History Of Duchenne Muscular Dystrophy Research Articles

Efficiency of CNV-seq in detecting fetal DMD gene deletion or duplication in prenatal diagnosis

Objective: To evaluate the diagnostic efficiency of copy number variation sequencing (CNV-seq) to detect the deletion or duplication of DMD gene in prenatal diagnosis. Methods: A retrospective analysis was carried out on the CNV-seq results of 34 544 fetuses diagnosed in the First People's Hospital of Yunnan Province from January 2018 to July 2023. A total of 156 cases of fetuses were collected, including Group 1:125 cases with family history of Duchenne muscular dystrophy or Becker muscular dystrophy (DMD/BMD), and Group 2:31 cases with no family history but a DMD gene deletion or duplication was detected unexpectedly by CNV-seq. Multiplex ligation-dependent probe amplification (MLPA) was used as a standard method to detect the deletion or duplication. Consistency test was carried out basing on the results of CNV-seq and MLPA of all 156 cases. Results: Comparing to MLPA, CNV-seq had a coincidence rate of 92.3% (144/156) for DMD gene deletion or duplication, with a sensitivity and positive predictive value of 88.2%, with a specificity and negative predictive value of 94.3%, a missed detection rate of 3.8%, and a Kappa value of 0.839. CNV-seq missed 4 cases with deletions and 2 with duplications due to involved fragments less than 100 Kb, among 20 cases of deletions and 6 cases of duplications detected by MLPA in Group 1. In Group 2, the deletions and duplications detected by CNV-seq were 42% (13/31) and 58% (18/31), respectively, in which the percentage of duplication was higher than that in Group 1. Among those 18 cases with duplications, 3 cases with duplication locating in exon 42~67 were likely pathogenic; while 9 cases with duplication covering the 5' or 3' end of the DMD gene, containing exon 1 or 79 and with only one breakpoint within the gene, along with the last 6 cases with duplications locating at chrX: 32650635_32910000 detected only by CNV-seq, which might be judged as variants of uncertain significance. Conclusions: CNV-seq has a good efficiency to detect fetal DMD gene deletion or duplication in prenatal diagnosis, while a further verification test by MLPA is recommended. The duplications on chrX: 32650635_32910000, 5' or 3' end of DMD gene detected by CNV-seq should be carefully verified and assessed because those variants appear to be nonpathogenic polymorphisms.

A female patient carrying a novel DMD mutation with non-random X-chromosome inactivation from a DMD family

ObjectiveTo analyze the clinical phenotype and genetic characteristics of a female proband carrying a novel mutation in the DMD gene with non-random X-chromosome inactivation in a large pedigree with pseudohypertrophic muscular dystrophy.MethodsClinical information of the female proband, her monozygotic twin sister, and other family members were collected. Potential pathogenic variants were detected with Multiplex Ligation-dependent Probe Amplification (MLPA) and whole-exome sequencing (WES). Methylation-sensitive restriction enzyme (HhaI) was employed for X-chromosome inactivation analysis.ResultsThe proband was a female over 5 years old, displayed clinical manifestations such as elevated creatine kinase (CK) levels and mild calf muscle hypertrophy. Her monozygotic twin sister exhibited normal CK levels and motor ability. Her uncle and cousin had a history of DMD. WES revealed that the proband carried a novel variant in the DMD (OMIM: 300,377) gene: NM_004006.3: c.3051_3053dup; NP_003997.2: p.Tyr1018*. In this pedigree, five out of six female members were carriers of this variant, while the cousin and uncle were hemizygous for this variant. X-chromosome inactivation analysis suggested non-random inactivation in the proband.ConclusionThe c.3051_3053dup (p.Tyr1018*) variant in the DMD gene is considered to be the pathogenic variant significantly associated with the clinical phenotype of the proband, her cousin, and her uncle within this family. Integrating genetic testing with clinical phenotype assessment can be a valuable tool for physicians in the diagnosis of progressive muscular dystrophies, such as Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD).

