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

Abstract

Background and purposeThe clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated.MethodsClinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data.ResultsIn all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18–78 years), the mean age at death was 53 years (range 23–84 years) and the mean disease duration was 6.8 years (range 1–29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158–11.177). There was an age‐dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion‐restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy‐nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype−genotype correlations.ConclusionsThe characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation

“…Fluid-attenuated inversion recovery sagittal imaging is recommended to evaluate changes in the corpus callosum. Abnormal signaling in the pyramidal tracts and diffusion-restricted lesions are observed in some cases [5,11]. None of the ALSP cases showed middle cerebellar peduncle lesions, which are known as a characteristic finding of some leukoencephalopathies On brain CT scans, calcifications are often observed bilaterally in the frontal white matter adjacent to the anterior horn of the lateral ventricle and the subcortical region of the parietal lobe.…”

“…Calcifications can be very small. Thus, thin-slice CT (1 mm) is recommended to detect them [5,11]. Characteristic 'stepping stone appearance' can be seen on sagittal view [10] …”

“…The diagnostic criteria were created based on the clinical characteristics obtained from our case series and review of the literature and further discussions among the study working group [5]. We defined five core diagnostic features (Table 1).…”

“…CSF1R mutation All reported mutations were located within the tyrosine kinase domain of CSF1R except for two frameshift mutations [5] ALSP, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; CSF1R, colony-stimulating factor 1 receptor; CT, computed tomography; MRI, magnetic resonance imaging.…”

Sporadic Japanese case of adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia caused by a de novo p.Phe849del mutation in CSF1R

“…Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leukoencephalopathy with spheroids, is an autosomal dominant, rapidly progressing cerebral white matter disease caused by various mutations in the colony‐stimulating factor 1 receptor ( CSF1R ) gene . Clinical features vary and can include cognitive impairment, psychiatric symptoms, and frontal lobe dysfunction . In addition to bilateral white matter lesions and cortical atrophy, thinning of the corpus callosum with abnormal signals are common MRI findings .…”