Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations

P. Corcia, P. Valdmanis, S. Millecamps, C. Lionnet, H. Blasco, K. Mouzat, H. Daoud, Veronique Belzil, R. Morales, N. Pageot, V. Danel-Brunaud, N. Vandenberghe, P. F. Pradat, P. Couratier, F. Salachas, S. Lumbroso, G. A. Rouleau, V. Meininger, W. Camu

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Abstract

Objective: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. Methods: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. Results: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). Conclusion: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.

Original languageEnglish (US)
Pages (from-to)1519-1526
Number of pages8
JournalNeurology
Volume78
Issue number19
DOIs
StatePublished - May 8 2012
Externally publishedYes

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Amyotrophic Lateral Sclerosis
Genotype
Phenotype
Mutation
Upper Extremity
Genes
Genetic Association Studies
Survival
Glycine
Lower Extremity
Physicians
Amyotrophic lateral sclerosis 1

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Corcia, P., Valdmanis, P., Millecamps, S., Lionnet, C., Blasco, H., Mouzat, K., ... Camu, W. (2012). Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology, 78(19), 1519-1526. https://doi.org/10.1212/WNL.0b013e3182553c88

Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. / Corcia, P.; Valdmanis, P.; Millecamps, S.; Lionnet, C.; Blasco, H.; Mouzat, K.; Daoud, H.; Belzil, Veronique; Morales, R.; Pageot, N.; Danel-Brunaud, V.; Vandenberghe, N.; Pradat, P. F.; Couratier, P.; Salachas, F.; Lumbroso, S.; Rouleau, G. A.; Meininger, V.; Camu, W.

In: Neurology, Vol. 78, No. 19, 08.05.2012, p. 1519-1526.

Research output: Contribution to journalArticle

Corcia, P, Valdmanis, P, Millecamps, S, Lionnet, C, Blasco, H, Mouzat, K, Daoud, H, Belzil, V, Morales, R, Pageot, N, Danel-Brunaud, V, Vandenberghe, N, Pradat, PF, Couratier, P, Salachas, F, Lumbroso, S, Rouleau, GA, Meininger, V & Camu, W 2012, 'Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations', Neurology, vol. 78, no. 19, pp. 1519-1526. https://doi.org/10.1212/WNL.0b013e3182553c88
Corcia P, Valdmanis P, Millecamps S, Lionnet C, Blasco H, Mouzat K et al. Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology. 2012 May 8;78(19):1519-1526. https://doi.org/10.1212/WNL.0b013e3182553c88
Corcia, P. ; Valdmanis, P. ; Millecamps, S. ; Lionnet, C. ; Blasco, H. ; Mouzat, K. ; Daoud, H. ; Belzil, Veronique ; Morales, R. ; Pageot, N. ; Danel-Brunaud, V. ; Vandenberghe, N. ; Pradat, P. F. ; Couratier, P. ; Salachas, F. ; Lumbroso, S. ; Rouleau, G. A. ; Meininger, V. ; Camu, W. / Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. In: Neurology. 2012 ; Vol. 78, No. 19. pp. 1519-1526.
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abstract = "Objective: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. Methods: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. Results: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3{\%} UL onset for TARDBP+ and 74.1{\%} on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3{\%} of had UL onset, while 58.8{\%} of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). Conclusion: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.",
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T1 - Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations

AU - Corcia, P.

AU - Valdmanis, P.

AU - Millecamps, S.

AU - Lionnet, C.

AU - Blasco, H.

AU - Mouzat, K.

AU - Daoud, H.

AU - Belzil, Veronique

AU - Morales, R.

AU - Pageot, N.

AU - Danel-Brunaud, V.

AU - Vandenberghe, N.

AU - Pradat, P. F.

AU - Couratier, P.

AU - Salachas, F.

AU - Lumbroso, S.

AU - Rouleau, G. A.

AU - Meininger, V.

AU - Camu, W.

PY - 2012/5/8

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N2 - Objective: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. Methods: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. Results: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). Conclusion: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.

AB - Objective: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. Methods: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. Results: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). Conclusion: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.

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