Defining ambulation status in patients with Duchenne muscular dystrophy using the 10-metre walk test and the motor function measure scale

Purpose Timed functional tests have been explored to understand the natural history of Duchenne muscular dystrophy (DMD) and to establish warning signs of loss of gait. This study verified whether the combination of the 10-metre walk test (10MWT) and the motor function measure (MFM) could classify the ambulation status of DMD patients. Method Thirty-two patients, aged between 5 and 22 years, with independent gait initially evaluated over 11 years participated in the study. Two groups were created: ambulators and non-ambulators. For both groups, we calculated a 10MWT ratio, by dividing the time spent to perform the last evaluation by the penultimate evaluation, and a MFM dimension-1 score (MFM-D1), collected in the same period. For the statistical analysis, the CART algorithm (“rpart” package in R) classified the patients into ambulators and non-ambulators according to two continuous variables: the 10MWT ratio and the MFM-D1 score. Results The cut-off points were 1.1 for the 10MWT ratio and 26 points for the MFM-D1, which distinguished 70% of the patients as either ambulators or non-ambulators. Conclusion This simple measurement strategy can be used by therapists to adjust their rehabilitation strategies and goals. Implications for rehabilitation Combination of 10MWT ratio with MFM-D1 reveal an "indicator" for the ambulation status of patients with DMD. Physiotherapists can guide clinical care and prepare the patient and family for loss of gait. CART algorithm describes how we classified the patients according to two continuous variables. 70% Of the patients with DMD can be distinguished as either ambulators or non-ambulators.

The role of imaging in characterizing the cardiac natural history of Duchenne muscular dystrophy.

Duchene muscular dystrophy (DMD) is a rare but devastating disease resulting in progressive loss of ambulation, respiratory failure, DMD-associated cardiomyopathy (DMD-CM), and premature death. The use of corticosteroids and supportive respiratory care has improved outcomes, such that DMD-CM is now the leading cause of death. Historically, most programs have focused on skeletal myopathy with less attention to the cardiac phenotype. This omission is rather astonishing since patients with DMD possess an absolute genetic risk of developing cardiomyopathy. Unfortunately, heart failure signs and symptoms are vague due to skeletal muscle myopathy leading to limited ambulation. Traditional assessment of cardiac symptoms by the New York Heart Association American College of Cardiology/American Heart Association Staging (ACC/AHA) classification is of limited utility, even in advanced stages. Echocardiographic assessment can detect cardiac dysfunction late in the disease course, but this has proven to be a poor surrogate marker of early cardiovascular disease and an inadequate predictor of DMD-CM. Indeed, one explanation for the paucity of cardiac therapeutic trials for DMD-CM has been the lack of a suitable end-point. Improved outcomes require a better proactive treatment strategy; however, the barrier to treatment is the lack of a sensitive and specific tool to assess the efficacy of treatment. The use of cardiac imaging has evolved from echocardiography to cardiac magnetic resonance imaging to assess cardiac performance. The purpose of this article is to review the role of cardiac imaging in characterizing the cardiac natural history of DMD-CM, highlighting the prognostic implications and an outlook on how this field might evolve in the future.

Natural History of Serum Enzyme Levels in Duchenne Muscular Dystrophy and Implications for Clinical Practice.

In Duchenne muscular dystrophy, creatine kinase and transaminases are released into the circulation, indicating muscle injury. Their usefulness in monitoring muscle injury or disease progression has not yet been fully evaluated. Thus, this study examined serum creatine kinase and transaminase concentrations at different ages in patients with Duchenne muscular dystrophy and evaluated their association with muscle injury. This is a prospective cohort study that included 110 patients with Duchenne muscular dystrophy categorized by age groups. Creatine kinase and transaminases were quantified in the serum; the Vignos scale evaluated the muscle function. Creatine kinase and transaminase levels were higher in ambulatory than that in nonambulatory patients, which significantly decreased as age increased. Serum creatine kinase and transaminase concentrations were elevated in all ages, and those aged 3-4 yrs had the highest concentrations. Age and Vignos Scale were significantly correlated with creatine kinase and transaminase concentrations. Age, creatine kinase, and transaminases explained the 42.5% of loss of muscle function. This study added the knowledge on the natural history of Duchenne muscular dystrophy at different ages and confirmed that creatine kinase and transaminases decrease with age and loss of muscle function, making them generally inappropriate for monitoring response to therapy, although they are useful for the clinical diagnosis.

