Symptomatic dystrophinopathies in female children

Seemann, Natashia M.; Selby, Kathy; McAdam, Laura; Biggar, Doug; Kolski, Hanna; Goobie, Sharan; Yoon, Grace; Campbell, Craig

doi:10.1016/j.nmd.2010.11.001

Cited by 33 publications

(26 citation statements)

References 29 publications

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“…15,[28][29][30] In our study, we found that 7 out of our 26 female carriers had cognitive impairment, 2 with intellectual disability and 5 with learning disabilities thus highlighting the high rate (27%) of cognitive impairment in manifesting carriers. The prevalence of intellectual disability is estimated at B2-3% in the general population and males are more often affected than females.…”

Section: Discussionmentioning

confidence: 85%

“…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%

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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: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…Based on this evidence, skewed X-inactivation has classically been considered as the mechanism most likely to explain the dystrophic phenotype in female carriers, and this hypothesis has been lent weight by various X-inactivation studies performed on DNA from peripheral blood lymphocytes [15,16]. Nevertheless, other studies based on X-inactivation tests, performed on either peripheral blood [17-20] or muscle tissue [21], have highlighted the absence of a clear correlation between X-inactivation pattern and phenotype, reporting manifesting carriers with both skewed and completely random X-inactivation.…”

Section: Introductionmentioning

confidence: 99%

Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype

et al. 2012

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BackgroundAlthough Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial.MethodsEighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative DMD gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females.ResultsThe study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers.ConclusionsThis is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total DMD transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype.

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“…These include X-autosomal translocations disrupting the DMD gene [13], mutations on both DMD alleles [10,14] and co-occurrence of DMD mutations together with other genetic abnormalities such as X-chromosome monosomy [15-17], X-chromosome uniparental disomy [18] as well as male pseudohermaphroditism caused by a mutation in the androgen receptor gene [19]. However, the most frequently reported mechanism to provoke symptoms in DMD carriers is skewed X-inactivation, favouring the expression of the X chromosome with the DMD mutated allele [8,20-22]. Although some studies suggest the use of X-inactivation analysis for prognostic purposes, the results of different reports are controversial [21,23,24].…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

Juan-Mateu

Rodríguez

Nascimento

et al. 2012

Orphanet J Rare Dis

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BackgroundBetween 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy.MethodsWe reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females.ResultsSymptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found.ConclusionsSkewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.

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Symptomatic dystrophinopathies in female children

Cited by 33 publications

References 29 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

Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype

Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

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