Phenotypic features of adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): presenting symptoms and clinical course

Abstract

AbstractBackgroundALSP is an underdiagnosed, rapidly progressive, fatal autosomal dominant neurodegenerative disease caused by CSF1R gene mutations that result in microglial dysfunction. There are no published prospective studies on the natural history of ALSP. As a result, descriptions of phenotypic features of ALSP are derived from small case series and single case reports. To better understand the phenotypic characteristics of ALSP, a systematic literature review of these published case reports was performed.MethodA comprehensive, systematic literature review of the clinical and genetic features of ALSP was conducted to identify published case studies (January 1, 1980, through April 30, 2021) from a MEDLINE search using prespecified selection criteria. The search identified 76 published reports with data extracted from 274 ALSP patients and is the most extensive case series of ALSP to date.ResultThe mean±SD age (years) of onset of symptoms was 43.1±11.3, survival time (years) 6.3±4.6, and age of death (years) 52.9±10.8. The most common initial symptoms consisted of cognitive impairment (n = 113, 41.2%), behavioral and psychiatric dysfunction (n = 70, 25.6%), extrapyramidal motor abnormalities (n = 28, 10.2%), pseudo‐bulbar affects (n = 13 4.7%) and speech difficulty (n = 11, 4.0%) and confirmed the phenotypic heterogeneity of ALSP at disease onset, a major contributor to ALSP misdiagnosis. Clinical features associated with disease progression involved cognitive impairment (n = 216, 78.8%), behavioral and psychiatric dysfunction (n = 175, 63.9%), extrapyramidal motor abnormalities (n = 147, 53.7%), and pyramidal motor abnormalities, (n = 136, 49.6%). Less frequent clinical findings (each < 25% incidence) were pseudo‐bulbar symptoms, seizures and aphasia or speech difficulty.ConclusionThe findings of this systematic literature review are consistent with previous, smaller reports on the phenotype of ALSP. Since cognitive impairment, behavioral and psychiatric dysfunction, and pyramidal and extrapyramidal motor abnormalities were identified as the most frequent clinical features in this review, endpoints quantifying these symptoms should be considered in the design of future interventional trials of ALSP.