title: ALS-FUS pathology revisited: singleton FUS mutations and an unusual case with both a FUS and TARDBP mutation.
abstract: BACKGROUND
  Mutations in the FUS gene have been shown to be a rare cause of amyotrophic lateral sclerosis (ALS-FUS) and whilst well documented clinically and genetically there have been relatively few neuropathological studies.Recent work suggested a possible correlation between pathological features such as frequency of basophilic inclusions in neurons and rate of clinical decline, other studies have revealed a discrepancy between the upper motor neuron features detected clinically and the associated pathology. The purpose of this study was to describe the pathological features associated with more recently discovered FUS mutations and reinvestigate those with well recognised mutations in an attempt to correlate the pathology with mutation and/or clinical phenotype. The brains and spinal cords of seven cases of ALS-FUS were examined neuropathologically, including cases with the newly described p.K510E mutation and a case with both a known p.P525L mutation in the FUS gene and a truncating p.Y374X mutation in the TARDBP gene.
  
  
  RESULTS
  The neuropathology in all cases revealed basophilic and FUS inclusions in the cord. The density and type of inclusions varied markedly between cases, but did not allow a clear correlation with clinical progression. Only one case showed significant motor cortical pathology despite the upper motor neuron clinical features being evident in 4 patients. The case with both a FUS and TARDBP mutation revealed FUS positive inclusions but no TDP-43 pathology. Instead there were unusual p62 positive, FUS negative neuronal and glial inclusions as well as dot-like neurites.
  
  
  CONCLUSIONS
  The study confirms cases of ALS-FUS to be mainly a lower motor neuron disease and to have pathology that does not appear to neatly correlate with clinical features or genetics. Furthermore, the case with both a FUS and TARDBP mutation reveals an intriguing pathological profile which at least in part involves a very unusual staining pattern for the ubiquitin-binding protein p62.
authors.affiliation: Department Of Clinical Neuropathology, Academic Neuroscience Building, King's College Hospital, Denmark Hill, SE5 9RS, London, UK. andrewking@nhs.net.|MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF, London, UK. andrewking@nhs.net.
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.affiliation: MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF, London, UK.|King's Health Partners Centre for Neurodegeneration Research, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, SE5 8AF, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: King's Health Partners Centre for Neurodegeneration Research, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, SE5 8AF, London, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.affiliation: MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF, London, UK.|King's Health Partners Centre for Neurodegeneration Research, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, SE5 8AF, London, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Nolan
authors.affiliation: Department Of Clinical Neuropathology, Academic Neuroscience Building, King's College Hospital, Denmark Hill, SE5 9RS, London, UK.|MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF, London, UK.
authors.forename: Olimpia
authors.initials: O
authors.lastname: Curran
authors.affiliation: King's Health Partners Centre for Neurodegeneration Research, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, SE5 8AF, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.affiliation: King's Health Partners Centre for Neurodegeneration Research, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, SE5 8AF, London, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Department Of Clinical Neuropathology, Academic Neuroscience Building, King's College Hospital, Denmark Hill, SE5 9RS, London, UK.|MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D016472:Motor Neuron Disease; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D000071456:Sequestosome-1 Protein; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055815:Young Adult; D000097382:CD68 Molecule
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; D000071456:Sequestosome-1 Protein; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000599550:FUS protein, human; C099718:SQSTM1 protein, human; C000598624:TARDBP protein, human