Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions.
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.
Huang
Eric J
EJ
Department of Pathology, University of California, San Francisco, CA, USA. eric.huang2@ucsf.edu
Zhang
Jiasheng
J
Geser
Felix
F
Trojanowski
John Q
JQ
Strober
Jonathan B
JB
Dickson
Dennis W
DW
Brown
Robert H
RH
Shapiro
Barbara E
BE
Lomen-Hoerth
Catherine
C
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
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016900:Neurofilament Proteins; D034702:RNA-Binding Protein FUS; C067980:CD68 antigen, human; D000097382:CD68 Molecule