Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms.
TLDR
A novel classification of leukodystrophies is proposed that takes into account the primary involvement of any white matter component, and Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin; astrocytopathies; leuko-axonopathies; microgliopathy; andLeuko-vasculopathies.Abstract:
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.read more
Citations
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Myelin in the Central Nervous System: Structure, Function, and Pathology.
TL;DR: The biology of myelin, the expanded relationship of myelinating oligodendrocytes with its underlying axons and the neighboring cells, and its disturbances in various diseases such as multiple sclerosis, acute disseminated encephalomyelitis, and neuromyELitis optica spectrum disorders are reviewed.
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Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia.
Nynke Oosterhof,Irene J. Chang,Ehsan Ghayoor Karimiani,Laura E. Kuil,Dana M. Jensen,Ray A. M. Daza,Erica Young,Lee Astle,Herma C. van der Linde,Giridhar M. Shivaram,Jeroen Demmers,Caitlin S. Latimer,C. Dirk Keene,Emily Loter,Reza Maroofian,Tjakko J. van Ham,Robert F. Hevner,James T. Bennett +17 more
TL;DR: The results suggest that CSF1R is required for human brain development and establish the csf1rDM fish as a model for microgliopathies and exemplify an under-recognized form of phenotypic expansion.
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White matter degeneration in vascular and other ageing-related dementias
TL;DR: It is demonstrated that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment.
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CSF1R-related leukoencephalopathy: A major player in primary microgliopathies
TL;DR: The current knowledge of CSF1R-related leukoencephalopathy is addressed and the putative pathophysiology is discussed, with a focus on microglia, as well as future research directions.
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Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System.
TL;DR: Emerging evidence of astrocyte-oligodendrocytes communication in health and disease is reviewed to reveal important insights into the pathogenesis and treatment of CNS diseases.
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