軸索スフェロイド形成を伴う遺伝性びまん性白質脳症（HDLS）とCSF-1R遺伝子変異

Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS): A Review of the Literature on its Clinical Characteristics and Mutations in the Colony-Stimulating Factor-1 Receptor Gene

Hereditary diffuse leukoencephalophathy with spheroids（HDLS）は白質障害を伴う若年性認知症である。HDLSの原因遺伝子としてCSF-1R（colony stimulating factor 1 receptor）が最近同定された。われわれはわが国のCSF-1R変異例を解析し，HDLSに特徴的な臨床的所見と画像所見を明らかにした。また分子遺伝学的な解析から，CSF-1Rのハプロ不全がHDLSの病態になることを明らかにした。HDLS患者脳ではミクログリアの異常が認められ，CSF-1Rシグナル不全により生じるミクログリア異常がHDLSの病態の本態と考えられた。

Abstract

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an early-onset dementia that predominantly affects the cerebral white matter. After the discovery of a gene encoding the colony stimulating factor 1 receptor (CSF-1R) as a causative gene in patients with HDLS, gene analysis of CSF-1R enabled the diagnosis of HDLS without histopathological evidence. To clarify the genetic and clinical characteristics of HDLS, here, we reviewed the characteristics of patients with HDLS with CSF-1R mutations in the literature. Seventy-three patients from 54 pedigrees with HDLS from various ethnic backgrounds have been reported. Among them, Japanese patients account for 22% (16 patients from 15 pedigrees). Mean age at onset was 45 years (18 to 78 years). A wide range of clinical features including cognitive decline, behavioral changes, seizures, pyramidal signs, and parkinsonism have been described in these patients. Various kinds of mutations were found in the tyrosine kinase domain of CSF-1R. A frameshift mutation causing nonsense-mediated mRNA decay was also described. This suggests that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Neuropathological analysis revealed that microglia in the brains of patients demonstrated distinct morphology and distribution. These results suggest that primary microglial dysfunction due to CSF-1R signaling perturbation may underlie the pathogenesis of HDLS.