Hereditary diffuse leukoencephalopathy with axonal spheroids: three patients with stroke-like presentation carrying new mutations in the CSF1R gene

Abstract

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disorder characterized by white matter neurodegeneration, progressive cognitive decline, and motor symptoms. Histologically, it is characterized by axonal swellings ("spheroids"). To date, over 20 different mutations affecting the tyrosine kinase domain of the protein have been identified in the colony stimulating factor 1 receptor (CSF1R) gene. Our goal is to describe three unrelated Italian patients affected by HDLS and carrying new CSF1R mutations, thus expanding the mutational spectrum and phenotypic presentation. CSF1R gene analysis was performed in 15 patients (age range 25-83 years) with undefined leukoencephalopathy and progressive cognitive decline. In three patients (two males and one female, aged 58, 37, and 48 years, respectively), new heterozygous missense mutations affecting the protein tyrosine kinase domain of the CSF1R gene were detected. In all of these patients, behavioural and cognitive changes were preceded by an ischemic stroke-like episode. A positive family history was present in only one case.

Clinical and genetic characterization of adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation

“…Next, the literature on ALSP cases with CSF1R mutations reported from other institutions since 2012 was reviewed using the search terms ‘adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia’, ‘hereditary diffuse leukoencephalopathy with spheroids’ and ‘CSF1R’ in PubMed (searched in December 2015). Ninety‐nine CSF1R mutation carriers in 66 families were identified, including one obligate carrier . After excluding three asymptomatic carriers, the investigation sheets were filled out for 96 symptomatic carriers based on the information described in the literature.…”

Hereditary diffuse leukoencephalopathy with spheroids with phenotype of primary progressive multiple sclerosis

“…Over 30 different mutations in the CSF1R gene have been discovered. All of the mutations are located in the intracellular tyrosine kinase domain of the receptor, which is encoded by CSF1R exons 12À22 [1,[5][6][7][8][9][10][11][12][13]. Carriers of CSF1R mutations have been clinically diagnosed as having primary progressive multiple sclerosis (PPMS), frontotemporal dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy or atypical parkinsonism [1,14].…”

A Novel CSF1R Mutation in a Patient with Clinical and Neuroradiological Features of Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids

“…This patient is from Puglia; the three previously reported families [5] included one from Puglia and the other two from Campania and Sicily, respectively. The different mutations in all families exclude common ancestors.…”

“…Most consist of missense substitutions within the protein tyrosine kinase domain, predicted to lead to a loss of autophosphorylation. To date, more than 20 different mutations have been detected in familial cases, among which, three unrelated Italian patients with HDLS, described by our group [5].…”