title: Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations.
abstract: BACKGROUND
  TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease.
  
  
  OBJECTIVE
  To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations.
  
  
  METHODS
  Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non-superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls. Main Outcome Measure We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTLD.
  
  
  RESULTS
  The p.Ala382Thr missense mutation of the TARDBP gene was absent in the 280 controls. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography.
  
  
  CONCLUSIONS
  Three apparently unrelated families with familial ALS carrying the p.Ala382Thr TARDBP missense mutation developed FTLD. In these families, FTLD cosegregates with ALS. Patients with ALS carrying TARDBP mutations may develop FTLD.
authors.affiliation: Department of Neuroscience, University of Turin, via Cherasco 15, 10126 Turin, Italy. achio@usa.net
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.forename: Cristina
authors.initials: C
authors.lastname: Moglia
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
authors.forename: Irene
authors.initials: I
authors.lastname: Ossola
authors.forename: Maura
authors.initials: M
authors.lastname: Brunetti
authors.forename: Anna
authors.initials: A
authors.lastname: Montuschi
authors.forename: Angelina
authors.initials: A
authors.lastname: Cistaro
authors.forename: Anna
authors.initials: A
authors.lastname: Ticca
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Schymick
authors.forename: Roberto
authors.initials: R
authors.lastname: Mutani
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Murru
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borghero
mesh_terms: D000328:Adult; D000368:Aged; D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000150:complications / Q000235:genetics*; D007839:Functional Laterality; D006801:Humans; D007558:Italy; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D049268:Positron-Emission Tomography / Q000379:methods; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013912:Threonine / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; D013912:Threonine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000409:Alanine