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Rare Research Report: November 2023

November 14, 2023

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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Developmental Synaptopathies Consortium (DSC)

Developing a Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist

Tuberous sclerosis complex (TSC) is a genetic condition in which typically benign tumors affect multiple organs including the brain, kidneys, heart, lungs, eyes, and skin. TSC-associated neuropsychiatric disorders (TAND) include difficulties at the behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial levels. Although TAND are often present in individuals with TSC, they are also underidentified and undertreated.
In this study, researchers developed a self-report quantified TAND Checklist (TAND-SQ). The team conducted feasibility and acceptability testing of the TAND-SQ Checklist with 23 technical experts from the TAND consortium and 58 caregivers and individuals with TSC.
The resulting Checklist can be completed by caregivers or individuals with TSC and used to quantify TAND difficulties. Authors state that next steps include further validation of the checklist and development of a smartphone application.
Heunis TM, Chambers N, Vanclooster S, Bissell S, Byars AW, Capal JK, Cukier S, Davis PE, de Vries MC, De Waele L, Flinn J, Gardner-Lubbe S, Gipson T, Kingswood JC, Krueger DA, Kumm AJ, Sahin M, Schoeters E, Smith C, Srivastava S, Takei M, van Eeghen AM, Waltereit R, Jansen AC, de Vries PJ. Development and Feasibility of the Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ). Pediatr Neurol. 2023 Oct;147:101-123. doi: 10.1016/j.pediatrneurol.2023.07.001. Epub 2023 Jul 7. PMID: 37598571.

Dystonia Coalition (DC)

Comparing Clinician- and Patient-Rated Measures to Assess the Severity of Cervical Dystonia

Cervical dystonia is a rare, often painful, movement disorder associated with characteristic sustained or jerky involuntary muscle contractions of the neck. The severity of cervical dystonia can be assessed using either clinician-rated scales (CRS) or patient-rated outcome (PRO) tools. However, these two measures are often poorly correlated.   
In this study, researchers aimed to determine if the correlation between a CRS and PRO for the movement disorder of cervical dystonia improves by accounting for non-movement features. The team evaluated 209 patients with cervical dystonia using a CRS and a PRO.
The results revealed a weak correlation between the two measures, even when considering only the movement. However, the correlation improved with a model that included non-motor symptoms of pain, depression, and disability. These results suggest that assessing the movement disorder with a PRO should also include assessments of non-motor symptoms that may contribute to the patient’s perception of the disorder. Findings may apply to other disorders, especially those with frequent non-motor co-morbidities.
Cotton AC, Scorr L, McDonald W, Comella C, Perlmutter JS, Goetz CG, Jankovic J, Marsh L, Factor S, Jinnah HA. Assessing the Severity of Cervical Dystonia: Ask the Doctor or Ask the Patient? Mov Disord Clin Pract. 2023 Aug 3;10(9):1399-1403. doi: 10.1002/mdc3.13827. PMID: 37772296; PMCID: PMC10525044.

Identifying Longitudinal Predictors of Health-Related Quality of Life in Patients with Isolated Dystonia

Isolated dystonia is a movement disorder characterized by uncontrollable, sometimes painful, involuntary muscle contractions without other neurological symptoms. Patients with isolated dystonia often experience nonmotor symptoms—such as depression, generalized anxiety disorder, social anxiety disorder, self-esteem, and acceptance of illness—which can impact their health-related quality of life (HR-QoL).
In this study, researchers identified longitudinal predictors of HR-QoL in an international multicenter cohort of patients with isolated dystonia. The team analyzed data from a Dystonia Coalition natural history study to identify predictors of HR-QoL at 2 years after baseline examination.
Results demonstrate the longitudinal impact of psychiatric symptoms on HR-QoL in patients with isolated dystonia. Authors note that these findings emphasize the importance of incorporating mental health treatments for dystonia.
Junker J, Hall J, Berman BD, Vidailhet M, Roze E, Bäumer T, Malaty IA, Shukla AW, Jankovic J, Reich SG, Espay AJ, Duque KR, Patel N, Perlmutter JS, Jinnah HA; Dystonia Coalition Study Group; Brandt V, Brüggemann N. Longitudinal predictors of health-related quality of life in isolated dystonia. J Neurol. 2023 Oct 15. doi: 10.1007/s00415-023-12022-4. Epub ahead of print. PMID: 37839041.

Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC)

Discussing Transcriptomics and Machine Learning Strategies to Reveal Splicing Defects in Rare Diseases

Many rare diseases are caused by genomic variants that affect the process of pre-messenger RNA splicing and its regulation. However, these splice-altering variants are often overlooked by common workflows for genetic diagnosis and clinical variant interpretation.
In this review, researchers summarized recent developments and challenges in using RNA sequencing technologies to investigate rare diseases. Discussion included the use of new computational splicing prediction tools to reveal splice-altering variants.
Authors predict that continuous improvements to sequencing technologies and predictive modeling will expand our understanding of splicing regulation and improve diagnoses for rare disease patients.
Wang R, Helbig I, Edmondson AC, Lin L, Xing Y. Splicing defects in rare diseases: transcriptomics and machine learning strategies towards genetic diagnosis. Brief Bioinform. 2023 Sep 20;24(5):bbad284. doi: 10.1093/bib/bbad284. PMID: 37580177; PMCID: PMC10516351.

Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN)

Exploring Craniofacial Features of POLR3-Related Leukodystrophy

RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is a rare genetic disorder characterized by hypomyelination (inability to produce sufficient myelin, the fatty coating surrounding nerve fibers, at normal levels during development), neurological dysfunction, hypodontia (missing teeth), and hypogonadotropic hypogonadism (delayed puberty). Description of craniofacial features in individuals with POLR3-HLD is currently very limited.
In this study, researchers assessed the craniofacial features of 31 patients with POLR3-HLD. The team also proposed genotype-phenotype correlations based on patients’ facial features.
Results demonstrate that craniofacial abnormalities are common in patients with POLR3-HLD. Authors note that these findings will assist clinicians in diagnosing POLR3-HLD, help to provide care directed to this patient population’s specific needs, and allow future studies characterizing the underlying pathophysiology. 
Mirchi A, Guay SP, Tran LT, Wolf NI, Vanderver A, Brais B, Sylvain M, Pohl D, Rossignol E, Saito M, Moutton S, González-Gutiérrez-Solana L, Thiffault I, Kruer MC, Moron DG, Kauffman M, Goizet C, Sztriha L, Glamuzina E, Melançon SB, Naidu S, Retrouvey JM, Lacombe S, Bernardino-Cuesta B, De Bie I, Bernard G. Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C. J Med Genet. 2023 Oct;60(10):1026-1034. doi: 10.1136/jmg-2023-109223. Epub 2023 May 16. PMID: 37197783.

Inherited Neuropathy Consortium (INC)

Demonstrating the Role of microRNA Regulation in Charcot-Marie-Tooth Disease Type 1A

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of inherited peripheral neuropathy, is caused by a copy number variation (CNV) in the PMP22 gene. In rodent models of CMT1A, overexpression of miR-29a, a type of microRNA, has been shown to reduce the PMP22 transcript and protein level.
In this study, researchers demonstrate for the first time how imbalance in the microRNA-mediated regulation of gene expression can mimic a CNV-associated disease in humans. Study participants included a family of CMT1A patients enrolled in a natural history study.
Authors state that these findings show the importance of miR-29a in regulating PMP22 expression and could lead to development of new therapeutic drugs.
Pipis M, Won S, Poh R, Efthymiou S, Polke JM, Skorupinska M, Blake J, Rossor AM, Moran JJ, Munot P, Muntoni F, Laura M, Svaren J, Reilly MM. Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1. Brain. 2023 Oct 3;146(10):4025-4032. doi: 10.1093/brain/awad203. PMID: 37337674; PMCID: PMC10545524.

