ALSP is a progressive, fatal autosomal dominant neurodegenerative disease caused by CSF1R gene mutations resulting in microglial dysfunction and profound white matter changes. ALSP prevalence is estimated at 10,000 in the US alone. The phenotype associated with ALSP is cognitive and motor impairment and can be misdiagnosed as FTD, MS or AD.  Diagnostic accuracy of ALSP has modestly improved due to published diagnostic criteria. However, the rate of initial ALSP misdiagnosis remains high and involves a spectrum of neurodegenerative and neuroimmune disorders.

A systematic literature review of ALSP clinical and genetic features was conducted with published case studies (1/1/1980-3/22/2022). Data were extracted for 292 ALSP patients from 90 published case reports. Categorical variables were stratified by initial diagnosis, dichotomized by ALSP versus misdiagnosis categories and presented as frequency distribution. P-values for differences in frequency distribution between stratification factors were generated by Chi-square test.

Demographic data revealed the mean (SD) age (years) of patients was 43.2 (11.6), median (minimum, maximum) of 42.0 (18.0, 86.0). Family history of ALSP was identified in 58.9% of patients. Due to phenotypic heterogeneity at disease onset, accurate initial diagnosis was detected in only 31.5% of ALSP patients. FTD (11.6%), MS (7.9%), AD (4.5%), adult-onset leukodystrophy (6.8%), and familial leukoencephalopathy (6.8%) were common misdiagnoses. Cognitive impairment (45.9%) and behavioral and psychiatric dysfunction (26.4%) were the most common initial symptoms.

This review confirms ALSP is commonly misdiagnosed as a cognitive disorder, AD/FTD, MS or other leukodystrophy.  The presenting symptoms of ALSP family history, white matter MRI lesions and early-onset cognitive impairment with behavioral and/or motor dysfunction should trigger suspicion for ALSP and initiate genetic testing. To avoid misdiagnosis, screening patients for ALSP should be considered. Accurate diagnosis can allow for early intervention with investigational therapies currently in development.