Journal Article

DZNE-2024-01111

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Novel variants in CSF1R associated with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Schmitz, A. S. (First author)DZNE* ; Raju, J.DZNE* ; Köhler, W. ; Klebe, S. ; Cheheb, K. ; Reschke, F. ; Biskup, S. ; Haack, T. B. ; Röben, B.Extern* ; Kellner, M. ; Rahner, N. ; Bloch, T. ; Lemke, J. ; Bender, B. ; Schöls, L.DZNE* ; Hengel, H. ; Hayer, S. (Last author)DZNE*

2024
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00415-024-12557-0

Abstract: The CSF1R gene, located on chromosome 5, encodes a 108 kDa protein and plays a critical role in regulating myeloid cell function. Mutations in CSF1R have been identified as a cause of a rare white matter disease called adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP, also known as CSF1R-related leukoencephalopathy), characterized by progressive neurological dysfunction. This study aimed to broaden the genetic basis of ALSP by identifying novel CSF1R variants in patients with characteristic clinical and imaging features of ALSP. Genetic analysis was performed through whole-exome sequencing or panel analysis for leukodystrophy genes. Variant annotation and classification were conducted using computational tools, and the identified variants were categorized following the recommendations of the American College of Medical Genetics and Genomics (ACMG). To assess the evolutionary conservation of the novel variants within the CSF1R protein, amino acid sequences were compared across different species. The study identified six previously unreported CSF1R variants (c.2384G>T, c.2133_2919del, c.1837G>A, c.2304C>A, c.2517G>T, c.2642C>T) in seven patients with ALSP, contributing to the expanding knowledge of the genetic diversity underlying this rare disease. The analysis revealed considerable genetic and clinical heterogeneity among these patients. The findings emphasize the need for a comprehensive understanding of the genetic basis of rare diseases like ALSP and underscored the importance of genetic testing, even in cases with no family history of the disease. The study's contribution to the growing spectrum of ALSP genetics and phenotypes enhances our knowledge of this condition, which can be crucial for both diagnosis and potential future treatments.

Keyword(s): Humans (MeSH) ; Female (MeSH) ; Leukoencephalopathies: genetics (MeSH) ; Leukoencephalopathies: pathology (MeSH) ; Male (MeSH) ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor: genetics (MeSH) ; Adult (MeSH) ; Middle Aged (MeSH) ; Mutation (MeSH) ; Neuroglia: pathology (MeSH) ; Aged (MeSH) ; Receptor, Macrophage Colony-Stimulating Factor (MeSH) ; ALSP ; CSF1R ; CSF1R-related leukoencephalopathy ; Genetic diagnostics ; CSF1R protein, human ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ; Receptor, Macrophage Colony-Stimulating Factor

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Contributing Institute(s):

1. Cell Biology of Neurological Diseases (AG Jucker)
2. Clinical Neurogenetics (AG Schöls)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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