Expanding the Phenotype of CRYAB-Related Disease to Include Charcot–Marie–Tooth Disease Type 2

Charcot–Marie–Tooth disease type 2 (CMT2), also known as hereditary motor and sensory neuropathy, is a disorder affecting nerve axons (ends of the nerves) which carry signals from the brain to the extremities. While mutations in the alpha-B-crystallin (CRYAB) gene have been associated with myofibrillar myopathy, dilated cardiomyopathy, and cataracts, they have not previously included peripheral neuropathy.
In this study, researchers expand the phenotype (observable characteristics) of CRYAB-related disease to include CMT2. The team performed whole-exome sequencing in two unrelated families with genetically unsolved axonal CMT2, assessing clinical, neurophysiological, and radiological features.
Results identify CRYAB mutations as a cause of CMT2 in these patients. Authors note that CRYAB mutations should be suspected in cases with late-onset CMT2, especially in the presence of congenital cataracts.
Cortese A, Currò R, Ronco R, Blake J, Rossor AM, Bugiardini E, Laurà M, Warner T, Yousry T, Poh R, Polke J, Rebelo A, Dohrn MF, Saporta M, Houlden H, Zuchner S, Reilly MM. Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot-Marie-Tooth disease with congenital cataracts. Eur J Neurol. 2023 Sep 29. doi: 10.1111/ene.16063. Epub ahead of print. PMID: 37772343.

Myasthenia Gravis Rare Disease Network (MGNet)

Assessing High-Dose Chemotherapy and Hematopoietic Cell Transplantation in Severe Myasthenia Gravis

Myasthenia gravis (MG) is a rare neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors (AChRs) on muscles. High-dose chemotherapy (HDIT) and autologous hematopoietic cell transplantation (HCT), also known as bone marrow transplant, are potential treatments for MG.
In this study, researchers investigated the safety and efficacy of HDIT and HCT in a patient with severe, treatment-resistant MG. Results show that HDIT and HCT induced remission of MG. The team also assessed the effect of treatment on the underlying immunopathology. Intriguingly, the AChR autoantibodies—the known pathogenic mediators of MG—did not appreciably lower after the treatment.
Authors state that these findings suggest a cell-based disease mechanism, which responds to high-dose therapy, may play a role in the pathology in addition to AChR autoantibodies. Further studies are needed to establish whether HDIT and HCT can be an effective therapy for severe MG.
Schlatter MI, Yandamuri SS, O'Connor KC, Nowak RJ, Pham MC, Obaid AH, Redman C, Provost M, McSweeney PA, Pearlman ML, Tees MT, Bowen JD, Nash RA, Georges GE. Remission of severe myasthenia gravis after autologous stem cell transplantation. Ann Clin Transl Neurol. 2023 Sep 19. doi: 10.1002/acn3.51898. Epub ahead of print. PMID: 37726935.

Defining a Treatment-Responsive Biomarker for Corticosteroid Therapy in Myasthenia Gravis

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. The primary initial therapy for MG is high-dose prednisone use. However, more than a third of patients do not respond to this treatment. Currently, there are no biomarkers to predict clinical responsiveness to corticosteroid treatment.
In this study, researchers defined a treatment-responsive biomarker for MG patients undergoing corticosteroid therapy. The team used serum from MG patients collected for a clinical trial of thymectomy (removal of the thymus gland) and prednisone to create metabolomic and lipidomic profiles. Next, researchers correlated these profiles with treatment response.
Results show that metabolomic and lipidomic profiles could be used to predict treatment response. Authors note that variation in prednisone metabolism may determine how well patients respond to treatment.
Sikorski P, Li Y, Cheema M, Wolfe GI, Kusner LL, Aban I, Kaminski HJ. Serum metabolomics of treatment response in myasthenia gravis. PLoS One. 2023 Oct 10;18(10):e0287654. doi: 10.1371/journal.pone.0287654. PMID: 37816000; PMCID: PMC10564178.

