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Rare Research Report: April 2024

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.

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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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