Carriers Of Duchenne Muscular Dystrophy Research Articles

Myocardial Fibrosis and Left Ventricular Dysfunction in Duchenne Muscular Dystrophy Carriers Using Cardiac Magnetic Resonance Imaging.

The goal of our study was to characterize the degree of myocardial fibrosis and left ventricular dysfunction in our cohort of Duchenne muscular dystrophy (DMD) carriers using cardiac magnetic resonance imaging (CMR). Seventy percent of males with DMD have mothers who are carriers of the Xp21 mutation. Carrier phenotypic characteristics range from asymptomatic to left ventricular (LV) dysfunction and cardiomyopathy. The true prevalence of cardiac involvement in DMD carriers is unknown. We performed a retrospective observational study. All female DMD carriers who underwent clinical CMR studies at Cincinnati Children's Hospital Medical Center from December 6, 2006, to August 28, 2013, were evaluated. Patients underwent standard CMR assessment with LV function assessment and late gadolinium enhancement (LGE). In addition, offline feature tracking strain analysis was performed on the basal, mid, and apical short axis. Twenty-two patients were studied, of which 20 underwent adequate testing for myocardial LGE. Four of 22 patients (18 %) were found to have LV dysfunction (ejection fraction <55 %). Seven of 20 DMD carriers (35 %) were found to have LGE. The patients with evidence of LGE had an overall trend to lower absolute deformation parameters; however, this did not meet statistical significance when correcting for multiple comparisons. Our study demonstrates a high rate of LGE as well as LV dysfunction in DMD carriers. Cardiovascular and musculoskeletal symptoms were not statistically different between those with and without cardiac involvement. This study demonstrates the importance of surveillance CMR evaluation of DMD carriers.

Cardiac pathologies in female carriers of Duchenne muscular dystrophy assessed by cardiovascular magnetic resonance imaging.

Duchenne muscular dystrophy (DMD) is the most common and severe dystrophinopathy. DMD carriers rarely present with clinical symptoms, but may suffer from cardiac involvement. Because echocardiographic findings are inconsistent and cardiac magnetic resonance imaging (CMRI) data are limited, this study sought to investigate asymptomatic carriers for cardiac abnormalities using CMRI. Fifteen genetically confirmed DMD carriers (age, 32.3 ± 10.2 years) were prospectively examined on a 1.5T MR system. Cine, T2, and late-gadolinium-enhanced (LGE) images were acquired, and were evaluated in consensus by two experienced readers. Left ventricular (LV) parameters were analysed semiautomatically, normalized to BSA. Normalized LV end-diastolic volume was increased in 7% (73.7 ± 16.8 ml/m(2); range, 48-116 ml/m(2)) and normalized LV end-systolic volume in 20% (31.5 ± 13.3 ml/m(2); range, 15-74 ml/m(2)). EF was reduced in 33% (58.4 ± 7.6%; range, 37-69%) and normalized LV myocardial mass in 80% (40.5 ± 6.8 g/m(2); range, 31-55 g/m(2)). In 80%, regional myocardial thinning was detected in more than one segment. In 13% and 40%, apical-lateral accentuation of LV non-compaction was present. LGE was found in 60% (midmyocardial inferolateral accentuation). Given the high frequency of cardiac pathologies detected by CMRI, regular cardiac risk assessment is advisable for DMD carriers. Besides clinical examination, CMRI is an excellent tool for this purpose. • Fifteen Duchenne muscular dystrophy carriers investigated using CMRI all showed cardiac pathologies. • Myocardial mass reduction, regional myocardial thinning, and late gadolinium enhancement were common. • Regular cardiac risk assessment is thus advisable in Duchenne muscular dystrophy carriers. • Besides clinical examination, CMRI is an excellent tool for this purpose.

Differences in cardiac involvement between carriers of Duchenne and Becker muscular dystrophy - a cardiovascular magnetic resonance study

Background Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Although BMD patients present milder skeletal muscle involvement, they have been shown to present more advanced cardiomyopathy than DMD. Female DMD/BMD carriers are usually free of skeletal muscle symptoms but they may also develop cardiomyopathy. The present study aimed at characterizing the presence and pattern of cardiac abnormalities in a group of genetically-proven MD-carriers by means of comprehensive CMR studies. Moreover, we wanted to test whether DMD carriers (DMDc) and BMD carriers (BMDc) are differently affected.

