Clinical Features And Genetic Characteristics Of Hereditary Diffuse Leukoencephalopathy With Spheroids Due To CSF1R Mutations

Backgroud: Hereditary diffuse leukoencephalopathy with spheroids(HDLS)is an autosomal dominant inherited white matter disease with high penetrance.Clinical manifestations are characterized by adult-onset cognitive impairment,behavioral or emotional changes,paresis,Parkinsonism,and seizures.Mutations in the colony-stimulating factor 1 receptor(CSF1R)gene have been identified as the cause of HDLS.There are few reports of HDLS related to CSF1R mutations in China.Methods: We reported two patients with leukoencephalopathy presented with cognitive decline and limb weakness.Next generation sequencing was performed to detect the causative mutations.An extensive literature research was then performed to identify all patients with HDLS previously reported.The clinical characteristics,brain imaging and genetic features of all patients with HDLS were reviewed.Results: Patient 1 was a 40-year-old male with clinical manifestations of progressive right limb weakness and cognitive decline.His mother and aunt had similar clinical symptoms and died in middle age.Genetic test found a heterozygous missense variant c.1952G> A(p.G651E)in the CSF1R gene,which was not detected in the HGMDpro database and Ex AC database.SIFT,Polyphen2,and Mutation Taster and other bioinformatics softwares predicted that the mutation would affect function of protein.The p.G651 E variant was interpreted to be likely pathogenic according to ACMG standards.Patient 2 was a 39-year-old female presented with clinical signs of limb weakness and speech impairment.Genetic testing identified a known heterozygous CSF1R missense mutation,c.2701C> T(p.P901S).Brain MRI imaging of both patients revealed bilateral paraventricular white matter lesions and atrophy of corpus callosum.Literature review shows that the age of onset of HDLS is 10-71 years,with an average age of 43 years.The most common clinical symptoms are cognitive impairment(87%),followed by mental and behavioral abnormalities(55%)and Parkinson’s syndrome(41%).Other symptoms include hemiplegia,seizures,gait disorders,and difficulty of swallowing.The most common imaging findings are bilateral white matter lesions(90%),brain atrophy(37%)and corpus callosum atrophy(35%).All 80 CSF1R mutations reported are located in the tyrosine kinase domain(TKD)encoded by exons 12-21 of CSF1R gene,and are mainly in the distal kinase domain encoded by exons 18-19(43 mutations).Conclusion: The main clinical symptoms and the most common initial symptoms of HDLS are cognitive impairment,followed by mental and behavioral abnormalities and hemiplegia.The characteristic features of MRI are bilateral white matter lesions,lateral ventricular dilatation,and atrophy of corpus callosum.CT showed calcification in white matter.The majority of CSF1R mutations in HDLS patients are located in the TKD domain,and mainly in the distal part of the TKD domain.Loss of tyrosine kinase activity may be the cause of HDLS.