Duchenne Muscular Dystrophy-Related Acute Heart Failure: Multicenter Study of Hospitalizations and Outcomes

Our understanding of the natural history of Duchenne Muscular Dystrophy (DMD) related cardiomyopathy is improving, but there is a lack of data on outcomes of acute heart failure (HF) in DMD.

Early Diagnosis and Treatment – The Use of Ataluren in the Effective Management of Duchenne Muscular Dystrophy

The understanding of the natural history of Duchenne muscular dystrophy (DMD) is increasing rapidly and new treatments are emerging that have the potential to substantially improve the prognosis for patients with this disabling and life-shortening disease. For many, however, there is a long delay between the appearance of symptoms and DMD diagnosis, which reduces the possibility of successful treatment. DMD results from mutations in the large dystrophin gene of which one-third are de novo mutations and two-thirds are inherited from a female carrier. Roughly 75% of mutations are large rearrangements and 25% are point mutations. Certain deletions and nonsense mutations can be treated whereas many other mutations cannot currently be treated. This emphasises the need for early genetic testing to identify the mutation, guide treatment and inform genetic counselling. Treatments for DMD include corticosteroids and more recently, ataluren has been approved in Europe, the first disease-modifying therapy for treating DMD caused by nonsense mutations. The use of ataluren in DMD is supported by positive results from phase IIb and phase III studies in which the treatment produced marked improvements in the 6-minute walk test, timed function tests such as the 10 m walk/run test and the 4-stair ascent/descent test compared with placebo. In these trials, ataluren was well tolerated and adverse event profiles were similar to placebo. As such disease-modifying treatments become more widely available, the outlook for children with DMD will improve but physicians must be aware of the disease, rapidly initiate testing where it is suspected and promptly begin appropriate treatment.

Progression of Duchenne Cardiomyopathy Presenting with Chest Pain and Troponin Elevation.

Improved neuromuscular and respiratory therapies have altered the natural history of Duchenne muscular dystrophy (DMD) such that the most common cause of mortality is progressive cardiomyopathy. Despite imaging evidence of progressive cardiomyopathy, troponin I (cTn) is not significantly elevated in asymptomatic DMD patients. We describe eight boys with DMD evaluated for acute chest pain (ACP) and found to have acute cTn elevation with depressed left ventricular ejection fraction (LVEF). Of our eight patients, five presented with a primary complaint of ACP, while three presented with secondary myocardial injury in the context of systemic illness requiring hospitalization. Electrocardiograms showed diffuse ST changes and mean peak cTn level was 44±15.4 ng/mL (reference range <0.03 ng/mL). cTn levels normalized with only supportive care. Cardiac magnetic resonance imaging (CMR) was performed during the event on all but one patient, demonstrating increased late gadolinium enhancement (LGE) from 12.4±11.4% to 36.5±10.3% with associated deterioration of LVEF from 61±4.4% to 47.6±6.6% which remained depressed on follow-up CMR study (49.1±7.8%). All viral studies were negative. Additional investigations varied among patients, but no causative findings were demonstrated. ACP with cTn elevation occurs in DMD boys and may be indicative of cardiomyopathy progression as evidenced by acute left ventricular dysfunction and development or progression of myocardial fibrosis. This clinical presentation is under recognized. These events may represent an important pathophysiological mechanism in cardiomyopathy progression.

New Survival Target for Duchenne Muscular Dystrophy

We report a patient with a typical phenotype and clinical history of Duchenne muscular dystrophy who is currently 53 years old. Because of improvements in cardiopulmonary care, there has been a great improvement in survival and preservation of quality of life for many of these patients. Whereas it is no longer rare to find patients with Duchenne muscular dystrophy living into their fifth decade, this is the first report of a patient in his sixth decade of life. We believe that besides use of continuous noninvasive respiratory support, the fortuitous absence of dilated cardiomyopathy associated with the particular point mutation of his dystrophin gene has permitted prolonged survival.

