CSF1R-related leukoencephalopathy

A major player in primary microgliopathies

Takuya Konno, Koji Kasanuki, Takeshi Ikeuchi, Dennis W Dickson, Zbigniew K Wszolek

Research output: Contribution to journalReview article

4 Citations (Scopus)

Abstract

Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.

Original languageEnglish (US)
Pages (from-to)1092-1104
Number of pages13
JournalNeurology
Volume91
Issue number24
DOIs
StatePublished - Dec 11 2018

Fingerprint

Colony-Stimulating Factor Receptors
Leukoencephalopathies
Macrophage Colony-Stimulating Factor
Microglia
Mutation
Phenotype
Haploinsufficiency
Frontotemporal Dementia
Frameshift Mutation
Corpus Callosum
Demyelinating Diseases
Neuroimaging
Cultured Cells

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

CSF1R-related leukoencephalopathy : A major player in primary microgliopathies. / Konno, Takuya; Kasanuki, Koji; Ikeuchi, Takeshi; Dickson, Dennis W; Wszolek, Zbigniew K.

In: Neurology, Vol. 91, No. 24, 11.12.2018, p. 1092-1104.

Research output: Contribution to journalReview article

Konno, Takuya ; Kasanuki, Koji ; Ikeuchi, Takeshi ; Dickson, Dennis W ; Wszolek, Zbigniew K. / CSF1R-related leukoencephalopathy : A major player in primary microgliopathies. In: Neurology. 2018 ; Vol. 91, No. 24. pp. 1092-1104.
@article{d6066e49fbd849cc8c26295d91f037e5,
title = "CSF1R-related leukoencephalopathy: A major player in primary microgliopathies",
abstract = "Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.",
author = "Takuya Konno and Koji Kasanuki and Takeshi Ikeuchi and Dickson, {Dennis W} and Wszolek, {Zbigniew K}",
year = "2018",
month = "12",
day = "11",
doi = "10.1212/WNL.0000000000006642",
language = "English (US)",
volume = "91",
pages = "1092--1104",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "24",

}

TY - JOUR

T1 - CSF1R-related leukoencephalopathy

T2 - A major player in primary microgliopathies

AU - Konno, Takuya

AU - Kasanuki, Koji

AU - Ikeuchi, Takeshi

AU - Dickson, Dennis W

AU - Wszolek, Zbigniew K

PY - 2018/12/11

Y1 - 2018/12/11

N2 - Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.

AB - Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.

UR - http://www.scopus.com/inward/record.url?scp=85058590102&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058590102&partnerID=8YFLogxK

U2 - 10.1212/WNL.0000000000006642

DO - 10.1212/WNL.0000000000006642

M3 - Review article

VL - 91

SP - 1092

EP - 1104

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 24

ER -