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
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Transmembrane topology and oligomeric nature of an astrocytic membrane protein, MLC1.
Junmo Hwang,Kunwoong Park,Ga-Young Lee,Bo Young Yoon,Hyun-Min Kim,Sung Hoon Roh,Byoung-Cheol Lee,Kipom Kim,Hyun-Ho Lim +8 more
TL;DR: MLC1 is a membrane protein mainly expressed in astrocytes, and genetic mutations lead to the development of a leukodystrophy, megalencephalic leukoencephalopathy with subcortical cysts disease.
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Single-cell transcriptomic landscape of the developing human spinal cord
Jimena Andersen,Nicholas Thom,Jennifer L. Shadrach,Xiaoyu Chen,Neal D. Amin,Se-Jin Yoon,William J. Greenleaf,Fabian Müller,Anca M. Pasca,Julia A. Kaltschmidt,Sergiu P. Paşca +10 more
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Further Delineation of the Clinical and Pathologic Features of HIKESHI-Related Hypomyelinating Leukodystrophy.
Guy Helman,Ayelet Zerem,Akshata Almad,Julia L. Hacker,Sarah Woidill,Sunetra Sase,Alexandra N. LeFevre,Josef Ekstein,Martin Johansson,Chloe A Stutterd,Ryan J. Taft,Cas Simons,Cas Simons,Judith B. Grinspan,Amy Pizzino,Johanna L. Schmidt,Brian Harding,Yoel Hirsch,Angela N. Viaene,Aviva Fattal-Valevski,Aviva Fattal-Valevski,Adeline Vanderver,Adeline Vanderver +22 more
TL;DR: In this article, a recurrent homozygous missense variant, c.160G>C;p (Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population.
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Hypomyelinating leukodystrophy – NKX6–2 gene variant as a cause
TL;DR: A 16-year-old boy from Syria is described with spastic ataxia 8 (SPAX8, MIM: 617,560) caused by a novel homozygous nonsense variant in the NKX6–2 gene, leading to an early stop in hypomyelinating leukodystrophy.
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Sensitivity to myelin using model-free analysis of the water resonance line-shape in postmortem mouse brain.
Sean Foxley,Gregg A. Wildenberg,Vandana Sampathkumar,Gregory S. Karczmar,Pedro Brugarolas,Narayanan Kasthuri +5 more
TL;DR: This work examines the effects on measurements of voxel‐wise, high‐resolution water spectra acquired using a 3D echo‐planar spectroscopic imaging (EPSI) pulse sequence from both postmortem fixed control mouse brains and a dysmyelination mouse brain model.
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