GM1 Gangliosidosis—A Mini-Review
GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2021.734878/full |
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| author | Elena-Raluca Nicoli Ida Annunziata Alessandra d’Azzo Alessandra d’Azzo Frances M. Platt Cynthia J. Tifft Cynthia J. Tifft Karolina M. Stepien Karolina M. Stepien |
| author_facet | Elena-Raluca Nicoli Ida Annunziata Alessandra d’Azzo Alessandra d’Azzo Frances M. Platt Cynthia J. Tifft Cynthia J. Tifft Karolina M. Stepien Karolina M. Stepien |
| author_sort | Elena-Raluca Nicoli |
| collection | DOAJ |
| description | GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451). |
| first_indexed | 2024-12-16T14:15:35Z |
| format | Article |
| id | doaj.art-423c31796ca64df4bc25068835d99bfd |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-16T14:15:35Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-423c31796ca64df4bc25068835d99bfd2022-12-21T22:28:36ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-09-011210.3389/fgene.2021.734878734878GM1 Gangliosidosis—A Mini-ReviewElena-Raluca Nicoli0Ida Annunziata1Alessandra d’Azzo2Alessandra d’Azzo3Frances M. Platt4Cynthia J. Tifft5Cynthia J. Tifft6Karolina M. Stepien7Karolina M. Stepien8Glycosphingolipid and Glycoprotein Disorders Unit, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United StatesDepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN, United StatesDepartment of Genetics, St. Jude Children’s Research Hospital, Memphis, TN, United StatesDepartment of Anatomy and Neurobiology, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Pharmacology, University of Oxford, Oxford, United KingdomGlycosphingolipid and Glycoprotein Disorders Unit, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United StatesOffice of the Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United StatesAdult Inherited Metabolic Disorders, Salford Royal NHS Foundation Trust, Salford, United KingdomDivision of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, United KingdomGM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).https://www.frontiersin.org/articles/10.3389/fgene.2021.734878/fullGM1 gangliosidosisglycoconjugates metabolismbeta galactosidasegene therapymouse model |
| spellingShingle | Elena-Raluca Nicoli Ida Annunziata Alessandra d’Azzo Alessandra d’Azzo Frances M. Platt Cynthia J. Tifft Cynthia J. Tifft Karolina M. Stepien Karolina M. Stepien GM1 Gangliosidosis—A Mini-Review Frontiers in Genetics GM1 gangliosidosis glycoconjugates metabolism beta galactosidase gene therapy mouse model |
| title | GM1 Gangliosidosis—A Mini-Review |
| title_full | GM1 Gangliosidosis—A Mini-Review |
| title_fullStr | GM1 Gangliosidosis—A Mini-Review |
| title_full_unstemmed | GM1 Gangliosidosis—A Mini-Review |
| title_short | GM1 Gangliosidosis—A Mini-Review |
| title_sort | gm1 gangliosidosis a mini review |
| topic | GM1 gangliosidosis glycoconjugates metabolism beta galactosidase gene therapy mouse model |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2021.734878/full |
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