LAUSR

Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is the collective disease referring to patients previously diagnosed with hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmented orthochromatic leukodystrophy (POLD). ALSP is a white matter disease with a complex neurological phenotype consisting of pyramidal tract dysfunction, parkinsonism, and frontal-predominant cognitive impairment. This autosomal-dominant disease typically affects females earlier than males with symptom onset in the fourth decade of life and average disease duration of 7 years. In 2011, a mutation in the colonystimulating factor 1 receptor (CSF1R) gene was first identified in the initial collection of HDLS families. Two separate POLD families were later found to carry CSF1R mutations, therefore confirming that HDLS and POLD were actually a single CSF1Rrelated leukoencephalopathy. There are now more than 70 different pathogenic mutations, most of which occur in the tyrosine kinase domain resulting in disruption of protein function. The disease is currently known as CSF1R-related leukoencephalopathy to distinguish it from a somewhat similar condition produced by mutations in the AARS2 gene or other unknown genetic causes. For the genetic or sporadic cases of unknown cause, the nomenclature of ALSPgene negative seems to be appropriate for now. The CSF-1R protein is mainly expressed in microglia leading to the disease designation of microgliopathy. Recent studies from a mouse model of ALSP strongly support this designation. Role of the CSF-1R in Microglia