Abstract Details

ALSP is a fatal and rapidly progressive rare genetic disease caused by loss-of-function mutations in the CSF1R gene resulting in microglia dysfunction. At least 106 different CSF1R mutations have been identified in peer-reviewed literature worldwide. So far, no major correlation of genotype and phenotype has been identified. Interestingly, there are several reports where family members with identical CSF1R gene mutations do not share the same clinical phenotype.

To further understand the phenotype/genotype correlations of ALSP through a systematic literature review of case reports.

A comprehensive, systematic literature review was conducted of the clinical and genetic features of ALSP derived from published case studies identified through a MEDLINE search based on prespecified selection criteria, published from January 1, 1980 through April 30, 2021. The search identified 76 published case reports that were reviewed with data extracted from 274 ALSP patients. This review represents the largest cases series of ALSP patients analyzed to date.

CSF1R mutations had the highest occurrence in exon numbers 18 (n=91, 39.1%), 19 (n=32, 13.7%), and 20 (n=26, 11.2%). These frequencies and findings are comparable to those reported in previous studies. Pyramidal motor abnormalities were significantly associated with the CSF1R kinase domain mutation, whereas extrapyramidal motor abnormalities were significantly correlated with non-kinase regions. There were no other major phenotype/genotype correlations based on exon number or kinase domain mutations versus non-kinase domain mutations. 

This systematic analysis did not identify any major phenotype/genotype correlations and confirmed previously published ALSP literature. These results support inclusion of all CSF1R mutation carriers in future ALSP clinical trials without stratification based on mutation type. Larger genetic studies are necessary to fully evaluate genotype/phenotype correlations of ALSP.