G.P.180: Evaluation of cardiologic status in carriers of Duchenne Muscular Dystrophy

With an incidence of 1:5000 male newborns, Duchenne muscular Dystrophy (DMD) is the most common hereditary muscular disorder. Cardiac involvement (e.g. dilated cardiomyopathy) is well known in DMD patients. Since described as an X-linked recessive disorder, women can be identified as carriers for DMD. Our objective was to characterize cardiac findings in a defined group of genetically confirmed DMD carriers. Monocentric, prospective, non-randomized, cross-sectional study, <i>n</i>=16 aged 15–54years. The women had a physical examination for anthropometric data (BP, BMI, etc.) and MRC testing for muscular strength. Cardiologic examination included NYHA classification, 6MWT, 12 lead ECG, Holter ECG, echocardiography and cardiac MRI (function, late gadolinium enhancement (LGE)). Results: 8/10 women showed walking distances below average in 6MWT despite NYHA Class I in all cases and 5/5 points in MRC testing. 12/16 women showed negative ST-segments in right precordial leads, polymorphic premature supra-/ ventricular beats (12 lead and Holter ECG). Echocardiography was suspicious in 18, 8% with reduced shortening fraction or regurgitation in mitral/tricuspid valve. Cardiac MRI showed LGE in 56%, 73% had normalized LV endsystolic volume above average, 20% LV enddiastolic volume below average, and reduced EF in 33%. The left ventricular mass was reduced in all women. <i>Conclusion</i>: Despite the lack of clinical problems and only minor abnormal findings in physical evaluation, all DMD carriers show pathologies in either ECG, echo or cardiac MRI (or all of the above). Findings need further evaluation and are not related to age; therefore we suggest cardiac exams (incl.cardiac MRI+LGE) once per year starting at the time of positive molecular analysis for DMD carrier status. Establishing a register for DMD carriers should be the next step towards further assessment of data and better maintenance or prospects for therapy.

A Carrier of Duchenne Muscular Dystrophy in an 8-month-old Girl

Duchenne muscular dystrophy (DMD) is the most common and severe form of childhood muscular dystrophy. Females are affected in rare cases because of...

Patterns of late gadolinium enhancement in Duchenne muscular dystrophy carriers.

BackgroundThis study was designed to assess whether cardiovascular magnetic resonance imaging (CMR) in Duchenne muscular dystrophy carriers (DMDc) may index any cell milieu elements of LV dysfunction and whether this cardiac phenotype may be related to genotype. The null hypothesis was that myocardial fibrosis, assessed by late gadolinium enhancement (LGE), might be similarly accounted for in DMDc and gender and age-matched controls.MethodsThirty DMDc patients had CMR and genotyping with 37 gender and age-matched controls. Systolic and diastolic LV function was assessed by 2D-echocardiography.ResultsAbsolute and percent LGE were higher in muscular symptomatic (sym) than asymptomatic (asy) DMDc (1.77 ± 0.27 vs 0.76 ± 0.17 ml; F = 19.6, p < 0.0001 and 1.86 ± 0.26% vs 0.68 ± 0.17%, F = 22.1, p < 0.0001, respectively). There was no correlation between LGE and age. LGE was seen most frequently in segments 5 and 6; segment 5 was involved in all asy-DMDc. Subepicardial LGE predominated, compared to the mid-myocardial one (11 out of 14 DMDc). LGE was absent in the subendocardium. No correlations were seen between genotyping (type of mutation, gene region and protein domain), confined to the exon’s study, and cardiac phenotype.ConclusionsA typical myocardial LGE-pattern location (LV segments 5 and 6) was a common finding in DMDc. LGE was more frequently subepicardial plus midmyocardial in sym-DMDc, with normal LV systolic and diastolic function. No genotype-phenothype correlation was found.

Non-invasive fetal sex determination by maternal plasma sequencing and application in X-linked disorder counseling

Objective: To develop a fetal sex determination method based on maternal plasma sequencing (MPS), assess its performance and potential use in X-linked disorder counseling.Methods: 900 cases of MPS data from a previous study were reviewed, in which 100 and 800 cases were used as training and validation set, respectively. The percentage of uniquely mapped sequencing reads on Y chromosome was calculated and used to classify male and female cases. Eight pregnant women who are carriers of Duchenne muscular dystrophy (DMD) mutations were recruited, whose plasma were subjected to multiplex sequencing and fetal sex determination analysis.Results: In the training set, a sensitivity of 96% and false positive rate of 0% for male cases detection were reached in our method. The blinded validation results showed 421 in 423 male cases and 374 in 377 female cases were successfully identified, revealing sensitivity and specificity of 99.53% and 99.20% for fetal sex determination, at as early as 12 gestational weeks. Fetal sex for all eight DMD genetic counseling cases were correctly identified, which were confirmed by amniocentesis.Conclusions: Based on MPS, high accuracy of non-invasive fetal sex determination can be achieved. This method can potentially be used for prenatal genetic counseling.

