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Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort.
Cumming, Sarah A; Jimenez-Moreno, Cecilia; Okkersen, Kees; Wenninger, Stephan; Daidj, Ferroudja; Hogarth, Fiona; Littleford, Roberta; Gorman, Gráinne; Bassez, Guillaume; Schoser, Benedikt; Lochmüller, Hanns; van Engelen, Baziel G M; Monckton, Darren G.
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  • Cumming SA; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Jimenez-Moreno C; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Okkersen K; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Wenninger S; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Daidj F; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Hogarth F; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Littleford R; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Gorman G; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Bassez G; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Schoser B; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Lochmüller H; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • van Engelen BGM; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
  • Monckton DG; From the Institute of Molecular, Cell and Systems Biology (S.A.C., D.G.M.), University of Glasgow; Institute of Genetic Medicine (C.J.-M., H.L.) and Institute of Neurosciences (G.G.), Newcastle University, Newcastle upon Tyne, UK; Department of Neurology (K.O., B.G.M.v.E.), Donders Institute for Bra
Neurology ; 93(10): e995-e1009, 2019 09 03.
Article en En | MEDLINE | ID: mdl-31395669
ABSTRACT

OBJECTIVE:

To evaluate the role of genetic variation at the DMPK locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial.

METHODS:

We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats.

RESULTS:

We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed t test t = -3.7, p = 0.0019).

CONCLUSIONS:

Careful characterization of the DMPK CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Calidad de Vida / Índice de Severidad de la Enfermedad / Proteína Quinasa de Distrofia Miotónica / Distrofia Miotónica Tipo de estudio: Clinical_trials / Diagnostic_studies / Etiology_studies / Guideline / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Aspecto: Patient_preference Límite: Adult / Female / Humans / Male Idioma: En Revista: Neurology Año: 2019 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Calidad de Vida / Índice de Severidad de la Enfermedad / Proteína Quinasa de Distrofia Miotónica / Distrofia Miotónica Tipo de estudio: Clinical_trials / Diagnostic_studies / Etiology_studies / Guideline / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Aspecto: Patient_preference Límite: Adult / Female / Humans / Male Idioma: En Revista: Neurology Año: 2019 Tipo del documento: Article