GM1 gangliosidosis type II: Results of a 10-year prospective study

Precilla D'Souza, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Cristan Farmer, Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, Bethesda, MD.
Jean M. Johnston, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Sangwoo T. Han, Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
David Adams, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD.
Adam L. Hartman, Division of Clinical Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD.
Wadih Zein, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, MD.
Laryssa A. Huryn, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, MD.
Beth Solomon, Rehabilitation Medicine Department, Warren C. Magnuson Clinical Research Center, Bethesda, MD.
Kelly King, Neurology Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD.
Christopher P. Jordan, Cardiology Department, Inova Children's Hospital, Fairfax, VA.
Jennifer Myles, Nutrition Department, Warren C. Magnuson Clinical Research Center, Bethesda, MD.
Elena-Raluca Nicoli, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Caroline E. Rothermel, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Yoliann Mojica Algarin, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Reyna Huang, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Rachel Quimby, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Mosufa Zainab, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Sarah Bowden, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Anna Crowell, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Ashura Buckley, Sleep and Neurodevelopment Service, National Institute of Mental Health, Bethesda, MD.
Carmen Brewer, Neurology Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD.
Debra S. Regier, Genetics and Metabolism, Children's National Hospital, Washington, DC.
Brian P. Brooks, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, MD.
Maria T. Acosta, Undiagnosed Disease Program, National Human Genome Research Institute, Bethesda, MD.
Eva H. Baker, Department of Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, MD.
Gilbert Vézina, Program in Neuroradiology and Program in Radiology, Children's National Hospital, Washington, DC; Radiology and Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC.
Audrey Thurm, Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, Bethesda, MD.
Cynthia J. Tifft, Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD. Electronic address: cynthia.tifft@nih.gov.

Document Type

Journal Article

Publication Date

7-1-2024

Journal

Genetics in medicine : official journal of the American College of Medical Genetics

Volume

26

Issue

7

DOI

10.1016/j.gim.2024.101144

Keywords

GM1 gangliosidosis; Late infantile; Lysosomal storage disorder; Natural history study; Type 1

Abstract

PURPOSE: GM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments. METHODS: Forty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study. RESULTS: Classification of 37 distinct variants using American College of Medical Genetics and Genomics criteria resulted in the upgrade of 6 and the submission of 4 new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry-red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial magnetic resonance images demonstrated progressive brain atrophy, more pronounced in late infantile patients. Magnetic resonance 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, progressing more rapidly in late infantile compared with juvenile onset disease. CONCLUSION: Serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials.

Department

Radiology

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