title: Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age.
abstract: The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still to be precised. We report 26 cases of early symptomatic DMD carriers followed in the French neuromuscular network. Clinical presentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patterns using DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) or exercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype. Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers are concerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining (81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27% had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifesting DMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMD carriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to the dystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated with mutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum of clinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed.
authors.affiliation: Department of Medical Genetics, CHU Nantes, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mercier
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Aurélie
authors.initials: A
authors.lastname: Toussaint
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.forename: Claire
authors.initials: C
authors.lastname: de Barace
authors.forename: Pascale
authors.initials: P
authors.lastname: Marcorelles
authors.forename: Laurent
authors.initials: L
authors.lastname: Pasquier
authors.forename: Martine
authors.initials: M
authors.lastname: Blayau
authors.forename: Caroline
authors.initials: C
authors.lastname: Espil
authors.forename: Philippe
authors.initials: P
authors.lastname: Parent
authors.forename: Hubert
authors.initials: H
authors.lastname: Journel
authors.forename: Leila
authors.initials: L
authors.lastname: Lazaro
authors.forename: Jon
authors.initials: J
authors.lastname: Andoni Urtizberea
authors.forename: Alexandre
authors.initials: A
authors.lastname: Moerman
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Kim
authors.initials: K
authors.lastname: Maincent
authors.forename: Romain
authors.initials: R
authors.lastname: Gherardi
authors.forename: Denys
authors.initials: D
authors.lastname: Chaigne
authors.forename: Rabah
authors.initials: R
authors.lastname: Ben Yaou
authors.forename: France
authors.initials: F
authors.lastname: Leturcq
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001706:Biopsy; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005602:France / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D049951:X Chromosome Inactivation; D055815:Young Adult
chemical_list: C484258:DMD protein, human; D016189:Dystrophin