GM1 Gangliosidosis Type II: Results of a 10-Year Prospective Study.

Autor:	D'Souza P; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Farmer C; Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, 10 Center Drive, Bethesda MD USA., Johnston J; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Han ST; Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Adams D; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Hartman AL; Division of Clinical Research, National Institute of Neurological Disorders and Stroke, 6001 Executive Blvd, Rockville, MD, USA., Zein W; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, 10 Center Drive, Bethesda MD, USA., Huryn LA; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, 10 Center Drive, Bethesda MD, USA., Solomon B; Speech Language Pathology Section, Rehabilitation Medicine Department, Warren Grant Magnuson Clinical Research Center, 10 Center Drive Bethesda MD USA., King K; Neurotology Branch, Division of Intramural Research, National Institute on Deafness and Other Communication Disorders, 10 Center Drive, Bethesda, MD USA., Jordan C; Inova Children's Cardiology, 8260 Willow Oaks Corporate Drive; suite 400; Fairfax, VA, 22031., Myles J; Nutrition Department, Warren Grant Magnuson Clinical Research Center, 10 Center Drive Bethesda MD USA., Nicoli ER; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Rothermel CE; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Algarin YM; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Huang R; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Quimby R; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Zainab M; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Bowden S; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Crowell A; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA., Buckley A; Sleep and Neurodevelopment Service, National Institute of Mental Health, 10 Center Drive, Bethesda MD USA., Brewer C; Neurotology Branch, Division of Intramural Research, National Institute on Deafness and Other Communication Disorders, 10 Center Drive, Bethesda, MD USA., Regier D; Genetics and Metabolism, Children's National Hospital, 111 Michigan Avenue NW, Washington DC USA., Brooks B; Ophthalmic Genetics and Visual Function Branch, National Eye Institute, 10 Center Drive, Bethesda MD, USA., Baker E; Department of Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Research Center, 10 Center Drive, Bethesda, MD, USA., Vézina G; Program in Neuroradiology, Children's National Hospital, 111 Michigan Avenue NW, Washington DC USA; Radiology and Pediatrics, The George Washington University School of Medicine and Health Sciences, 2300 I St NW, Washington DC USA., Thurm A; Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, 10 Center Drive, Bethesda MD USA., Tifft CJ; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Jan 04. Date of Electronic Publication: 2024 Jan 04.
DOI:	10.1101/2024.01.04.24300778
Abstrakt:	Purpose: GM1 gangliosidosis (GM1) is an ultra-rare lysosomal storage disease caused by pathogenic variants in galactosidase beta 1 ( GLB1 ; NM_000404), primarily characterized by neurodegeneration, often in children. There are no approved treatments for GM1, but clinical trials using gene therapy (NCT03952637, NCT04713475) and small molecule substrate inhibitors (NCT04221451) are ongoing. Understanding the natural history of GM1 is essential for timely diagnosis, facilitating better supportive care, and contextualizing the results of therapeutic trials. Methods: Forty-one individuals with type II GM1 (n=17 late infantile and n=24 juvenile onset) participated in a single-site prospective observational study. Here, we describe the results of extensive multisystem assessment batteries, including clinical labs, neuroimaging, physiological exams, and behavioral assessments. Results: Classification of 37 distinct variants in this cohort was performed according to ACMG criteria and resulted in the upgrade of six and the submission of four new variants to pathogenic or likely pathogenic. In contrast to type I infantile, children with type II disease exhibited normal or near normal hearing and did not have cherry red maculae or significant hepatosplenomegaly. Some older children with juvenile onset developed thickened aortic and/or mitral valves with regurgitation. Serial MRIs demonstrated progressive brain atrophy that were more pronounced in those with late infantile onset. MR spectroscopy showed worsening elevation of myo-inositol and deficit of N -acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale and progress more rapidly in late infantile than juvenile onset disease. Conclusion: The comprehensive serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies some common misconceptions about type II patients. Findings from this 10-year endeavor are a pivotal step toward more timely diagnosis and better supportive care for patients. The wealth of data amassed through this effort will serve as a robust comparator for ongoing and future therapeutic trials. Competing Interests: Conflict of Interest Disclosure ALH receives consulting fees from Teladoc. The other authors declare no conflict of interest.
Databáze:	MEDLINE
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