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:
- Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)
- North American Mitochondrial Disease Consortium (NAMDC)
- Spastic Paraplegia Centers of Excellence Research Network (SP-CERN)
- Urea Cycle Disorders Consortium (UCDC)
Listen to these summaries on the Rare Research Report podcast.
Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)
Exploring the Use of Glial Fibrillary Acidic Protein as a Biomarker in Alexander Disease
Alexander disease is a rare disorder of the nervous system characterized by leukodystrophy, or the destruction of myelin (the fatty coating surrounding nerve fibers). In patients with Alexander disease, variants in the GFAP gene lead to the buildup of glial fibrillary acidic protein (GFAP) in the body. Not much is known about the relationship between GFAP levels and disease characteristics.
In this study, researchers explored the use of GFAP as a biomarker in Alexander disease. First, the team collected cerebrospinal fluid and plasma from participants with and without Alexander disease. Next, they compared the concentration of GFAP over time between these groups, including those with common disease characteristics or genetic variants.
Results showed that GFAP increases over time in young children with Alexander disease. The highest concentrations of GFAP were seen in those with the cerebral disease type. Authors note that these findings are a critical initial step in defining biomarker validation and context of use for GFAP in Alexander disease.
Waldman AT, Takanohashi A, Joung JY, Liu GW, Arnold K, Pizzino A, Faig W, Woidill S, Narula S, Vanderver AL. Characterization of Clinical Phenotype to Glial Fibrillary Acidic Protein Concentrations in Alexander Disease. Ann Clin Transl Neurol. 2026 Jan 9. doi: 10.1002/acn3.70305. Epub ahead of print. PMID: 41513585.
Reviewing Pathology and Interventions in Cerebral X-Linked Adrenoleukodystrophy
X-linked adrenoleukodystrophy (ALD) is a 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. More than half of male patients with ALD develop progressive, inflammatory cerebral demyelination (loss of the fatty coating surrounding nerves). Treatment for cerebral ALD is limited, with no standard therapies available for the advanced form.
In this study, researchers reviewed pathology and interventions in cerebral X-linked ALD. The review included over 50 years of published literature and expert opinion from clinicians caring for patients around the world. From these sources, the team gathered information on immunopathology, biomarkers, and therapies tested.
Findings revealed insights on inflammation and immunomodulation in cerebral X-linked ALD. Authors note that these findings highlight the potential of a future clinical trial of immunomodulatory agents for advanced cerebral ALD.
Wright MA, Demmitt-Rice C, Van Haren KP, Lund TC, Eichler F, Bonkowsky JL. Inflammation and Immunomodulation in Cerebral X-linked Adrenoleukodystrophy: Review of Pathology and Interventions. J Child Neurol. 2026 Feb;41(2):221-234. doi: 10.1177/08830738251353034. Epub 2025 Jul 23. PMID: 40696909; PMCID: PMC12313269.
North American Mitochondrial Disease Consortium (NAMDC)
Using a New Statistical Technique for Accelerometer Data to Assess a Treatment for Mitochondrial Disease
Mitochondrial diseases are multisystemic, genetic disorders involving dysfunction of the mitochondria (specialized cell structures that produce energy), which affects cellular metabolism. Development of new therapies for mitochondrial diseases is difficult due to a lack of outcome measures.
In this study, researchers used a new statistical technique for accelerometer data to assess a treatment for mitochondrial disease. First, the team collected data over several clinic visits from 14 patients with thymidine kinase 2 deficiency (TK2d), an ultra-rare autosomal recessive mitochondrial disease, in a clinical trial for nucleoside therapy. Next, the team used a combination of functional data analysis and longitudinal mixed-effects linear regression to compare accelerometer data over the course of treatment.
Results showed that nucleoside therapy resulted in significant improvement in activity levels among TK2d patients. Authors note that these findings could reveal a possible primary outcome biomarker in clinical trials for mitochondrial diseases as well as other types of diseases, both rare and common.
McKeague IW, Engelstad K, Ge Y, Tucker A, Li S, Uddin J, Zhao Z, Thompson JLP, Hirano M. Assessing a Mitochondrial Disease Treatment via a Novel Statistical Technique for Accelerometer Data. Ann Clin Transl Neurol. 2025 Dec;12(12):2505-2513. doi: 10.1002/acn3.70180. Epub 2025 Sep 12. PMID: 40938277; PMCID: PMC12698933.
