Abstract
Objectives: We describe the largest series of patients with TARDBP mutations presenting with frontotemporal dementia (FTD) and review the cases in the literature to precisely characterize FTD diseases associated with this genotype.
Methods: The phenotypic characteristics of 29 TARDBP patients, including 10 new French and Dutch cases and 19 reviewed from the literature, were evaluated.
Results: The most frequent phenotype was a behavioral variant frontotemporal dementia (bvFTD), but a significant proportion (40%) of our patients had semantic (svFTD) or nonfluent variants (nfvFTD) at onset; and svFTD was significantly more frequent in TARDBP carriers than in other FTD genotypes (p < 0.001). Remarkably, only a minority (40%) of our patients secondarily developed amyotrophic lateral sclerosis (ALS). Two patients carried a homozygous mutation but strikingly different phenotypes (bvFTD and ALS) indicating that homozygosity does not result in a specific phenotype. Earlier age at onset in children than parent's generations, mimicking an apparent “anticipation” (21.8 ± 9.3 years, p = 0.001), and possible reduced penetrance were present in most families.
Conclusions: This study enlarges the phenotypic spectrum of TARDBP and will have important clinical implications: (1) FTD can be the only clinical manifestation of TARDBP mutations; (2) Initial language or semantic disorders might be indicative of a specific genotype; (3) Mutations should be searched in all FTD phenotypes after exclusion of major genes, even in the absence of ALS in the proband or in family history; (4) reduced penetrance and clinical variability should be considered to deliver appropriate genetic counseling.
GLOSSARY
- ALS=
- amyotrophic lateral sclerosis;
- CBS=
- corticobasal syndrome;
- FBI=
- Frontal Behavioral Inventory;
- FTD=
- frontotemporal dementia;
- 99mTc-ECD=
- 99mTc-ethylcysteinate dimer;
- nfvFTD=
- nonfluent variant of frontotemporal dementia;
- svFTD=
- semantic variant of frontotemporal dementia
Footnotes
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the Naturalia et Biologia (NEB).
↵* These authors equally contributed to this work.
Supplemental data at Neurology.org/ng
- Received November 15, 2015.
- Accepted in final form March 10, 2016.
- © 2016 American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
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