Challenges of clinical trial design for DMD

The natural history of Duchenne Muscular Dystrophy (DMD) is undoubtedly a shifting target, as shown by numerous recent studies [1–3]. And by “natural history” it is intended DMD-with-all-the-intervention-available-to-date, which are summarised and elucidated in the standard of care documents published by Bushby and colleagues [4,5]. The natural history of this disorder goes hand in hand with the on-going evolution of therapies; hence this phenomenon needs to be respected and factored into the design of clinical trials. Applying metrics based on old knowledge of the condition without taking into account new interventions, risks making clinical trial design poorly adapted or obsolete, and recruitment into studies is very challenging. For example, most ambulant patients are now on glucocorticoid therapy, and the age of starting steroids is indeed shifting towards a younger age as shown in the UK clinical practice [6]; hence, designing studies with steroid therapy as an exclusion criterion in the young ambulant population risks making recruitment virtually impossible in most specialised centres. This could in turn skew recruitment and introduce recruitment biases. Furthermore, cardiac medications used prophylactically (i.e. beta blockers and ACE-inhibitors) are increasingly supported by evidence that their use is beneficial for DMD patients [7–9], although a consensus on what is the optimal age for commencing therapy is still lacking. An on-going 5-year clinical trial funded by the British Heart Foundation testing ACE-inhibitor (perindopril) combined with beta-blocker therapy (bisoprolol) is targeting DMD boys 7–12 years of age who have not developed signs of cardiomyopathy (EudraCT number: 2007-005932-10). This study will likely strengthen the body of literature in support of early intervention [10] and indeed prevention; hence, clinical trial design will have to become permissive towards heart medication given prophylactically. However, at least in animal models, medications targeting angiotensin not only impact on cardiac load, but appear also beneficial for skeletal muscle [11] making it difficult to assess if such medications introduce a bias into skeletal muscle-based trial outcome. A similar scenario will apply to anti-oxidative treatment such as ibedenone; with the recently published study [12] supporting the beneficial effect on respiratory function it is expected that soon enough many patients will be treated with ibedenone alongside steroids, although the study results were obtained on steroid-naive patients and it is unknown to what degree the two drugs are complementary.

Dystrophinopathies.

The dystrophinopathies fall along a spectrum of muscular dystrophy phenotypes, with variable involvement of skeletal and cardiac muscle. The diagnosis of dystrophinopathy should be suspected in any patient with a highly elevated creatine kinase level beyond the context of rhabdomyolysis secondary to toxic or metabolic myopathy. Genetic testing for dystrophinopathy is highly sensitive and specific, and identifying a proband will often lead to implications for several relatives at risk for cardiomyopathy, weakness, or anesthetic reactions. Management of the dystrophinopathies is focused primarily on supportive care, although steroid therapy has changed the natural history of Duchenne muscular dystrophy and it is now standard-of-care internationally. An exciting and ongoing area of investigation of the dystrophinopathies is focused on the potential for altering gene expression, as a way of improving muscle health and slowing the rate of muscle degeneration.

Review the history of Duchenne muscular dystrophy and seize the cutting-edge research

Review the history of Duchenne muscular dystrophy and seize the cutting-edge research

Modeling induced pluripotent stem cells from fibroblasts of Duchenne muscular dystrophy patients

The generation of disease-specific induced pluripotent stem cell (iPS cell) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and for drug screening. Such innovation enables us to obtain autologous cell sources for regenerative medicine. Herein, we report the generation and characterization of iPS cells from the fibroblasts of patients with a family history of Duchenne muscular dystrophy (DMD); these fibroblasts were obtained from patients at 22 gestational weeks of age and exhibit exon duplication from exons 16 to 42. The DMD-iPS cells were generated by the ectopic expression of four transcription factors: OCT4, SOX2, KLF4, and c-MYC; the DMD-iPS cells expressed several pluripotency markers and could be differentiated into various somatic cell types both in vitro and in vivo. Furthermore, DMD-iPSCs showed the differentiation potential to neuronal lineage. Thus, DMD-iPS cells are expected to serve as an in vitro disease model system, which will lay a foundation for the production of autologous cell therapies that avoid immune rejection and enable the correction of gene defects prior to tissue reconstitution.

