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.
authors.affiliation: Department of Neurological Sciences, Dino Ferrari Centre, University of Milan, I.R.C.C.S. Foundation Ca' Granda, Ospedale Maggiore Policlinico, Padiglione Ponti, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Govoni
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: D'Angelo
authors.forename: Roberto
authors.initials: R
authors.lastname: Del Bo
authors.forename: Serena
authors.initials: S
authors.lastname: Ghezzi
authors.forename: Gandossini
authors.initials: G
authors.lastname: Sandra
authors.forename: Anna Carla
authors.initials: AC
authors.lastname: Turconi
authors.forename: Monica
authors.initials: M
authors.lastname: Sciacco
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ciscato
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Silvana
authors.initials: S
authors.lastname: Tedeschi
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucchini
authors.forename: Sara
authors.initials: S
authors.lastname: Bonato
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Domenico
authors.initials: D
authors.lastname: Coviello
authors.forename: Yvan
authors.initials: Y
authors.lastname: Torrente
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo Pietro
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D015897:Comorbidity / Q000639:trends; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D056726:Genetic Association Studies / Q000379:methods; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D009224:Myotonia Congenita / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D012189:Retrospective Studies; D055815:Young Adult