• Online Features  This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on Web of Science (7)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Neurology  • Amyotrophic Lateral Sclerosis  • Dementias  • Neurogenetics  • Motor Neuron Disease  • Neuromuscular diseases  • Neurology, Other  • Genetic Disorders  • Alert me on articles by topic  Social Bookmarking   What's this?

Adriano Chiò, MD; Andrea Calvo, MD, PhD; Cristina Moglia, MD; Gabriella Restagno, MD; Irene Ossola, BS; Maura Brunetti, BS; Anna Montuschi, PsyD; Angelina Cistaro, MD; Anna Ticca, MD; Bryan J. Traynor, MD; Jennifer C. Schymick, PhD; Roberto Mutani, MD; Maria Giovanna Marrosu, MD; Maria Rita Murru, BS; Giuseppe Borghero, MD

Arch Neurol. 2010;67(8):1002-1009. doi:10.1001/archneurol.2010.173

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.

Design, Setting, and Participants  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.

Author Affiliations: Department of Neuroscience, University of Turin (Drs Chiò, Calvo, Moglia, Montuschi, and Mutani), Laboratory of Molecular Genetics, Azienda Sanitaria Ospedaliera Ospedale Infantile Regina Margherita–Sant’Anna (Dr Restagno and Mss Ossola and Brunetti), and Positron Emission Tomography Center, IRMET Diagnostic Imaging Torino (Dr Cistaro), Turin, Italy; Department of Neurology, Azienda Ospedaliera San Francesco, Nuoro, Italy (Dr Ticca); Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland (Drs Traynor and Schymick); and Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy (Drs Marrosu and Borghero and Ms Murru).

CiteULike    Connotea    Delicious    Digg    Facebook    Reddit    Technorati    Twitter     What's this?