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

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.

Assessment of a symptomatic Duchenne muscular dystrophy carrier 20years after myoblast transplantation from her asymptomatic identical twin sister

Because it is due to a mutation on the X-chromosome, Duchenne muscular dystrophy rarely affects women, unless there is an unequal lyonisation of the X-chromosome containing the normal dystrophin gene. We report here the unique situation of a symptomatic Duchenne muscular dystrophy woman who was transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago. Specific dynamometry was performed to possibly detect a long-term effect of this cell therapy. Long-term safety of myoblast transplantation was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects.

Development of a comprehensive real-time PCR assay for dystrophin gene analysis and prenatal diagnosis of Chinese families

BackgroundTo develop a comprehensive method to analyze deletions or duplications of the dystrophin gene in both patients and carriers of Duchenne muscular dystrophy (DMD), likewise applied to prenatal diagnosis. MethodsA total of thirty Chinese families were recruited, composed of 29 DMD affected males and 38 female relatives containing four pregnant women. Deletions were previously screened by multiplex PCR. A comprehensive real-time PCR assay using SYBR Green I dye was performed for the initial detection of duplications in patients with a seven-exon primer set, carrier detection for female relatives and prenatal diagnosis for the 4 of them. The results were later confirmed by multiple ligation-dependent probe amplification (MLPA) and linkage analysis. ResultsThree out of 4 duplications were first discovered by real-time PCR. Carrier status was ascertained in 22 and rejected in the remaining sixteen female relatives. Furthermore, 4 fetuses were diagnosed as two normal females, one normal male and one female carrier, respectively. ConclusionsOur real-time PCR assay is useful in duplication screen with a detection rate of >70%, as well as rapid and reliable in both carrier detection and prenatal diagnosis of DMD families with known deletions and duplications.

ON and OFF Electroretinography and Contrast Sensitivity in Duchenne Muscular Dystrophy

The study investigated possible asymmetric dysfunction of the ON and OFF visual mechanisms in DMD (Duchenne muscular dystrophy) patients associated with specific genetic alterations. nineteen DMD patients and 7 heterozygous dmd carriers were tested, as well as 19 age-matched controls.Full-field ergs were recorded using mesopic (1 cd/m(2)) and photopic (250 cd/m(2)) sawtooth luminance modulations as stimuli: rapid increase and ramping decrease (to isolate ON responses) or rapid decrease and ramping increase (for OFF responses). In addition, a psychophysical study comprised contrast sensitivity tests using two checkerboard stimuli at either higher (ON) or lower (OFF) luminance relative to the background: 0.3 cycles per degree (cpd) presented for 33 ms (low spatial frequency, short duration) and 2 cpd presented for 1500 ms (high spatial frequency, long duration). A significant ERG amplitude reduction, relative to controls, was detected in the DMD patients in the mesopic positive peaks for both ON and OFF stimuli, as well as for the photopic ON stimulus (P < 0.05). Contrast sensitivity was significantly lower in the DMD patients (P < 0.05) relative to controls for the ON stimuli. Neither the ERG nor the contrast sensitivities were altered in the carriers. This study suggests that there are ON and OFF ERG alterations when both rods and cones contribute to the ERG responses in DMD patients. When only cones are activated there is an asymmetrical ERG alteration, also revealed by the contrast sensitivity measurements.

Muscle-specific discordant skewing of X-chromosome inactivation leads to different clinical phenotypes of Duchenne muscular dystrophy in two monozygotic female twins

Background: Mutations within the DMD gene leading to the absence or vast reduction of dystrophin cause Duchenne muscular dystrophy (DMD). The majority of female heterozygous carriers of X-linked recessive DMD mutations are asymptomatic or mildly affected due to the balanced X-inactivation. However, in rare cases of female DMD carriers skewed X-inactivation leads to clinical symptoms.

Progressive Respiratory Insufficiency in the Absence of Cardiac Disease in Late-Stage Duchenne Muscular Dystrophy

Not only the skeletal muscle but also the heart is frequently affected by the dystrophic process in Duchenne muscular dystrophy (DMD) patients[1][1] and DMD carriers.[2][2] Contrary to this paradigm, there are some reports showing absence of cardiac involvement in DMD, even in the late stages of the

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

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.

