X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes

Azofeifa, Jorge; Voït, Thomas; Hübner, Christoph; Cremer, Marion

doi:10.1007/bf00207374

Cited by 72 publications

(75 citation statements)

References 37 publications

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“…4,20 In our patients, like in the other pediatric series, hyperCKemia was constant. [27][28][29][30] Muscle weakness was also prevalent and found in 88% of cases. Exercise intolerance was the first symptom in 27% and remained the only muscular symptom during childhood in three cases, including one case with acute rhabdomyolysis episodes mimicking a metabolic myopathy.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…To our knowledge, several different genetic abnormalities have been documented for female DMD and the milder allelic form Becker muscular Dystrophy (BMD): (1) an X-autosome reciprocal translocation and a preferential inactivation of the normal X-chromosome (Verellen-Dumoulin et al 1984); (2) in a classical 45, X0 karyotype of Turner syndrome, simultaneously, the only X-chromosome with a dystrophin mutation (Chelly et al 1986); (3) skewed X inactivation in the normal X-chromosome of the female DMD mutation carriers. (Azofeifa et al 1995); (4) uniparental disomy of female with DMD mutation in both X-chromosome (Quan et al 1997); (5) co-occurrence of mutations in both dystrophin and androgen-receptor genes in the patient (Katayama et al 2006); and (6) girl with homozygous dystrophin mutation caused by consanguinity, whose parents have the same mutations in the DMD gene (Fujii et al 2009). While our patient is similar to the case of Turner syndrome with the dystrophin gene mutation in the remaining X chromosome as originally reported (Chelly et al 1986), the karyotype of our patient is unique.…”

Section: Discussionmentioning

confidence: 99%

Duchenne Muscular Dystrophy in a Female Patient with a Karyotype of 46,X,i(X)(q10)

et al. 2010

Tohoku J. Exp. Med.

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Duchenne muscular dystrophy (DMD) is a severe recessive X-linked form of muscular dystrophy caused by mutations in the dystrophin gene and it affects males predominantly. Here we report a 4-year-old girl with DMD from a healthy family, in which her parents and sister have no DMD genotype. A PCR-based method of multiple ligation-dependent probe amplification (MLPA) analysis showed the deletion of exons 46 and 47 in the dystrophin gene, which led to loss of dystrophin function. No obvious phenotype of Turner syndrome was observed in this patient and cytogenetic analysis revealed that her karyotype is 46,X,i(X)(q10). In conclusion, we describe the first female patient with DMD who carries a de novo mutation of the dystrophin gene in one chromosome and isochromosome Xq, i(Xq), in another chromosome.

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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: 93%

“…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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X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes

Cited by 72 publications

References 37 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

Duchenne Muscular Dystrophy in a Female Patient with a Karyotype of 46,X,i(X)(q10)

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

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