Absence of correlation between skewed X inactivation in blood and serum creatine‐kinase levels in Duchenne/Becker female carriers

Sumita, Denilce R.; Vainzof, Mariz; Campiotto, S; Cerqueira, A. H.; Cánovas, Manuel Fernández; Otto, Paulo Alberto; Passos‐Bueno, Maria Rita; Zatz, Mayana

doi:10.1002/(sici)1096-8628(19981204)80:4<356::aid-ajmg10>3.3.co;2-f

Cited by 16 publications

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“…In the two largest reported series of DMD carriers, the proportion of manifesting carriers varied from 5 to 22% and the pediatric cases remained rare. 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.…”

Section: Discussionsupporting

confidence: 79%

“…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: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…In other Xlinked recessive disorders, differences between clinical phenotypes of female carriers and the X-inactivation ratios in peripheral blood were found. Sumita et al [20] reported that no significant correlation was found between the X-inactivation ratio in blood and serum CK activity in Duchenne/Becker muscular dystrophy carriers. Orstavik et al [21] reported that the wide range in plasma concentration of factor VIII and IX in haemophilia A and B carriers could not be explained by the X chromosome inactivation patterns in peripheral blood cells.…”

Section: Discussionmentioning

confidence: 99%

Correlation between Clinical Phenotypes and X-inactivation Patterns in Six Female Carriers with Heterozygote Vasopressin Type 2 Receptor Gene Mutations

2008

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Abstract. About 90% of patients with congenital nephrogenic diabetes insipidus (NDI) have vasopressin type 2 receptor (V2R) gene mutations that are inherited in an X-linked recessive manner. Although most female carriers are asymptomatic, some female carriers show polydipsia and polyuria. The reason why female carriers show NDI symptoms is explained by skewed X-inactivation. We studied X-inactivation patterns of six female carriers with heterozygote V2R gene mutations. The X-inactivation pattern in peripheral blood leukocytes was examined using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene. Two asymptomatic female carriers showed random Xinactivation (61.9% and 60.7%). Skewed X-inactivation patterns (71.6%, 79.4%, and 91.2%) occurring preferentially to normal X alleles were recognized in three female carriers who showed clinical NDI symptoms. However, in one female carrier who showed clinical NDI symptoms, random X-inactivation (55.4%) was recognized. In conclusion, the clinical NDI phenotypes may correlate with the X-inactivation patterns in female carriers with heterozygote V2R gene mutations. However, in some female carriers, we cannot predict the clinical phenotypes by the evaluation of the X-inactivation patterns in peripheral blood leukocytes, because X-inactivation ratios within an individual are sometimes different between tissues.

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confidence: 98%

“…In contrast, another study comprising 107 MD carriers clearly suggested that a highly skewed X-chromosome pattern in blood is not enough to predict the phenotypic development of muscular weakness in MD carriers. 4 Hence, we think that not performing this analysis in the reported patients was justified.Classifying cardiomyopathy on the basis of ejection fraction may only underestimate the extent of disease that is most evident in patients with hypertrophic cardiomyopathy. In our opinion, both mother and child have advanced cardiomyopathy because late gadolinium enhancement (LGE) cardiovascular MRI already revealed significant myocardial tissue damage (LGE in the child, 12.0%; in the mother, 17.6% of left ventricular mass).…”

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confidence: 99%

Response to Letter Regarding Article, “Cardiomyopathy in a Duchenne Muscular Dystrophy Carrier and Her Diseased Son: Similar Pattern Revealed by Cardiovascular MRI”

et al. 2010

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We appreciated the interest of Drs Giglio and Mangiola in our muscular dystrophy (MD) case report. 1 We agree with the suggestion of White et al 2 that for clinical diagnosis, duplications in the dystrophin gene should be treated with special care. Indeed, multiplex ligation-dependent probe amplification was performed in both the child with Duchenne muscular dystrophy (DMD) and his mother, proving the diagnosis. We also mentioned in our article that serum creatine kinase levels were elevated in the DMD carrier mother. However, we do not agree with Drs Giglio and Mangiola's opinion that "skewed X-chromosome inactivation assay must be performed because this factor is currently believed to be a main contributor to phenotypic manifestations in a Duchenne carrier." We do not consider the work of Yoshioka et al 3 to be compelling evidence because this study was based on only 9 MD carriers. In contrast, another study comprising 107 MD carriers clearly suggested that a highly skewed X-chromosome pattern in blood is not enough to predict the phenotypic development of muscular weakness in MD carriers. 4 Hence, we think that not performing this analysis in the reported patients was justified.Classifying cardiomyopathy on the basis of ejection fraction may only underestimate the extent of disease that is most evident in patients with hypertrophic cardiomyopathy. In our opinion, both mother and child have advanced cardiomyopathy because late gadolinium enhancement (LGE) cardiovascular MRI already revealed significant myocardial tissue damage (LGE in the child, 12.0%; in the mother, 17.6% of left ventricular mass). These areas of LGE were previously shown to represent the critical substrate for malignant arrhythmias in patients with nonischemic cardiomyopathy. 5 Future studies have to evaluate whether measurement of LGE might even be superior to the measurement of left ventricular ejection fraction relative to accurate risk prediction in MD patients and carriers.When preparing Figure 3 in our article, we intentionally chose images of a patient with Becker MD because, as outlined by Drs Giglio and Mangiola, dystrophin immunostaining of this subject showed a mosaic pattern (feature of DMD carrier and/or a patient with Becker MD) and the absence of dystrophin in most cardiomyocytes (feature of a patient with DMD). We think that this patient nicely illustrates the features present in both the DMD child and his carrier mother.Regarding the frequency and clinical value of LGE and its association with the severity of cardiomyopathy in MD carriers, we are currently preparing a manuscript that will emphasize the clinical value of our observation in this case report and further explore the questions raised by Drs Giglio and Mangiola about this interesting issue. Source of FundingThis work was financially supported by a grant from the German Heart Foundation (Deutsche Stiftung für Herzforschung, grant-ID F/15/07 to Dr Yilmaz). DisclosuresNone. Ali

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Absence of correlation between skewed X inactivation in blood and serum creatine‐kinase levels in Duchenne/Becker female carriers

Cited by 16 publications

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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

Correlation between Clinical Phenotypes and X-inactivation Patterns in Six Female Carriers with Heterozygote Vasopressin Type 2 Receptor Gene Mutations

Response to Letter Regarding Article, “Cardiomyopathy in a Duchenne Muscular Dystrophy Carrier and Her Diseased Son: Similar Pattern Revealed by Cardiovascular MRI”

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