Sporadic adult‐onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes

Fernández‐Vega, Iván; Heredia-Goñi, Katti Pérez de; Santos‐Juanes, Jorge; Imizcoz, Miguel Goñi; Zaldumbide, Laura; Zarranz, J.J.; Ferrer, Isidró

doi:10.1111/his.12741

Cited by 12 publications

(8 citation statements)

References 43 publications

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“…There have been several cases in which clinical and pathologic findings were consistent with ALSP, but CSF1R mutations were not identified. [17][18][19] Notably, no CSF1R mutation has been found in the original Swedish family, 20 implying that other genes may be associated with these cases. In 2016, homozygous or compound heterozygous mutations in AARS2 gene encoding mitochondrial alanyl-transfer RNA synthetase were identified in 5 patients who were clinically suspected to have ALSP, but were negative for CSF1R mutations.…”

Section: Historical Background and Nosologymentioning

confidence: 95%

CSF1R -related leukoencephalopathy

et al. 2018

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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.

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Section: Historical Background and Nosologymentioning

confidence: 95%

CSF1R -related leukoencephalopathy

et al. 2018

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“…However, there is also evidence that TREM2 can associate with other receptors, including PlexinA1 [ 273 , 274 ]. Other studies are suggestive that TREM2 could also bind to TREML1 [ 236 ] through co-IP experiments or CSF1R due to their close linkage in network analyses [ 101 ] and the strong commonalities in their downstream pathways [ 222 , 275 ]. While these last two interactions remain to be validated, it is certainly possible that TREM2 also acts through these alternative heteromeric complexes.…”

Section: Trem2 Structure and Signalingmentioning

confidence: 99%

TREM2 in Neurodegenerative Diseases

Jay

Saucken

Landreth

2017

Mol Neurodegeneration

321

283

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TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics. The expression, signaling and function of TREM2 in NDDs have been extensively investigated in an effort to understand the role of immune function in disease pathogenesis and progression. We provide a comprehensive review of our current understanding of TREM2 biology, including new insights into the regulation of TREM2 expression, and TREM2 signaling and function across NDDs. While many open questions remain, the current body of literature provides clarity on several issues. While it is still often cited that TREM2 expression is decreased by pro-inflammatory stimuli, it is now clear that this is true in vitro, but inflammatory stimuli in vivo almost universally increase TREM2 expression. Likewise, while TREM2 function is classically described as promoting an anti-inflammatory phenotype, more than half of published studies demonstrate a pro-inflammatory role for TREM2, suggesting that its role in inflammation is much more complex. Finally, these components of TREM2 biology are applied to a discussion of how TREM2 impacts NDD pathologies and the latest assessment of how these findings might be applied to immune-directed clinical biomarkers and therapeutics.

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“…The formation of axonal spheroid is considered as a pathological manifestation of CSF1R-related leukoencephalopathy. 71,72 Tada et al indicated that in layers 3 and 4 of the frontal cortex in CSF1Rrelated leukoencephalopathy fewer numbers of Iba1 positive microglia were recorded than healthy control brains. A high proliferation of microglia was noted in selective brain regions.…”

Section: Dovepressmentioning

confidence: 99%

A Novel Missense Mutation of the CSF1R Gene Causes Incurable CSF1R-Related Leukoencephalopathy: Case Report and Review of Literature

Chen¹,

Luo²,

Li³

et al. 2020

IJGM

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CSF1R -related leukoencephalopathy, mainly caused by the mutation of the colony stimulating factor 1 receptor ( CSF1R ) gene on chromosome 5, is an underestimated neurological disease typically presenting as early-onset cognitive decline and personality changes. Currently, there is no specific treatment for CSF1R -related leukoencephalopathy. Most clinicians failed to recognize this disease during an early disease stage, leading to a high rate of misdiagnosis. Although rare, an increasing amount of CSF1R -related leukoencephalopathy cases have been reported recently. In this study, we first report a 35-year-old woman with CSF1R -related leukoencephalopathy carrying a novel missense mutation c.2463G >C (p.W821C) of CSF1R . An extensive literature research was performed in order to better understand the broader genetic and clinical characteristics of CSF1R -related leukoencephalopathy. A total of 147 patients with CSF1R -related leukoencephalopathy confirmed either by the genetic test or brain biopsy were identified. Among them, 49 patients were sporadic, and the rest of individuals had a family history originating from 46 different families. Our study indicated that the average age of CSF1R -related leukoencephalopathy onset was 41.4 years. Typical clinical symptoms of CSF1R -related leukoencephalopathy include cognitive decline, movement disorders, behavior changes and mental disorders. Genetic studies have reported 93 missense mutations, 13 splicing mutations, 6 deletion/insertion mutations, 1 code shift mutation and 1 nonsense mutation of the CSF1R gene in patients with CSF1R -related leukoencephalopathy. Early genetic detection and brain biopsy would be helpful for a confirmed diagnosis, and more translational studies are needed to combat this devastating disease.

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Sporadic adult‐onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes

Cited by 12 publications

References 43 publications

CSF1R -related leukoencephalopathy

CSF1R -related leukoencephalopathy

TREM2 in Neurodegenerative Diseases

A Novel Missense Mutation of the CSF1R Gene Causes Incurable CSF1R-Related Leukoencephalopathy: Case Report and Review of Literature

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