P.7.2 Natural history of a steroid naive DMD cohort

The natural history of Duchenne muscular dystrophy (DMD) is useful for comparison with future studies on DMD with steroid treatment. Since 1983 the National Rehabilitation Centre for Neuromuscular Diseases in Denmark has registered and regularly monitored the total Danish population of boys with DMD from time of diagnosis. In Denmark steroid treatment in DMD started systematically in the years 2000 and therefore we have a steroid naive cohort of adult patients who were only treated with assisted ventilation when required due to respiratory insufficiency. The aim of this study is to examine the natural history in terms of major clinical events in a Danish birth cohort of DMD steroid naive patients born in the period 1983–1992. Methods. Major clinical events are defined as loss of ambulation, spinal surgery, loss of 50% VC, introduction of assisted ventilation, and death. Data on clinical events are collated from the notes of systematic and regular assessments of all the patients born in the period. Kaplan–Meier estimates of time from birth to loss of ambulation, spinal surgery, less than 50% VC, assisted ventilation, and death are calculated. Additional information on heart disease and cause of death will be presented. Preliminary results. Sixty-two patients were born with DMD in Denmark in the period 1983–1992. Thirty-nine of these were alive on 1 April 2013. Average age at loss of ambulation was nine years, age at initiating non-invasive and invasive assisted ventilation was 17 and 20 years, respectively. The natural history of Duchenne muscular dystrophy (DMD) is useful for comparison with future studies on DMD with steroid treatment. Since 1983 the National Rehabilitation Centre for Neuromuscular Diseases in Denmark has registered and regularly monitored the total Danish population of boys with DMD from time of diagnosis. In Denmark steroid treatment in DMD started systematically in the years 2000 and therefore we have a steroid naive cohort of adult patients who were only treated with assisted ventilation when required due to respiratory insufficiency. The aim of this study is to examine the natural history in terms of major clinical events in a Danish birth cohort of DMD steroid naive patients born in the period 1983–1992. Methods. Major clinical events are defined as loss of ambulation, spinal surgery, loss of 50% VC, introduction of assisted ventilation, and death. Data on clinical events are collated from the notes of systematic and regular assessments of all the patients born in the period. Kaplan–Meier estimates of time from birth to loss of ambulation, spinal surgery, less than 50% VC, assisted ventilation, and death are calculated. Additional information on heart disease and cause of death will be presented. Preliminary results. Sixty-two patients were born with DMD in Denmark in the period 1983–1992. Thirty-nine of these were alive on 1 April 2013. Average age at loss of ambulation was nine years, age at initiating non-invasive and invasive assisted ventilation was 17 and 20 years, respectively.

P.20.15 Assessing T cell-mediated immune response to dystrophin in the natural history of Duchenne muscular dystrophy

The pre-symptomatic induction of inflammatory cascades and invasion of muscle by immune cells in dystrophin deficient muscle contributes to the pathology of Duchenne muscular dystrophy (DMD). Traditional and RNA-based gene therapy approaches for DMD are progressing through clinical development. Whilst in one study a post-treatment reduction in inflammatory infiltrate after antisense oligonucleotide-mediated exon skipping has been reported; another study, on viral delivered mini-dystrophin, has shown evidence that dystrophin epitopes expressed in revertant fibres can elicit T cell production in untreated patients which may accelerate a post-treatment immune response. To extend this observation, we are performing annual ELISPOT IFN-gamma assays on patients recruited into a four year DMD natural history study. The study is recruiting 30 ambulant and 30 non-ambulant DMD boys with exon skippable deletions from three clinical centres. ELISPOT assays on all patients are performed with a full length dystrophin peptide set whilst patients with exon 51 or 53 skippable deletions are also assessed with peptides corresponding to unique epitopes generated by exon skipping. This allows us to assess pre-existing immunological responses to dystrophin epitopes in patients prior to inclusion in clinical trials, as well as the likelihood of a post-exon skipping immune response to newly-generated dystrophin protein. Here we present the results to date from patients recruited during the first year; we correlated data to factors such as age, ambulation status, steroid regime and DMD deletion. The majority of patients did not have significant T cell activity against the full length or unique epitope peptide sets; whilst in those that did (approximately 1/6), the activity was relatively low. These ’positive’ patients are presented and the responses mapped to specific dystrophin peptides. Our data provides a useful immunological baseline for future DMD clinical trials.

Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids

In order to understand contemporary natural history of Duchenne muscular dystrophy (DMD), we report 6-minute walk distance (6MWD) and its change over time from a large single centre population of corticosteroid treated DMD boys. Sixty-five boys on daily corticosteroid treatment were identified with a mean (SD) age of 9.5 (2.3) years at first observation. 6MWD was described for 1year age groupings. In addition, changes in 6MWD at 1, 1.5 and 2years (±12weeks) of follow-up were evaluated. The same evaluations were applied to 6MWD data converted to percent predicted values based on the Geiger equation. 6MWD showed an increase from age group 4.5-5.5years to age group 6.5-7.5years, followed by a decline, which became precipitous from 12.5years onwards. From 15.5years, all boys were unable to perform the 6-min test. Changes in 6MWD demonstrated a mean (median, SD) decline of -43 (-14, 90) m at 1year (N=25, mean baseline age 9.5years), -64 (-56, 99) m at 1.5years (N=18, mean baseline age 9.6years), -125 (-106, 139) m at 2years (N=14, mean baseline age 10.0years). Conversion to percent predicted values showed the same pattern of evolution.This study provides data on the ambulatory capacity and its changes over time in a homogenous cohort of 65 DMD boys on daily corticosteroids. The variability, the age-related aspects and the slope of decline of the 6MWD should be considered in the design and interpretation of therapeutic trials in ambulant DMD patients.

Transition from childhood to adulthood in Duchenne muscular dystrophy (DMD)

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy, affecting 1 in 3500 live male births. Mutations in the X chromosome result in an absence of dystrophin, causing progressive muscle degeneration and loss of ambulation by the early teens with respiratory, orthopaedic and cardiac complications. Without intervention these complications lead to death at a mean age of 19 years. However, the natural history of DMD is well-known and can be changed with proactive multidisciplinary management to address predictable complications[1]. Better care has led to a growing adult DMD population, challenging the notion of DMD as a “paediatric” disease. This population faces particular challenges, not only medical (e.g. associated with long-term steroid usage, orthopaedic, ventilation, and cardiac, gastrointestinal or genitourinary problems), but those associated with wider issues of transition. These include medical transfer from paediatric to adult services, and social transition to independent living and full societal inclusion. Transfer arrangements to adult facilities, which vary considerably between clinics and countries, are usually needed due to regulations governing access to paediatric services. As DMD requires co-ordinated care, this move from cohesive paediatric clinics to disjointed adult services is often problematic, and a successful transfer should be the culmination of a period of planned transition. Wider social transition, enabling independent living and further education/employment, is also very important[2]. However, as with many other disabilities, adults with DMD face obstacles to full participation. Planning is crucial, and preparation for adulthood should be considered in partnership with families as part of a comprehensive package of psychosocial care from diagnosis. Recent research suggests that despite legal and health frameworks, DMD transition care in the UK is highly diverse and sometimes lacking[3]. Positive experiences were characterised by forward planning and long-standing relationships between the family and healthcare professionals. In Denmark an integrated model of care is provided by the National Rehabilitation Centre for NMDs (RCfM), which supports families from diagnosis with a comprehensive programme of courses and interventions at significant life milestones[4]. Patient advocacy groups also play a very important role in transition, particularly through programmes such as the MDA Transitions Center. Although there is no one-size-fits-all model for DMD transition care, some features seem particularly important to successful transitions. These include continuity and stability in care; the integration of wider social issues; the involvement of the young man and his family in decision-making; and the support of patient advocacy groups.

