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Rare Research Report: August 2023

August 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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Listen to these summaries on the Rare Research Report podcast.


Developmental Synaptopathies Consortium (DSC) 

Updating Guidelines for Clinical Management of Phelan–McDermid Syndrome

Phelan–McDermid syndrome (PMS) is a genetic condition caused by the deletion of a small portion of chromosome 22 or a mutation in the SHANK3 gene resulting in a wide range of neurodevelopmental and systemic characteristics. The first guidelines for assessment and monitoring in individuals with PMS were published in 2014. Due to recent studies and investigations, knowledge about PMS has since grown significantly.

In this study, researchers aimed to update clinical management guidelines for PMS based on the latest knowledge. A taskforce of clinical experts in PMS and representatives from the parent community collaborated to produce specialty-specific guidelines—including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry.

These updated guidelines allow for improved assessment and monitoring of individuals with PMS. Authors highlight several areas for future research with plans to update the guidelines as new knowledge becomes available.

Srivastava S, Sahin M, Buxbaum JD, Berry-Kravis E, Soorya LV, Thurm A, Bernstein JA, Asante-Otoo A, Bennett WE Jr, Betancur C, Brickhouse TH, Passos Bueno MR, Chopra M, Christensen CK, Cully JL, Dies K, Friedman K, Gummere B, Holder JL Jr, Jimenez-Gomez A, Kerins CA, Khan O, Kohlenberg T, Lacro RV, Levi LA, Levy T, Linnehan D, Eva L, Moshiree B, Neumeyer A, Paul SM, Phelan K, Persico A, Rapaport R, Rogers C, Saland J, Sethuram S, Shapiro J, Tarr PI, White KM, Wickstrom J, Williams KM, Winrow D, Wishart B, Kolevzon A. Updated consensus guidelines on the management of Phelan-McDermid syndrome. Am J Med Genet A. 2023 Jul 1. doi: 10.1002/ajmg.a.63312. Epub ahead of print. PMID: 37392087.

Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) 

Investigating Neurodegenerative Disease After Hematopoietic Stem Cell Transplantation in Metachromatic Leukodystrophy

Metachromatic leukodystrophy is a lysosomal storage disease characterized by progressive destruction of white matter of the brain. This damage may stabilize or improve with hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant. However, some patients still deteriorate despite successfully treated leukodystrophy.

In this study, researchers investigated the role of gray matter of the brain in neurodegenerative disease after HSCT. The team clinically and radiologically analyzed three patients with metachromatic leukodystrophy treated with HSCT. The team also examined the histopathology of three other patients deceased after treatment, comparing with six untreated patients.

Results show neurological deterioration after HSCT, including gray matter atrophy and absence of donor cells in gray matter structures. Authors note that these findings point to a clinically relevant gray matter component of metachromatic leukodystrophy that does not seem to be sufficiently affected by transplantation.

Al-Saady M, Beerepoot S, Plug BC, Breur M, Galabova H, Pouwels PJW, Boelens JJ, Lindemans C, van Hasselt PM, Matzner U, Vanderver A, Bugiani M, van der Knaap MS, Wolf NI. Neurodegenerative disease after hematopoietic stem cell transplantation in metachromatic leukodystrophy. Ann Clin Transl Neurol. 2023 Jul;10(7):1146-1159. doi: 10.1002/acn3.51796. Epub 2023 May 22. PMID: 37212343; PMCID: PMC10351661.

Lysosomal Disease Network (LDN) 

Evaluating Bone and Joint Disease in Children with Mucopolysaccharidosis

Mucopolysaccharidosis (MPS) is a group of inherited disorders in which the body is unable to properly break down complex carbohydrates called mucopolysaccharides. Although advancements in the treatment of MPS have been made through hematopoietic cell transplantation (HCT) and enzyme replacement therapy (ERT)—significantly improving the duration and quality of life for many individuals with MPS—the long-term benefits and limitations of these treatments on the connective tissue are not known.

In this study, researchers systematically evaluated bone and joint disease in 55 children with four types of MPS—MPS IH, MPS IA, non-neuronopathic MPS II, and MPS VI—who had been treated with hematopoietic cell transplantation and/or enzyme replacement therapy. Annual measurements and mixed effects modeling were used to evaluate changes over the course of 10 years.

Results show that despite current treatments for MPS I, II, and VI, patients continue to experience short stature, joint contractures, and elevation in average BMI. Authors note that data from this study could be used to expedite testing of experimental therapies for bones and joints, as well as highlight the need for weight management as part of routine clinical care for patients with MPS.

Miller BS, Fung EB, White KK, Lund TC, Harmatz P, Orchard PJ, Whitley CB, Polgreen LE. Persistent bone and joint disease despite current treatments for mucopolysaccharidosis types I, II, and VI: Data from a 10-year prospective study. J Inherit Metab Dis. 2023 Jul;46(4):695-704. doi: 10.1002/jimd.12598. Epub 2023 Mar 6. PMID: 36840680.