Peripartum Cardiomyopathy in a Previously Asymptomatic Carrier of Duchenne Muscular Dystrophy

A 40 year-old woman presented to hospital with 12h of progressive shortness of breath. She was 11 days postpartum, having delivered a full-term male infant. She was discharged on antibiotics for presumed pneumonia, but represented two days later with NYHA class IV symptoms and in acute decompensated heart failure confirmed on clinical examination and chest X-ray. Echocardiography showed a left ventricular ejection fraction (LVEF) of 20%. She was treated for peripartum cardiomyopathy (PPCM) with angiotensin converting enzyme inhibitors (ACEi), beta-blockers and diuretics with normalisation of her cardiac function within six months. Four years later, her son was diagnosed with Duchenne muscular dystrophy (DMD) and she tested positive as a carrier of the mutant gene. It is unclear whether the DMD carrier state alone is associated with increased susceptibility to PPCM or if this is merely the first expression of cardiomyopathy in a previously asymptomatic carrier.

Comparison of X‐chromosome inactivation in Duchenne muscle/myocardium‐manifesting carriers, non‐manifesting carriers and related daughters

Female carriers of Duchenne muscular dystrophy (DMD) are usually asymptomatic. However, 2.5-7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of dystrophin, probably because of skewed patterns of X-chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non-manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation-based assay. The results showed that DMD-manifesting carriers had a preferential inactivation of the X-chromosome carrying the normal allele, while non-manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother-daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers are associated with non-random patterns of X inactivation.

Camptocormia as a late presentation in a manifesting carrier of duchenne muscular dystrophy

Camptocormia, or bent spine syndrome, is an abnormal posture consisting of forward flexion of the spine that disappears when a patient is supine. It is associated with a wide variety of myopathic disorders that affect paraspinal muscles, including inflammatory and inherited myopathies. We describe a woman who presented with camptocormia in her eighth decade. Skeletal muscle biopsy showed mild nonspecific changes, but her family history was significant for a son who died of Duchenne muscular dystrophy (DMD). Genetic analysis of DMD confirmed that she was a heterozygous carrier of a mutation. In the absence of any alternate explanation, we interpret her symptoms to be a manifestation of her DMD carrier state. To our knowledge, this represents the first reported example of camptocormia as the presenting symptom in a carrier and suggests that a manifesting carrier state should be considered in the differential diagnosis for women with unexplained camptocormia.

MRI/MRS evaluation of a female carrier of Duchenne muscular dystrophy

The purpose of this study was to evaluate skeletal muscle composition of lower extremity muscles in a manifesting female carrier of Duchenne muscular dystrophy (MFC(DMD)) using magnetic resonance imaging (MRI) and spectroscopy (MRS). MRI/MRS was performed on the lower extremities and heart of a MFC(DMD) (47 years, 51 kg) on four occasions within 21 months and in a control subject. Heterogeneity and asymmetry among muscles in the MFC(DMD) was observed in lipid fraction and mean transverse relaxation time (T(2)) of lower extremity muscles with some muscles presenting as unaffected (e.g., rectus femoris) and others showing substantial deterioration and lipid infiltration (e.g., vasti muscles). There was an association of abnormal MRI findings and strength and motor function. Over the 21 months a small decrease in CSA(max) and increase in lipid fraction and T(2) was observed in the MFC(DMD) in some muscles. In summary, this MFC(DMD) revealed significant imaging evidence of pathologic heterogeneity among muscles. Furthermore, this study shows the feasibility of combining various quantitative MRI and MRS approaches to monitor skeletal muscle involvement.

Muscle MRI in female carriers of dystrophinopathy

Duchenne muscular dystrophy carriers represent a rare condition that needs to be recognized because of the possible implications for prenatal diagnosis. Muscle biopsy is currently the diagnostic instrument of choice in sporadic patients. We wanted to verify whether muscle magnetic resonance imaging (MRI) could identify a pattern of involvement suggestive of this condition and whether it was similar to that reported in Duchenne and Becker muscular dystrophy. Evaluation of pelvic and lower limb MRI scans of 12 dystrophinopathy carriers was performed. We found a frequent involvement of the quadratus femoris, gluteus maximus and medius, biceps femoris long head, adductor magnus, vasti and paraspinal muscles, whilst the popliteus, iliopsoas, recti abdominis, sartorius, and gracilis were relatively spared. Asymmetry was a major feature on MRI; it could be detected significantly more often than with sole clinical examination and even in patients without weakness. The pattern we describe here is similar to that reported in Duchenne and Becker muscular dystrophy, although asymmetry represents a major distinctive feature. Muscle MRI was more sensitive than clinical examination for detecting single muscle involvement and asymmetry. Further studies are needed to verify the consistency of this pattern in larger cohorts and to assess whether muscle MRI can improve diagnostic accuracy in carriers with normal dystrophin staining on muscle biopsy.

Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades?

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as 'cascade screening'. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer-held DMD register. Over the period, 1971-2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks.