Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up

Research output: Contribution to journalArticle

Abstract

Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders with different clinical presentations and severity determined by mutations in the gene DMD, which encodes the sarcolemmal protein dystrophin. Diagnosis is based on clinical aspects and muscle protein analysis, followed by molecular confirmation. We revised the main aspects of the natural history of dystrophinopathies to define genotype-phenotype correlations in large patient cohorts with extended follow-up. We also specifically explored subjects carrying nucleotide substitutions in the DMD gene, a comparatively less investigated DMD/BMD subgroup. We studied 320 dystrophinopathic patients (205 DMD and 115 BMD), defining muscular, cardiac, respiratory, and cognitive involvement. We also subdivided patients according to the kind of molecular defect (deletions, duplications, nucleotide substitutions or other microrearrangements) and the mutation sites (proximal/distal to exon 45), studying phenotype-genotype correlations for each group. In DMD, mutation type did not influence clinical evolution; mutations located in distal regions (irrespective of their nature) are more likely to be associated with lower IQ levels (p = 0.005). BMD carrying proximal deletions showed a higher degree of cardiac impairment than BMD with distal deletions (p = 0.0046). In the BMD population, there was a strong correlation between the entity of muscle dystrophin deficiency and clinical course (p = 0.002). An accurate knowledge of natural history may help in the clinical management of patients. Furthermore, several clinical trials are ongoing or are currently planned, some of which aim to target specific DMD mutations: a robust natural history is therefore essential to correctly design these experimental trials.

Original languageEnglish
Pages (from-to)1610-1623
Number of pages14
JournalJournal of Neurology
Volume258
Issue number9
DOIs
Publication statusPublished - Sep 2011

Fingerprint

Genotype
Phenotype
Mutation
Natural History
Dystrophin
Genetic Association Studies
Nucleotides
Duchenne Muscular Dystrophy
Muscle Proteins
Genes
Exons
Research Design
Clinical Trials
Muscles
Population
Proteins

Keywords

  • Becker muscular dystrophy
  • Cardiac involvement in DMD and BMD
  • Duchenne muscular dystrophy
  • Dystrophin gene sequencing
  • Protein analysis
  • Respiratory involvement in DMD and BMD

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

@article{86cccd2133b244ea9b83a6389bf2c0aa,
title = "Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up",
abstract = "Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders with different clinical presentations and severity determined by mutations in the gene DMD, which encodes the sarcolemmal protein dystrophin. Diagnosis is based on clinical aspects and muscle protein analysis, followed by molecular confirmation. We revised the main aspects of the natural history of dystrophinopathies to define genotype-phenotype correlations in large patient cohorts with extended follow-up. We also specifically explored subjects carrying nucleotide substitutions in the DMD gene, a comparatively less investigated DMD/BMD subgroup. We studied 320 dystrophinopathic patients (205 DMD and 115 BMD), defining muscular, cardiac, respiratory, and cognitive involvement. We also subdivided patients according to the kind of molecular defect (deletions, duplications, nucleotide substitutions or other microrearrangements) and the mutation sites (proximal/distal to exon 45), studying phenotype-genotype correlations for each group. In DMD, mutation type did not influence clinical evolution; mutations located in distal regions (irrespective of their nature) are more likely to be associated with lower IQ levels (p = 0.005). BMD carrying proximal deletions showed a higher degree of cardiac impairment than BMD with distal deletions (p = 0.0046). In the BMD population, there was a strong correlation between the entity of muscle dystrophin deficiency and clinical course (p = 0.002). An accurate knowledge of natural history may help in the clinical management of patients. Furthermore, several clinical trials are ongoing or are currently planned, some of which aim to target specific DMD mutations: a robust natural history is therefore essential to correctly design these experimental trials.",
keywords = "Becker muscular dystrophy, Cardiac involvement in DMD and BMD, Duchenne muscular dystrophy, Dystrophin gene sequencing, Protein analysis, Respiratory involvement in DMD and BMD",
author = "Francesca Magri and Alessandra Govoni and D'Angelo, {Maria Grazia} and {Del Bo}, Roberto and Serena Ghezzi and Gandossini Sandra and Turconi, {Anna Carla} and Monica Sciacco and Patrizia Ciscato and Andreina Bordoni and Silvana Tedeschi and Francesco Fortunato and Valeria Lucchini and Sara Bonato and Costanza Lamperti and Domenico Coviello and Yvan Torrente and Stefania Corti and Maurizio Moggio and Nereo Bresolin and Comi, {Giacomo Pietro}",
year = "2011",
month = "9",
doi = "10.1007/s00415-011-5979-z",
language = "English",
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pages = "1610--1623",
journal = "Journal of Neurology",
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T1 - Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up

