The white matter in $${\text{G}}_{{\text{M}}_{\text{2}} } $$ gangliosidosis

Haberland, Catherine; Brunngraber, Eric G.; Witting, Lloyd A.; Brown, Barbara D.

doi:10.1007/bf00691417

Cited by 19 publications

(13 citation statements)

References 29 publications

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“…Cln8 -deficient mice modeling NCL show delayed myelination and increased OPC numbers, suggesting a defect in OPC maturation [ 115 ]. Neuropathology of patients with GM1 and GM2 gangliosidoses reveals failed myelin development and paucity of oligodendrocyte lineage cells, which may be compatible with a defect in OPC proliferation or survival [ 75 , 250 ].…”

Section: White Matter Integrity and Function: Teamwork Is Requiredmentioning

confidence: 99%

“…Peripheral neuropathy, central hypomyelination, Waardenburg-Hirschsprung [ 36 ] c. Early-onset neuronal degenerative disorders c. Cx47-related Pelizaeus-Merzbacher-like disease [ 36 ] 1. Gangliosidosis GM1 and GM2 [ 75 , 250 ] d. Hypomyelination of early myelinated structures [ 104 ] 2. Infantile neuronal ceroid lipofuscinosis [ 79 ] Demyelination 3.…”

Section: A Novel Classification Of Genetic White Matter Disorders Basmentioning

confidence: 99%

“…In line with this hypothesis, axonal spheroids are easily detected in the white matter of H-ABC patients. Early-onset neuronal and axonal dysfunction impairs developmental myelination and is typically associated with oligodendrocyte loss in the white matter [ 33 , 75 , 250 ], as observed in H-ABC. Ongoing axonal dysfunction is associated with myelin loss.…”

Section: Pathology and Mechanisms Of Genetic White Matter Disorders: mentioning

confidence: 99%

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Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

2017

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Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.

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Section: White Matter Integrity and Function: Teamwork Is Requiredmentioning

confidence: 99%

Section: A Novel Classification Of Genetic White Matter Disorders Basmentioning

confidence: 99%

Section: Pathology and Mechanisms Of Genetic White Matter Disorders: mentioning

confidence: 99%

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Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

2017

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“…Upon activation, astrocyte secretes the chemokines CCL2 and CXCL10, which correlates with a robust microglial activation and the invasion of peripheral immune cells. This astrocytes activation could lead to degeneration and death of myelinating oligodendrocytes, promoting active demyelination [ 84 , 85 ], which is frequently observed in infantile forms of GM2 gangliosidoses [ 4 , 86 , 87 ]. Together, these findings highlight the pivotal interplay between microglia and astrocytes in the inflammatory response observed in GM2 gangliosidoses, which could be the functional consequence of neuronal injury due to GM2 ganglioside accumulation and that may contribute to the neurodegenerative process.…”

Section: Physiopathology Of Gm2 Gangliosidosesmentioning

confidence: 99%

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Leal

Benincore-Flórez

Solano-Galarza

et al. 2020

IJMS

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GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

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“…These investigators postulated that arrested myelinogenesis played a major part in the clinicopathological evolution of GM2 gangliosidosis and that secondary myelin loss was a contributing factor. They attributed the failure in myelination to interference with cerebroside synthesis [ 134 ]. Alterations in myelin composition in animal models of GM2 gangliosidosis have also been described [ 135 , 136 ].…”

Section: Pathologymentioning

confidence: 99%

Genetics and Therapies for GM2 Gangliosidosis

Cachón‐González

Zaccariotto

Cox

2018

CGT

105

129

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Tay-Sachs disease, caused by impaired β-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from disease-causing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Hitherto, none of these stratagems has materially altered the course of the disease. Authentic animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, shows great promise. This review outlines current knowledge pertaining the pathobiology as well as potential innovative treatments for the GM2 gangliosidoses.

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The white matter in $${\text{G}}_{{\text{M}}_{\text{2}} } $$ gangliosidosis

Cited by 19 publications

References 29 publications

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Genetics and Therapies for GM2 Gangliosidosis

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