title: Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions.
abstract: Juvenile amyotrophic lateral sclerosis (ALS) with basophilic inclusions is a well-recognized entity. However, the molecular underpinnings of this devastating disease are poorly understood. Here, we present genetic and neuropathological characterizations in two young women with fatal rapidly progressive ALS with basophilic inclusions. In one case, a germline mutation (P525L) was detected in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene, whereas no mutation was identified in the other case. Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum. In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei. In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein. These results underscore the importance of FUS mutations and pathology in rapidly progressive juvenile ALS. Furthermore, our study represents the first detailed characterizations of neuropathological findings in rapidly progressive juvenile ALS patients with a mutation in the FUS/TLS gene.
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA. eric.huang2@ucsf.edu
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Strober
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Shapiro
authors.forename: Catherine
authors.initials: C
authors.lastname: Lomen-Hoerth
mesh_terms: D000293:Adolescent; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001491:Basophils / Q000473:pathology* / Q000648:ultrastructure; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016900:Neurofilament Proteins / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D055815:Young Adult; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016900:Neurofilament Proteins; D034702:RNA-Binding Protein FUS; C067980:CD68 antigen, human; D000097382:CD68 Molecule