Clinical and genetic characterization of manifesting carriers of DMD mutations

Soltanzadeh, Payam; Friez, Michael J.; Dunn, Diane M.; Niederhausern, Andrew von; Gurvich, Olga L.; Swoboda, Kathryn J.; Sampson, Jacinda B.; Pestronk, Alan; Connolly, Anne M.; Florence, Julaine; Finkel, Richard S.; Bönnemann, Carsten G.; Medne, Līvija; Mendell, Jerry R.; Mathews, Katherine D.; Wong, Brenda; Sussman, Michael D.; Zonana, Jonathan; Kovak, Karen; Gospe, Sídney M.; Gappmaier, Eduard; Taylor, Laura E.; Howard, Michael; Weiss, Robert B.; Flanigan, Kevin M.

doi:10.1016/j.nmd.2010.05.010

Cited by 137 publications

(139 citation statements)

References 24 publications

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“…In the two carriers with completely skewed XCI, the DMD mutations were inherited and there was no family history of XCI bias. Like Soltanzadeh et al 19 , we found a predominantly skewed XCI in deletions and duplications: the frequency was even higher in our series, 67% versus 57% in Soltanzadeh's series. On the opposite, we report skewed XCI in 50% of point mutations, whereas Soltanzadeh et al 19 did not find any bias in the six carriers of their study.…”

Section: Muscle Study and Protein Expression In The Musclesupporting

confidence: 75%

“…Like Soltanzadeh et al 19 , we found a predominantly skewed XCI in deletions and duplications: the frequency was even higher in our series, 67% versus 57% in Soltanzadeh's series. On the opposite, we report skewed XCI in 50% of point mutations, whereas Soltanzadeh et al 19 did not find any bias in the six carriers of their study. Using Fisher's test analysis, we did not observe a significant difference between rates of skewed XCI patterns in rearrangements and in point mutations (P ¼ 0.63).…”

Section: Muscle Study and Protein Expression In The Musclesupporting

confidence: 75%

“…18 However, whereas it is widely accepted that X-chromosome inactivation (XCI) has a role in the clinical variability in DMD carriers, XCI seems to be insufficient to predict the phenotypic status and degree of muscle weakness in young DMD carriers. 19,20 To better understand the mechanisms of this variability, we reviewed clinical, histological and genetic parameters including XCI pattern of 26 early pediatric symptomatic DMD carriers.…”

Section: Introductionmentioning

confidence: 99%

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Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age

et al. 2013

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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. European Journal of Human Genetics (2013) 21, 855-863; doi:10.1038/ejhg.2012.269; published online 9 January 2013 Keywords: dystrophin; female carrier; X inactivation INTRODUCTION Duchenne muscular dystrophy (DMD) has always been extensively described in its clinical presentation, evolution and severity. 1 However, recent studies pointed out that the same mutation can be responsible for DMD phenotypes of different severity suggesting involvement of modifier and/or epigenetic factors. 2,3 It has been estimated that about 8% of DMD female carriers have some manifestations including cardiomyopathy and/or some degree of weakness that could be highlighted by careful clinical examination. [4][5][6][7][8] Relationships between clinical phenotype and dystrophin abnormalities in muscle tissue among female carriers of DMD gene mutations were previously investigated. 9 However, a comprehensive view of factors underlying clinical symptoms occurrence and severity is still lacking.

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Section: Muscle Study and Protein Expression In The Musclesupporting

confidence: 75%

Section: Muscle Study and Protein Expression In The Musclesupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age

et al. 2013

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“…However, in cases with a skewed X-inactivation in the majority of the fibers (for example 80%) some muscle cells should have dystrophin-positive fibers. In these cases the results concerning the correlation between the patient phenotype and an Xinactivation pattern are controversial [7,8,22]. All the symptomatic females studied in our laboratory presented a skewed X-inactivation pattern (XIP), showing a relationship between the clinical phenotype and the pattern of X-inactivation.…”

Section: Accepted M Manuscriptmentioning

confidence: 92%

“…DMD and BMD usually affect males, with the majority of females being asymptomatic carriers. However, some of these females can reveal symptoms that vary from mild muscle weakness to a more severe clinical course and are classified as manifesting or symptomatic carriers [6,7,8,9,10]. Studies on muscle biopsy suggest that female dystrophinopathy patients show a skewed X inactivation, where the X chromosome that carries the normal dystrophin gene is preferentially inactivated [11,12].…”

Section: Introductionmentioning

confidence: 99%

Symptomatic female carriers of Duchenne muscular dystrophy (DMD): Genetic and clinical characterization

Giliberto

Radic

Luce

et al. 2014

Journal of the Neurological Sciences

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Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the dystrophin gene and is characterized by muscle degeneration and death. DMD affects males; females being asymptomatic carriers of mutations. However, some of them manifest symptoms due to a translocation between X chromosome and an autosome or to a heterozygous mutation leading to inactivation of most of their normal X chromosome. Six symptomatic female carriers and two asymptomatic were analyzed by: I) Segregation of STRs-(CA)n and MLPA assays to detect a hemizygous alteration, and II) X chromosome inactivation pattern to uncover the reason for symptoms in these females. The symptomatic females shared mild but progressive muscular weakness and increased serum creatin kinase (CK) levels. Levels of dystrophin protein were below normal or absent in many fibers. Segregation of STRs-(CA)n revealed hemizygous patterns in three patients, which were confirmed by MLPA. In addition, this analysis showed a duplication in another patient. X chromosome inactivation assay revealed a skewed X inactivation pattern in the symptomatic females and a random inactivation pattern in the asymptomatic ones. Our results support the hypothesis that the DMD phenotype in female carriers of a dystrophin mutation has a direct correlation with a skewed X-chromosome inactivation pattern.

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Interventions to prevent steroid-induced osteoporosis and osteoporotic fractures in Duchenne muscular dystrophy

Bell

Blackwood

Shields

et al. 2014

Cochrane Database of Systematic Reviews

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Clinical and genetic characterization of manifesting carriers of DMD mutations

Cited by 137 publications

References 24 publications

Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age

Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age

Symptomatic female carriers of Duchenne muscular dystrophy (DMD): Genetic and clinical characterization

Interventions to prevent steroid-induced osteoporosis and osteoporotic fractures in Duchenne muscular dystrophy

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