Spastic Paraplegia Centers of Excellence Research Network (SP-CERN)
Assessing Health-Related Quality of Life in Children with Rare Forms of Hereditary Spastic Paraplegia
Hereditary spastic paraplegia (HSP) is a large group of inherited disorders that affect nerves that send messages to the muscles. Patients with HSP commonly have difficulty walking due to muscle weakness and spasticity (muscle rigidity) in the legs. In patients with rare forms of HSP, these symptoms can be more complex, including developmental delay, intellectual disability, movement disorders, dysphagia (difficulty swallowing), or incontinence. While previous studies have examined how common forms of HSP affect health-related quality of life, less is known about the impact of rare childhood-onset forms.
In this study, researchers assessed health-related quality of life in 80 children with rare forms of HSP. Using the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) and clinician-reported outcomes, the team examined how clinical features, age, and genotype correlate with quality of life.
Results showed that CPCHILD can be used to assess many different forms of childhood-onset HSP. Lower scores were seen in children with more complex forms. Motor, autonomic, and bulbar symptoms had the largest impact. Authors note that these insights can help clinicians prioritize interventions and inform strategies to improve quality of life for children with HSP.
Schmidt HJD, Battaglia N, Rong J, Tam A, Carty S, Quiroz V, Yang K, Zaman Z, Schierbaum L, Bernardi K, Alecu JE, Ebrahimi-Fakhari D. Health-Related Quality of Life in Rare Forms of Childhood-Onset Hereditary Spastic Paraplegia. Ann Clin Transl Neurol. 2026 Jan;13(1):193-199. doi: 10.1002/acn3.70244. Epub 2025 Nov 6. PMID: 41199121; PMCID: PMC12790169.
Investigating the ATG9A Ratio as a Diagnostic Tool for Adaptor Protein Complex 4–Associated Hereditary Spastic Paraplegia
Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders that cause the upper motor neurons to slowly degenerate, leading to progressive muscle stiffness and leg weakness. Adaptor protein complex 4–associated HSP (AP-4-HSP) is a childhood-onset and complex form of HSP that causes mislocalization—buildup in the wrong location—of the protein ATG9A. Gradual progression of initial symptoms, similarity with other developmental conditions like cerebral palsy, and unknown significance of genetic variants can make it challenging to diagnose AP-4-HSP.
In this study, researchers investigated the ATG9A ratio as a diagnostic tool for AP-4-HSP. The team measured the mislocalization of ATG9A in eight patients with suspected AP-4-HSP and genetic variants of unknown significance.
Results demonstrated loss of AP-4 function in six of the participants, revealing new disease-causing genetic variants. Authors note that the ATG9A ratio is a useful tool for diagnosing AP-4-HSP and classifying new genetic variants, which can help determine eligibility for clinical trials and guide treatment decisions.
Agianda HAP, Kim HM, Battaglia N, Rong J, Tam A, Gonzalez Saez-Diez E, Boerkoel CF, Saffari A, Quiroz V, Schierbaum L, Zaman Z, Bernardi K, Ebrahimi-Fakhari D. Diagnostic Utility of the ATG9A Ratio in AP-4-Associated Hereditary Spastic Paraplegia. Ann Clin Transl Neurol. 2026 Jan 5. doi: 10.1002/acn3.70308. Epub ahead of print. PMID: 41491634.
Urea Cycle Disorders Consortium (UCDC)
Evaluating a New Food Photography App for Measuring Dietary Intake in Urea Cycle Disorders
Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Nutrition management can help prevent hyperammonemia by limiting protein intake while providing enough energy for growth. However, traditional methods of assessing dietary intake—including three-day diet records, 24-hour recalls, and food frequency questionnaires—are often time-consuming and inaccurate.
In this study, researchers evaluated a new food photography app for measuring dietary intake in individuals with UCDs. Eight participants used the new app, mFood, to take photos of meals and snacks for remote analysis by a registered dietician. The team then compared the accuracy of mFood with traditional three-day diet records.
Results revealed few statistical differences between mFood and traditional methods. However, the majority of participants preferred using mFood, offering a more convenient way for individuals with UCDs to collect nutrition information.
Sim E, Gregor A, MacLeod E, Moore R, Ravelli MN, Schoeller DA, Harding CO, Jacobs P, Gillingham MB. Measuring dietary intake among participants with a urea cycle disorder using standard diet records or a novel food photography app. Mol Genet Metab. 2025 Dec;146(4):109291. doi: 10.1016/j.ymgme.2025.109291. Epub 2025 Nov 12. PMID: 41242089; PMCID: PMC12665291.
The Rare Diseases Clinical Research Network (RDCRN) is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). Now in its fifth five-year funding cycle, RDCRN is a partnership with funding and programmatic support provided by Institutes, Centers, and Offices across NIH, including the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, the National Institute of Mental Health, the Office of Dietary Supplements, the National Institute on Aging, the National Human Genome Research Institute, the National Institute on Deafness and Other Communication Disorders, and the Office of Research on Women’s Health.
