Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations.
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.
Chiò
Adriano
A
Department of Neuroscience, University of Turin, via Cherasco 15, 10126 Turin, Italy. achio@usa.net
Calvo
Andrea
A
Moglia
Cristina
C
Restagno
Gabriella
G
Ossola
Irene
I
Brunetti
Maura
M
Montuschi
Anna
A
Cistaro
Angelina
A
Ticca
Anna
A
Traynor
Bryan J
BJ
Schymick
Jennifer C
JC
Mutani
Roberto
R
Marrosu
Maria Giovanna
MG
Murru
Maria Rita
MR
Borghero
Giuseppe
G
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
D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; D013912:Threonine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000409:Alanine