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

Abstract

Background and purpose: The 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.

Methods: Clinical 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.

Results: In 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.

Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

Keywords: adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; colony stimulating factor 1 receptor; hereditary diffuse leukoencephalopathy with spheroids; leukoencephalopathy; pigmented orthochromatic leukodystrophy.

Figure 1

Distribution and disease penetrance of ALSP cases with CSF1R mutation. (a) The mean age of onset in women was significantly younger than that of men. (b) Kaplan–Meier curves showing the difference in probability of survival between sexes. There was no significant difference. (c) Kaplan–Meier curves showing the age‐dependent penetrance. There was a significant difference between sexes.

Figure 2

Initial symptoms of ALSP cases with CSF1R mutation. (a) Frequency of four major initial symptoms in all cases with a CSF1R mutation: cognitive, cognitive impairment; psychiatric, psychiatric symptoms; motor, motor dysfunction; speech, speech problem. Other symptoms include stroke‐like episodes, sensory disturbances, dizziness, fatigue and epilepsy. (b), (c) Initial symptoms in both sexes were distributed based on age of onset. Note that motor dysfunction was more often observed in younger women and was observed more frequently than cognitive impairment in affected women in their 20s.

Figure 3

CSF1R gene diagram with identified mutations and regional distribution of families carrying CSF1R mutations. (a) Exons 12–21 encoding protein tyrosine kinase of CSF1R and the protein tyrosine kinase domain (TKD) are shown based on the information from UniProt (http://www.uniprot.org/uniprot/P07333). TKD is interrupted by the kinase insert domain (KID). Splice‐site mutations are put above the diagram, and the other mutations are listed below. All mutations were located within TKD except the T567fsX44 and S688EfsX13 mutations. The numbers in parentheses represent the number of families. (b) Mutation‐positive families have been reported in the USA, Europe and Asia. The numbers in parentheses represent the number of families. Multiple locations separated by a slash indicate a mixed cohort from those regions.