A truncating SOD1 mutation, p.Gly141X, is associated with clinical and pathologic heterogeneity, including frontotemporal lobar degeneration.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting upper and lower motor neurons, but it is increasingly recognized to affect other systems, with cognitive impairment resembling frontotemporal dementia (FTD) in some patients. We report clinical and pathologic findings of a family with ALS due to a truncating mutation, p.Gly141X, in copper/zinc superoxide dismutase (SOD1). The proband presented clinically with FTD and later showed progressive motor neuron disease, while all other family members had early-onset and rapidly progressive ALS without significant cognitive deficits. Pathologic examination of both the proband and her daughter revealed degeneration of corticospinal tracts and motor neurons in brain and spinal cord compatible with ALS. On the other hand, the proband also had neocortical and limbic system degeneration with pleomorphic neuronal cytoplasmic inclusions. Extramotor pathology in her daughter was relatively restricted to the hypothalamus and extrapyramidal system, but not the neocortex. The inclusions in the proband and her daughter were immunoreactive for SOD1, but negative for TAR DNA-binding protein of 43 kDa (TDP-43). In the proband, a number of the neocortical inclusions were immunopositive for α-internexin, initially suggesting a diagnosis of atypical FTLD, but there was no evidence of fused in sarcoma (FUS) immunoreactivity, which is often detected in atypical FTLD. Analogous to atypical FTLD, neuronal inclusions had variable co-localization of SOD1 and α-internexin. The current classification of FTLD is based on the major constituent protein: FTLD-tau, FTLD-TDP-43, and FTLD-FUS. The proband in this family indicates that SOD1, while rare, can also be the substrate of FTLD, in addition to the more common presentation of ALS. The explanation for clinical and pathologic heterogeneity of SOD1 mutations, including the p.Gly141X mutation, remains unresolved.
Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Masataka
M
Nakamura
Kevin F
KF
Bieniek
Wen-Lang
WL
Lin
Neill R
NR
Graff-Radford
Melissa E
ME
Murray
Monica
M
Castanedes-Casey
Pamela
P
Desaro
Matthew C
MC
Baker
Nicola J
NJ
Rutherford
Janice
J
Robertson
Rosa
R
Rademakers
Dennis W
DW
Dickson
Kevin B
KB
Boylan
D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005190:Family; D017809:Fatal Outcome; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1