Journal
MUSCLE & NERVE
Volume 42, Issue 2, Pages 170-176Publisher
WILEY
DOI: 10.1002/mus.21665
Keywords
amyotrophic lateral sclerosis; clinicogenetic correlation; familial; fused in sarcoma; neuropathology; phenotype; translocated in liposarcoma
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Funding
- Canadian Institutes of Health Research [74580]
- Pacific Alzheimer Research Foundation
- ALS Association
- NIH/NIA [AG26251-03A1]
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Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS cases. Our findings suggest there are specific clinicogenetic correlations and provide the first detailed neuropathological description. Muscle Nerve 42: 170-176, 2010
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