AU - Magri, Francesca

AU - Govoni, Alessandra

AU - D'Angelo, Maria Grazia

AU - Del Bo, Roberto

AU - Ghezzi, Serena

AU - Sandra, Gandossini

AU - Turconi, Anna Carla

AU - Sciacco, Monica

AU - Ciscato, Patrizia

AU - Bordoni, Andreina

AU - Tedeschi, Silvana

AU - Fortunato, Francesco

AU - Lucchini, Valeria

AU - Bonato, Sara

AU - Lamperti, Costanza

AU - Coviello, Domenico

AU - Torrente, Yvan

AU - Corti, Stefania

AU - Moggio, Maurizio

AU - Bresolin, Nereo

AU - Comi, Giacomo Pietro

PY - 2011/9

Y1 - 2011/9

N2 - Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders with different clinical presentations and severity determined by mutations in the gene DMD, which encodes the sarcolemmal protein dystrophin. Diagnosis is based on clinical aspects and muscle protein analysis, followed by molecular confirmation. We revised the main aspects of the natural history of dystrophinopathies to define genotype-phenotype correlations in large patient cohorts with extended follow-up. We also specifically explored subjects carrying nucleotide substitutions in the DMD gene, a comparatively less investigated DMD/BMD subgroup. We studied 320 dystrophinopathic patients (205 DMD and 115 BMD), defining muscular, cardiac, respiratory, and cognitive involvement. We also subdivided patients according to the kind of molecular defect (deletions, duplications, nucleotide substitutions or other microrearrangements) and the mutation sites (proximal/distal to exon 45), studying phenotype-genotype correlations for each group. In DMD, mutation type did not influence clinical evolution; mutations located in distal regions (irrespective of their nature) are more likely to be associated with lower IQ levels (p = 0.005). BMD carrying proximal deletions showed a higher degree of cardiac impairment than BMD with distal deletions (p = 0.0046). In the BMD population, there was a strong correlation between the entity of muscle dystrophin deficiency and clinical course (p = 0.002). An accurate knowledge of natural history may help in the clinical management of patients. Furthermore, several clinical trials are ongoing or are currently planned, some of which aim to target specific DMD mutations: a robust natural history is therefore essential to correctly design these experimental trials.

AB - Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders with different clinical presentations and severity determined by mutations in the gene DMD, which encodes the sarcolemmal protein dystrophin. Diagnosis is based on clinical aspects and muscle protein analysis, followed by molecular confirmation. We revised the main aspects of the natural history of dystrophinopathies to define genotype-phenotype correlations in large patient cohorts with extended follow-up. We also specifically explored subjects carrying nucleotide substitutions in the DMD gene, a comparatively less investigated DMD/BMD subgroup. We studied 320 dystrophinopathic patients (205 DMD and 115 BMD), defining muscular, cardiac, respiratory, and cognitive involvement. We also subdivided patients according to the kind of molecular defect (deletions, duplications, nucleotide substitutions or other microrearrangements) and the mutation sites (proximal/distal to exon 45), studying phenotype-genotype correlations for each group. In DMD, mutation type did not influence clinical evolution; mutations located in distal regions (irrespective of their nature) are more likely to be associated with lower IQ levels (p = 0.005). BMD carrying proximal deletions showed a higher degree of cardiac impairment than BMD with distal deletions (p = 0.0046). In the BMD population, there was a strong correlation between the entity of muscle dystrophin deficiency and clinical course (p = 0.002). An accurate knowledge of natural history may help in the clinical management of patients. Furthermore, several clinical trials are ongoing or are currently planned, some of which aim to target specific DMD mutations: a robust natural history is therefore essential to correctly design these experimental trials.

KW - Becker muscular dystrophy

KW - Cardiac involvement in DMD and BMD

KW - Duchenne muscular dystrophy

KW - Dystrophin gene sequencing

KW - Protein analysis

KW - Respiratory involvement in DMD and BMD

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