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Four Swedish cases of CSF1R-related leukoencephalopathy : Visualization of clinical phenotypes

Rosenstein, Igal ; Andersen, Oluf ; Victor, Daniel ; Englund, Elisabet LU orcid ; Granberg, Tobias ; Hedberg-Oldfors, Carola LU ; Jood, Katarina ; Fitrah, Yusran Ady ; Ikeuchi, Takeshi and Danylaité Karrenbauer, Virginija (2022) In Acta Neurologica Scandinavica 145(5). p.599-609
Abstract

Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances. Objective: To describe four cases of CSF1R-related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter-individual diversity of clinical presentations. Methods: This is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed... (More)

Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances. Objective: To describe four cases of CSF1R-related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter-individual diversity of clinical presentations. Methods: This is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein. Results: Two heterozygous missense mutations in the CSF1R gene were identified, c.2344C>T; p.Arg777Trp and c.2329C>T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter-individual diversity in the loss of cognitive, motor-neuronal, and extrapyramidal functions. Conclusions: Including the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow-up for this and other leukoencephalopathies.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
adult-onset leukoencephalopathy with spheroids and pigmented glia, biomarkers, colony stimulating factor 1 receptor, CSF1R gene, neurodegeneration, primary microgliopathy
in
Acta Neurologica Scandinavica
volume
145
issue
5
pages
599 - 609
publisher
Wiley-Blackwell
external identifiers
  • scopus:85124460496
  • pmid:35119108
ISSN
0001-6314
DOI
10.1111/ane.13589
language
English
LU publication?
yes
id
31f25c26-aa03-4f1a-b454-5231eb28b908
date added to LUP
2022-04-13 12:36:30
date last changed
2024-06-18 15:54:07
@article{31f25c26-aa03-4f1a-b454-5231eb28b908,
  abstract     = {{<p>Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances. Objective: To describe four cases of CSF1R-related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter-individual diversity of clinical presentations. Methods: This is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein. Results: Two heterozygous missense mutations in the CSF1R gene were identified, c.2344C&gt;T; p.Arg777Trp and c.2329C&gt;T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter-individual diversity in the loss of cognitive, motor-neuronal, and extrapyramidal functions. Conclusions: Including the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow-up for this and other leukoencephalopathies.</p>}},
  author       = {{Rosenstein, Igal and Andersen, Oluf and Victor, Daniel and Englund, Elisabet and Granberg, Tobias and Hedberg-Oldfors, Carola and Jood, Katarina and Fitrah, Yusran Ady and Ikeuchi, Takeshi and Danylaité Karrenbauer, Virginija}},
  issn         = {{0001-6314}},
  keywords     = {{adult-onset leukoencephalopathy with spheroids and pigmented glia; biomarkers; colony stimulating factor 1 receptor; CSF1R gene; neurodegeneration; primary microgliopathy}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{599--609}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Acta Neurologica Scandinavica}},
  title        = {{Four Swedish cases of CSF1R-related leukoencephalopathy : Visualization of clinical phenotypes}},
  url          = {{http://dx.doi.org/10.1111/ane.13589}},
  doi          = {{10.1111/ane.13589}},
  volume       = {{145}},
  year         = {{2022}},
}