Change in Natural History of Duchenne Muscular Dystrophy With Long-term Corticosteroid Treatment: Implications for Management

In 2005, the American Academy of Neurology and the Child Neurology Society published a practice parameter, based primarily on studies that involved 6 to 18 months of treatment, indicating that prednisone has a beneficial effect on muscle strength and function in patients with Duchenne muscular dystrophy and recommended that corticosteroids be offered (prednisone 0.75 mg/kg/d and deflazacort 0.9 mg/kg/d) as treatment. Recent reports emphasize that longer term treatment with corticosteroids (greater than 3 years) produces important sustained benefits in neuromuscular function without causing major side effects. This review highlights these reports and indicates that long-term corticosteroid therapy (1) prolongs ambulation by 2 to 5 years, (2) reduces the need for spinal stabilization surgery, (3) improves cardiopulmonary function, (4) delays the need for noninvasive nasal ventilation, and (5) increases survival and the quality of life of patients with Duchenne muscular dystrophy. Educational, vocational, and other social counseling is now a vital part of management for Duchenne muscular dystrophy.

Left ventricular T2 distribution in Duchenne muscular dystrophy.

BackgroundAlthough previous studies have helped define the natural history of Duchenne Muscular Dystrophy (DMD)-associated cardiomyopathy, the myocardial pathobiology associated with functional impairment in DMD is not yet known.The objective of this study was to assess the distribution of transverse relaxation time (T2) in the left ventricle (LV) of DMD patients, and to determine the association of myocardial T2 heterogeneity to the severity of cardiac dysfunction. DMD patients (n = 26) and normal control subjects (n = 13) were studied by Cardiovascular Magnetic Resonance (CMR). DMD subject data was stratified based on subject age and LV Ejection Fraction (EF) into the following groups: A (<12 years old, n = 12); B (≥12 years old, EF ≤ 55%, n = 8) and C (≥12 years old, EF = 55%, n = 6). Controls were also stratified by age into Groups N1 (<12 years, n = 6) and N2 (>12 years, n = 5). LV mid-slice circumferential myocardial strain (εcc) was calculated using tagged CMR imaging. T2 maps of the LV were generated for all subjects using a black blood dual spin echo method at two echo times. The Full Width at Half Maximum (FWHM) was calculated from a histogram of LV T2 distribution constructed for each subject.ResultsIn DMD subject groups, FWHM of the T2 histogram rose progressively with age and decreasing EF (Group A FWHM= 25.3 ± 3.8 ms; Group B FWHM= 30.9 ± 5.3 ms; Group C FWHM= 33.0 ± 6.4 ms). Further, FWHM was significantly higher in those with reduced circumferential strain (|εcc| ≤ 12%) (Group B, and C) than those with |εcc| > 12% (Group A). Group A FWHM was not different from the two normal groups (N1 FWHM = 25.3 ± 3.5 ms; N2 FWHM= 24.0 ± 7.3 ms).ConclusionReduced EF and εcc correlates well with increased T2 heterogeneity quantified by FWHM, indicating that subclinical functional impairments could be associated with pre-existing abnormalities in tissue structure in young DMD patients.

Diagnosis and management of Duchenne muscular dystrophy in a developing country over a 10-year period

Clinical data on Duchenne muscular dystrophy (DMD) are lacking in developing countries. The objective of this study was to delineate the demographic characteristics, investigations, and outcome of 21 Malaysian males diagnosed with DMD over a period of 10 years. Mean age presentation was 3 years 8 months (SD 23mo; range 10 to 84mo), mean duration from first presentation to diagnosis was 3y 7mo (SD 26mo; range 5 to 84) and the mean age for loss of ambulation was 11 years (SD 25mo; range 102 to 168). There was family history of DMD in five of the 21 patients. Muscle biopsy showed confirmatory findings of DMD in the 16 patients tested. Molecular genetic analysis showed dystrophin gene deletions in 11 of these 16 patients. Four and seven of the students stopped schooling and had learning difficulties, respectively; only nine had satisfactory school performances. Eight out of 14 patients evaluated were classified as having severe to total dependency levels on the modified Barthel Index for activities of daily living assessment. DMD is associated with significant medical and social needs for a developing country such as Malaysia. Earlier referral, genetic counselling, and provision of support and rehabilitative services are the main priorities.