2024 Oct;159:48-55. doi: 10.1016/j.pediatrneurol.2024.06.013. Epub 2024 Jun 29. PMID: 39121557; PMCID: PMC11381174.
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.