Myasthenia Gravis Rare Disease Network (MGNet)

Developing a New Telehealth System to Compute Myasthenia Gravis Core Examination Metrics

Myasthenia gravis (MG) is a neuromuscular disorder caused by an autoimmune response which blocks or damages acetylcholine receptors in muscles. Recently, telemedicine practices have grown for neurological diseases, including MG. Telemedicine evaluation of patients with MG has been recommended via the Myasthenia Gravis Core Examination (MG-CE).

In this study, researchers developed a new telehealth system to automate data acquisition and analytics during the MG-CE. Using Zoom videos of patients with MG undergoing the MG-CE, the team created an algorithm toolbox—including computer vision and signal processing methods—to analyze eye motions, body motions, and vocalizations. 

Results show that this new system can objectively quantitate metrics from the MG-CE, allowing the medical examiner to concentrate on the patient instead of managing logistics. Authors note that the system could also be applied to many other neurological disorders, potentially improving clinical care.

Garbey M, Joerger G, Lesport Q, Girma H, McNett S, Abu-Rub M, Kaminski H. A Digital Telehealth System to Compute the Myasthenia Gravis Core Examination Metrics. JMIR Neurotechnol. 2023;2:e43387. doi: 10.2196/43387. Epub 2023 Apr 19. PMID: 37435094; PMCID: PMC10334459.


Investigating the Ability of Individual Autoantibody Clones to Drive Multiple Pathogenic Mechanisms of Myasthenia Gravis

In patients with myasthenia gravis (MG), an autoimmune response blocks or damages acetylcholine receptors in muscles. Autoantibody clones drive three different pathogenic (disease-causing) mechanisms of MG, including complement activation, receptor blockade, and antigenic modulation. However, it is unclear whether these mechanisms are driven by single or multiple antibody clones.

In this study, researchers investigated the ability of individual autoantibody clones to drive multiple pathogenic mechanisms of MG. First, the team produced monoclonal autoantibodies (mAbs) from patients with MG. Next, researchers assessed the binding properties and pathogenic capacities of the mAbs.

Results show that these mAbs can drive pathology through blocking the acetylcholine binding site, internalizing the AChR through crosslinking (modulation), and activating complement. While some mAbs can drive one or two of these mechanisms, several mAbs were able to drive all three simultaneously. Authors note that these new insights on the immunopathology of MG could help inform therapeutic approaches.

Pham MC, Masi G, Patzina R, Obaid AH, Oxendine SR, Oh S, Payne AS, Nowak RJ, O'Connor KC. Individual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology. Acta Neuropathol. 2023 Aug;146(2):319-336. doi: 10.1007/s00401-023-02603-y. Epub 2023 Jun 21. PMID: 37344701.

Primary Immune Deficiency Treatment Consortium (PIDTC) 

Exploring Factors Affecting Survival of Individuals with Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID) is a severe form of primary immune deficiency characterized by extreme weakness or absence of immune system function. SCID is fatal, unless durable adaptive immunity is established—most commonly through allogeneic hematopoietic cell transplantation (HCT).

In this study, researchers from the Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades. The team focused on the effects of population-based newborn screening for SCID, analyzing transplantation-related data from children with SCID treated at 34 PIDTC sites.

Results show that population-based newborn screening has helped to identify infants with SCID early in life, increasing the likelihood of prompt HCT prior to the development of serious infections. Authors state that public health programs worldwide can benefit from this demonstration of the value of newborn screening for SCID.

Thakar MS, Logan BR, Puck JM, Dunn EA, Buckley RH, Cowan MJ, O'Reilly RJ, Kapoor N, Satter LF, Pai SY, Heimall J, Chandra S, Ebens CL, Chellapandian D, Williams O, Burroughs LM, Saldana BD, Rayes A, Madden LM, Chandrakasan S, Bednarski JJ 2nd, DeSantes KB, Cuvelier GDE, Teira P, Gillio AP, Eissa H, Knutsen AP, Goldman FD, Aquino VM, Shereck EB, Moore TB, Caywood EH, Lugt MTV, Rozmus J, Broglie L, Yu LC, Shah AJ, Andolina JR, Liu X, Parrott RE, Dara J, Prockop S, Martinez CA, Kapadia M, Jyonouchi SC, Sullivan KE, Bleesing JJ, Chaudhury S, Petrovic A, Keller MD, Quigg TC, Parikh S, Shenoy S, Seroogy C, Rubin T, Decaluwe H, Routes JM, Torgerson TR, Leiding JW, Pulsipher MA, Kohn DB, Griffith LM, Haddad E, Dvorak CC, Notarangelo LD. Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium. Lancet. 2023 Jul 8;402(10396):129-140. doi: 10.1016/S0140-6736(23)00731-6. Epub 2023 Jun 20. PMID: 37352885.



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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