TY  - JOUR
AU  - Schmitz, Anne S
AU  - Raju, Janani
AU  - Köhler, Wolfgang
AU  - Klebe, Stephan
AU  - Cheheb, Khaled
AU  - Reschke, Franziska
AU  - Biskup, Saskia
AU  - Haack, Tobias B
AU  - Röben, Benjamin
AU  - Kellner, Melanie
AU  - Rahner, Nils
AU  - Bloch, Thomas
AU  - Lemke, Johannes
AU  - Bender, Benjamin
AU  - Schöls, Ludger
AU  - Hengel, Holger
AU  - Hayer, Stefanie
TI  - Novel variants in CSF1R associated with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
JO  - Journal of neurology
VL  - 271
IS  - 9
SN  - 0367-004X
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2024-01111
SP  - 6025 - 6037
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Female
KW  - Leukoencephalopathies: genetics
KW  - Leukoencephalopathies: pathology
KW  - Male
KW  - Receptors, Granulocyte-Macrophage Colony-Stimulating Factor: genetics
KW  - Adult
KW  - Middle Aged
KW  - Mutation
KW  - Neuroglia: pathology
KW  - Aged
KW  - Receptor, Macrophage Colony-Stimulating Factor
KW  - ALSP (Other)
KW  - CSF1R (Other)
KW  - CSF1R-related leukoencephalopathy (Other)
KW  - Genetic diagnostics (Other)
KW  - CSF1R protein, human (NLM Chemicals)
KW  - Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (NLM Chemicals)
KW  - Receptor, Macrophage Colony-Stimulating Factor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11377666
C6  - pmid:39031193
DO  - DOI:10.1007/s00415-024-12557-0
UR  - https://pub.dzne.de/record/271969
ER  -