Laura McAdam

Glucocorticoid treatment for the prevention of scoliosis in children with Duchenne muscular dystrophy: long-term follow-up.

BACKGROUND Duchenne muscular dystrophy, a progressive muscle disorder that occurs in males, causes a gradual decline in muscle strength. This progressive decline is associated with the development of scoliosis. Previous studies have shown that the use of glucocorticoids slows the progression of scoliosis, but it is unknown if the spine remains straight in the long term. We examined if glucocorticoid treatment has a long-term effect on the prevalence of scoliosis. METHODS Fifty-four boys who had been diagnosed with Duchenne muscular dystrophy while they were still walking were enrolled in a non-randomized comparative study of the glucocorticoid deflazacort. The families of thirty boys elected for them to use glucocorticoid treatment and the families of twenty-four boys elected for them not to have this treatment. The boys were matched for important baseline characteristics including age and pulmonary function. Every four to six months, they were examined for the development of scoliosis, and the duration of follow-up for surviving patients was fifteen years. Because surgery was recommended for spinal curves measuring >20° on sitting posteroanterior radiographs, a curve of this magnitude was used as the definition for a patient developing scoliosis. RESULTS Five boys (21%) in the non-treatment group and one boy (3%) in the glucocorticoid treatment group died. At the most recent follow-up, of the boys who survived, six (20%) in the glucocorticoid treatment group and twenty-two (92%) in the non-treatment group developed scoliosis and underwent spinal surgery. After fifteen years of follow-up, the survivorship analysis (avoiding surgery) was 78% (95% confidence interval, 57% to 89%) in the treatment group and 8.3% (95% confidence interval, 0.8% to 28%) in the non-treatment group. Significance (p = 5.8 × 10(-7)) was calculated with log-rank and chi-square tests. None of the patients in the glucocorticoid group developed scoliosis after ten years of deflazacort treatment. CONCLUSION The long-term use of the glucocorticoid results in a substantial decreased need for spinal surgery to treat scoliosis.

Bone health in boys with Duchenne Muscular Dystrophy on long-term daily deflazacort therapy

Quality of life in Duchenne Muscular Dystrophy (DMD) has improved significantly with corticosteroid treatment. However, corticosteroids decrease bone mass and increase vertebral fragility fracture risk. We report on bone health in 39 boys with DMD on long-term deflazacort (0.9 mg/kg/day) therapy. Bone health was defined by lumbar (L(1)-L(4)) bone mineral density (BMD), long-bone and/or symptomatic vertebral fractures. Lumbar BMD was reported as height-adjusted Z-scores at initiation of deflazacort (T(0)) and 1-2 year intervals thereafter. Subcapital body fat percentage and ambulatory status were recorded. At T(0), 39 boys, aged 6.6 ± 1.6 years had height-adjusted BMD Z-score -0.5 ± 0.8, and 23.5 ± 5.0% body fat. Height-adjusted Z-scores remained stable with years of deflazacort until loss of ambulation and accrual of body fat. Nine long-bone fractures occurred in eight ambulating boys, two before T(0). Seven vertebral fractures occurred in six non-ambulatory boys after ≥ 5 years of deflazacort with height-adjusted Z-score -1.8 ± 0.7, and 47.8 ± 12% body fat. Bone health in DMD is influenced by disease progression, corticosteroids, BMD Z-scores and fat mass accumulation. Adjustments for short stature must be considered during BMD interpretation. Percent body fat and ambulatory status are useful bone health indicators. Routine use of height adjusted Z-scores is advocated for use in routine clinical practice.

Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5’untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy.

Symptomatic dystrophinopathies in female children.

Although manifesting female carriers of dystrophinopathies have been documented in adults, there are few reports of females presenting with symptomatic dystrophinopathies during childhood. The Canadian Pediatric Neuromuscular Group identified and characterized nine cases of female children 16 years or younger with genetically and/or histologically confirmed symptomatic dystrophinopathy, with an age range of 2-10 years at presentation. Presenting symptoms included proximal muscle weakness (6/9), calf pseudohypertrophy (5/9), abnormal gait (5/9) and myalgias (5/9). Five patients were noted to have significant behavioural and learning issues. The patients had a delay in diagnosis of 4 years from symptom onset. Skewed X inactivation was noted in 5/9 patients, while one patient had X inactivation levels in the normal range. Two of the patients were found to have X/autosome translocation, one of whom also had skewed X-inactivation. Increased awareness of manifesting females with dystrophinopathies will allow for earlier diagnosis and appropriate management for this rare group of patients.