Developing a New Telehealth Platform to Test Ocular Symptoms in Patients with Myasthenia Gravis

Myasthenia gravis (MG) is a neuromuscular disorder which produces muscle weakness that can worsen over the course of a minute during an examination. Use of telemedicine has recently increased for monitoring MG, although these evaluations rely entirely on subjective evaluations of an examiner.
In this study, researchers developed a new telehealth platform to assist with telemedicine evaluations of ocular manifestations of patients with MG. The team created a hybrid algorithm that combines deep learning with computer vision, giving quantitative metrics of ptosis (eyelid droop) and ocular muscle fatigue leading to symptoms like double vision.
The method, which works on both a fixed image and frame by frame of the video in real-time, is able to operate in standard telehealth conditions. Authors note that this approach is general and can be applied to many disorders of ocular motility and ptosis.
Lesport Q, Joerger G, Kaminski HJ, Girma H, McNett S, Abu-Rub M, Garbey M. Eye Segmentation Method for Telehealth: Application to the Myasthenia Gravis Physical Examination. Sensors (Basel). 2023 Sep 7;23(18):7744. doi: 10.3390/s23187744. PMID: 37765800; PMCID: PMC10536520.

Nephrotic Syndrome Study Network (NEPTUNE)

Investigating the Association Between Hematuria and Kidney-Related Outcomes in Podocytopathies

Podocytopathies are kidney diseases in which injury to podocytes (cells that form the last barrier of the kidney filtration unit) cause nephrotic syndrome. Hematuria (blood in urine) is common in podocytopathies. However, the significance and predictive value of hematuria in these diseases is not well understood.
In this study, researchers describe the prevalence and association between hematuria and kidney-related outcomes in podocytopathies. The team assessed hematuria in urine samples from 1,516 adults and children with podocytopathies.
Results show that hematuria was prevalent among participants and associated with worse kidney-related outcomes, including progressive loss of kidney function and lower rates of proteinuria remission.
Marchel D, Trachtman H, Larkina M, Helmuth M, Lai Yee JY, Fermin D, Bomback AS, Canetta PA, Gipson DS, Mottl AK, Parekh RS, Saha MK, Sampson MG, Lafayette RA, Mariani LH; Nephrotic Syndrome Study Network (NEPTUNE); Cure Glomerulonephropathy (CureGN). The Significance of Hematuria in Podocytopathies. Clin J Am Soc Nephrol. 2023 Sep 21. doi: 10.2215/CJN.0000000000000309. Epub ahead of print. PMID: 37733352.

Urea Cycle Disorders Consortium (UCDC)

Assessing Health-Related Quality of Life in Children and Adults with Urea Cycle Disorders


Urea cycle disorders (UCDs) are a group of inherited, metabolic disorders characterized by hyperammonemia (high blood ammonia levels). Accumulation of ammonia is toxic to the nervous system, resulting in neurological symptoms that can impact health-related quality of life (HRQoL). However, only a few studies have systematically investigated the impact of UCDs on HRQoL.
In this study, researchers assessed HRQoL in a large cohort of children and adults with UCDs. The team reviewed HRQoL and clinical data from a Urea Cycle Disorders Consortium longitudinal study; compared to healthy individuals and those with PKU and diabetes; and assessed relationships between HRQoL, UCD diagnosis, and disease severity.
Results show that individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Authors state that future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.
Murali CN, Barber JR, McCarter R, Zhang A, Gallant N, Simpson K, Dorrani N, Wilkening GN, Hays RD, Lichter-Konecki U; Members of the Urea Cycle Disorders Consortium; Burrage LC, Nagamani SCS. Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders. Mol Genet Metab. 2023 Sep 8;140(3):107696. doi: 10.1016/j.ymgme.2023.107696. Epub ahead of print. PMID: 37690181. 


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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