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

• Published in: Acta neurologica Scandinavica Vol. 145; no. 5; pp. 599 - 609
• Main Authors: Rosenstein, Igal, Andersen, Oluf, Victor, Daniel, Englund, Elisabet, Granberg, Tobias, Hedberg‐Oldfors, Carola, Jood, Katarina, Fitrah, Yusran Ady, Ikeuchi, Takeshi, Danylaité Karrenbauer, Virginija
• Format: Journal Article
• Language: English
• Published: Denmark Hindawi Limited 01-05-2022; John Wiley and Sons Inc
• Subjects: adult-onset leukoencephalopathy with spheroids and pigmented glia; Basic Medicine; biomarkers; Cerebrospinal fluid; Cognitive ability; colony stimulating factor 1 receptor; Colony-stimulating factor; Computed tomography; CSF1R gene; Encephalopathy; Genetic disorders; Humans; Kinases; Leukoencephalopathies - diagnostic imaging; Leukoencephalopathies - genetics; Leukoencephalopathy; Magnetic Resonance Imaging; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Missense mutation; Mutation; Mutation - genetics; Neurodegeneration; Neuroimaging; Neuroimaging - methods; Neurologi; Neurology; Original; Phenotype; Phenotypes; Phosphorylation; primary microgliopathy; Protein-tyrosine kinase; Substantia alba; Sweden; Sweden; neurodegeneration; CSF1R gene; colony stimulating factor 1 receptor; adult-onset leukoencephalopathy with spheroids and pigmented glia; biomarkers; primary microgliopathy
• ISSN: 0001-6314; 1600-0404; 1600-0404
• DOI: 10.1111/ane.13589

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.