Long-Term Effects of Glucocorticoids on Function, Quality of Life, and Survival in Patients with Duchenne Muscular Dystrophy: A Prospective Cohort Study.

BACKGROUND Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. METHODS For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. FINDINGS 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). INTERPRETATION In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. FUNDING US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

Fat Embolism Syndrome following minor trauma in Duchenne muscular dystrophy.

We describe five patients with Duchenne muscular dystrophy who presented with acute neurologic and respiratory symptoms following minor trauma. Four of the five deteriorated rapidly and died within 36 h after falling. X-rays for fractures were negative. Four of the five patients were taking corticosteroids daily. All five patients fulfilled the clinical criteria for Fat Embolism Syndrome. Autopsy findings were consistent with fat embolism in two cases. Fat Embolism Syndrome needs to be considered in patients with Duchenne muscular dystrophy following minor trauma even without fractures. Early recognition of Fat Embolism Syndrome and aggressive resuscitation are important to improve survival. This report serves as an important reminder that seatbelts need to be used at all times.

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.

A feasibility study using solution-focused coaching for health promotion in children and young people with Duchenne muscular dystrophy

ABSTRACT Purpose: To evaluate the feasibility and acceptability of a coaching intervention (Solution-Focused Coaching in pediatric rehabilitation [SFC-Peds]) related to physical activity and diet in males with Duchenne muscular dystrophy. Methods: A pre-post design was employed. Participants had five coaching sessions over 8 weeks. The first session was face-to-face, followed by four virtual sessions. Feasibility criteria included recruitment rates, attrition, and intervention fidelity. The Canadian Occupational Performance Measure (COPM) and Goal Attainment Scaling (GAS) were employed to look at outcome trends. The acceptability was assessed using a survey. Results: Five males (11–19 years) participated. All feasibility criteria were met. Clinically significant increases were observed for GAS and COPM scores. Participants reported SFC-Peds to be acceptable. Broad barriers and facilitators to coaching success were identified. Conclusions: A SFC-Peds intervention for health promotion is feasible and acceptable in children with DMD and their families. A rigorous efficacy study assessing SFC-Peds intervention is warranted.

Enablers and barriers of men with Duchenne muscular dystrophy transitioning from an adult clinic within a pediatric hospital

BACKGROUND Young men with Duchenne muscular dystrophy (DMD) live into adulthood and need specialized care. However, services for adults are fragmented. We know little about young mens experiences, their parents, and clinicians who support them as they transition to adult care. OBJECTIVE To explore the enablers and barriers of clinicians, young men, and parents as they transition from an adult DMD clinic within a pediatric hospital to an adult health facility. METHODS We conducted semi-structured, in-depth interviews with 16 participants (7 clinicians, 5 parents, 4 youth). We used an open-coding, thematic approach to analyze the data. RESULTS Clinicians, youth and their parents experienced several enablers and barriers in transitioning to an adult health care center. Clinicians reported that structural factors including leadership and advocacy supported the transition. Clinicians and parents found that the availability and continuity of care both enabled and hindered the transition. Parents and youth conveyed the difficulties of adjusting to the different model of adult care and also accessing resources. All participants described how relational factors (i.e., effective communication and family involvement) enabled the transition. On an individual level, clinicians, parents and youth viewed transition readiness and other life skill supports as an enabler and a barrier to transitioning. All participants reported the difficulties of maintaining mental health for youth with DMD transitioning to adult health care. CONCLUSIONS Clinicians, youth, and parents experienced several enablers and barriers in transitioning to adult health care. Further work is needed to understand the complex transition needs of youth with DMD.

A Novel Mutation in DMD (c.10797+5G>A) Causes Becker Muscular Dystrophy Associated with Intellectual Disability.

Background: Severe intellectual disability has been reported in a subgroup of patients with Duchenne muscular dystrophy but is not typically associated with Becker muscular dystrophy. Patient: The authors report a 13-year-old boy, with severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile), attention-deficit hyperactivity disorder, and mild muscle weakness. He had elevated serum creatine kinase and dystrophic changes on muscle biopsy. Dystrophin immunohistochemistry revealed decreased staining with the C-terminal and mid-rod antibodies and essentially absent staining of the N-terminal immunostain. Sequencing of muscle mRNA revealed aberrant splicing due to a c.10797+5G > A mutation in DMD. Conclusion: Dystrophinopathy may be associated with predominantly cognitive impairment and neurobehavioral disorder, and should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males.