Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases

Wouter Van Rheenen, Marka Van Blitterswijk, Mark H B Huisman, Lotte Vlam, Perry T C Van Doormaal, Meinie Seelen, Jelena Medic, Dennis Dooijes, Marianne De Visser, Anneke J. Van Der Kooi, Joost Raaphorst, Helenius J. Schelhaas, W. Ludo Van Der Pol, Jan H. Veldink, Leonard H. Van Den Berg

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Abstract

Objective: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Methods: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. Results: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10 -5) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p=8 × 10 -4). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p=9 × 10 -4). Conclusions: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.

Original languageEnglish (US)
Pages (from-to)878-882
Number of pages5
JournalNeurology
Volume79
Issue number9
DOIs
StatePublished - Aug 28 2012
Externally publishedYes

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Motor Neuron Disease
Spinal Muscular Atrophy
Amyotrophic Lateral Sclerosis
Dementia
Parkinson Disease
Neuron
Repeats
Survival
Genetic Testing
Age of Onset
Netherlands

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Van Rheenen, W., Van Blitterswijk, M., Huisman, M. H. B., Vlam, L., Van Doormaal, P. T. C., Seelen, M., ... Van Den Berg, L. H. (2012). Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases. Neurology, 79(9), 878-882. https://doi.org/10.1212/WNL.0b013e3182661d14

Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases. / Van Rheenen, Wouter; Van Blitterswijk, Marka; Huisman, Mark H B; Vlam, Lotte; Van Doormaal, Perry T C; Seelen, Meinie; Medic, Jelena; Dooijes, Dennis; De Visser, Marianne; Van Der Kooi, Anneke J.; Raaphorst, Joost; Schelhaas, Helenius J.; Van Der Pol, W. Ludo; Veldink, Jan H.; Van Den Berg, Leonard H.

In: Neurology, Vol. 79, No. 9, 28.08.2012, p. 878-882.

Research output: Contribution to journalArticle

Van Rheenen, W, Van Blitterswijk, M, Huisman, MHB, Vlam, L, Van Doormaal, PTC, Seelen, M, Medic, J, Dooijes, D, De Visser, M, Van Der Kooi, AJ, Raaphorst, J, Schelhaas, HJ, Van Der Pol, WL, Veldink, JH & Van Den Berg, LH 2012, 'Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases', Neurology, vol. 79, no. 9, pp. 878-882. https://doi.org/10.1212/WNL.0b013e3182661d14
Van Rheenen, Wouter ; Van Blitterswijk, Marka ; Huisman, Mark H B ; Vlam, Lotte ; Van Doormaal, Perry T C ; Seelen, Meinie ; Medic, Jelena ; Dooijes, Dennis ; De Visser, Marianne ; Van Der Kooi, Anneke J. ; Raaphorst, Joost ; Schelhaas, Helenius J. ; Van Der Pol, W. Ludo ; Veldink, Jan H. ; Van Den Berg, Leonard H. / Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases. In: Neurology. 2012 ; Vol. 79, No. 9. pp. 878-882.
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abstract = "Objective: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Methods: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. Results: The expanded repeat was found in 33 (37{\%}) of all patients with fALS, in 87 (6.1{\%}) patients with sALS, in 4 (1.6{\%}) patients with PMA, and in 1 (0.9{\%}) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10 -5) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p=8 × 10 -4). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p=9 × 10 -4). Conclusions: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.",
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AU - Van Rheenen, Wouter

AU - Van Blitterswijk, Marka

AU - Huisman, Mark H B

AU - Vlam, Lotte

AU - Van Doormaal, Perry T C

AU - Seelen, Meinie

AU - Medic, Jelena

AU - Dooijes, Dennis

AU - De Visser, Marianne

AU - Van Der Kooi, Anneke J.

AU - Raaphorst, Joost

AU - Schelhaas, Helenius J.

AU - Van Der Pol, W. Ludo

AU - Veldink, Jan H.

AU - Van Den Berg, Leonard H.

PY - 2012/8/28

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N2 - Objective: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Methods: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. Results: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10 -5) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p=8 × 10 -4). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p=9 × 10 -4). Conclusions: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.

AB - Objective: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). Methods: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. Results: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10 -5) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p=8 × 10 -4). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p=9 × 10 -4). Conclusions: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.

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