Neurodevelopmental Needs in Young Boys with Duchenne Muscular Dystrophy (DMD): Observations from the Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DNHS).

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Introduction: Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular condition manifested by progressive skeletal muscle weakness, cardiopulmonary involvement and cognitive deficits. Neurodevelopmental symptoms and signs are under-appreciated in this population despite the recognition that cognition has a major impact on quality-of-life. We describe the neurodevelopmental needs in a large cohort of young boys with DMD from the DMD Natural History Study (DNHS). We explore the association between neurodevelopmental needs and DMD mutation location, and with glucocorticoid use.  

Methods: We prospectively evaluated 204 participants between ages 4 to less than 9 years of age with DMD as part of a large, longitudinal, international DNHS. We obtained parent- or primary care-giver report of neurodevelopmental needs as part of their study visit. We assessed the relationship between parent/care-giver neurodevelopmental needs and DMD mutation location, and glucocorticoid use.

Results: The neurodevelopmental needs that were most commonly reported included speech delay (33%), mild developmental delay (24%), significant behavioral problems (16.5%), language impairment (14.5%), learning disability (14.5%), attention-deficit hyperactivity disorder (5%) and autism spectrum disorder (3%). Neurodevelopmental needs were more commonly reported by care-givers in those with DMD mutations downstream of exon 51. There was no relationship between care-giver reported neurodevelopmental needs and glucocorticoid use.

Conclusion: Neurodevelopmental needs are highly prevalent in young boys with DMD. Care-givers report higher neurodevelopmental needs when subjects have DMD mutations downstream of exon 51. Early interventions aimed at cognitive health are critical to improve the quality-of-life of individuals with DMD.

Trial Registration: ClinicalTrials.gov NCT00468832

Exploratory Profiling of Urine MicroRNAs in the dy2J/dy2J Mouse Model of LAMA2-CMD: Relation to Disease Progression

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Circulating microRNAs (miRNAs) are being considered as non-invasive biomarkers for disease progression and clinical trials. Congenital muscular dystrophy with deficiency of laminin α2 chain (LAMA2-CMD) is a very severe form of muscular dystrophy, for which no treatment is available. In order to identify LAMA2-CMD biomarkers we have profiled miRNAs in urine from the dy2J/dy2J mouse model of LAMA2-CMD at three distinct time points (representing asymptomatic, initial and established disease). We demonstrate that unique groups of miRNAs are differentially expressed at each time point. We suggest that urine miRNAs can be sensitive biomarkers for different stages of LAMA2-CMD.

Health Care Transition Experiences of Males with Childhood-onset Duchenne and Becker Muscular Dystrophy: Findings from the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) Health Care Transitions and Other Life Experiences Survey

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Introduction: As the proportion of males with Duchenne muscular dystrophy (DMD) surviving into adulthood increases, more information is needed regarding their health care transition planning, an essential process for adolescents and young adults with DMD. The objective of this study was to describe the health care transition experiences of a population of males living with Duchenne or Becker muscular dystrophy (DBMD).

Methods: The eligible participants, identified through the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) surveillance project, were 16–31 years old and lived in Arizona, Colorado, Georgia, Iowa, or western New York (n=258). The MD STARnet Health Care Transitions and Other Life Experiences Survey was conducted in 2013 and administered online or in a telephone interview. Sixty-five males (25%) completed the survey. Among non-ambulatory males, response differences were compared by age group. Statistical comparisons were conducted using Fisher’s exact test, or when appropriate, the Chisquare test.

Results: Twenty-one percent of non-ambulatory males aged 16–18 years, 28% of non-ambulatory males aged 19–23 years, 25% of non-ambulatory males aged 24–30 years, and 18 ambulatory males had a written transition plan. Nineteen percent of non-ambulatory males aged 24–30 years had delayed or gone without needed health care in the past 12 months. Among non-ambulatory males aged 24–30 years, 75% had cardiology providers and 69% had pulmonology providers involved in their care in the past 12 months. Twentyeight percent of non-ambulatory males aged 19–23 years and 25% of non-ambulatory males aged 24–30 years reported that they did not receive health care or other services at least once because they were unable to leave their home. Non-ambulatory males aged 16–18 years (29%) were less likely to have ever discussed how to obtain or keep health insurance as they get older compared to non-ambulatory males aged 24-30 years (69%) (p <0.01).

Discussion: This study identified potential barriers to the successful health care transition of males with DBMD. The results of this study may indicate a lack of targeted informational resources and education focused on supporting the transition of young men with DBMD as they age from adolescence into adulthood within the healthcare system. Future studies could determine the reasons for the potential barriers to health care and identify the optimal transition programs for males with DBMD. There are a few online resources on transition available to adolescents and young adults with special health care needs.

A Pilot Survey Study of Adherence to Care Considerations for Duchenne Muscular Dystrophy

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Introduction Care Considerations supported by the Centers for Disease Control and Prevention for the management of Duchenne muscular dystrophy were published in 2010, but there has been limited study of implementation in the United States. Methods A questionnaire collecting information about standard care practices and perceived barriers was piloted by 9 clinic directors of facilities within the Muscular Dystrophy Surveillance, Tracking and Research network. Results Six clinic directors completed the questionnaire; 1 adult-only clinic was excluded. Over 80% adherence was found for 30 of 55 recommendations examined. Greatest variability was for initiation of corticosteroids, bone health monitoring, type of pulmonary function testing, and psychosocial management. Barriers included unclear guidelines, inadequate time and funding, family-specific barriers and lack of empirical support for some recommendations. Discussion This pilot study showed implementation of the 2010 Care Considerations, except for recommendations based largely on expert consensus. Complete adherence requires more studies and active promotion.

Greater Colo-Rectal Activation Phenotype in Exercised mdx Mice

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Introduction: Duchenne Muscular Dystrophy is a genetic disease that is caused by a deficiency of dystrophin protein. Both Duchenne Muscular Dystrophy patients and dystrophic mice suffer from intestinal dysfunction.

Methods: The present study arose from a chance observation of differences in fecal output of dystrophic vs. normal mice during 20­minutes of forced continuous treadmill exercise. Here, we report on the effects of exercise on fecal output in two different dystrophic mutants and their normal background control strains. All fecal materials evacuated during exercise were counted, dried and weighed.

Results: Mice of both mutant dystrophic strains produced significantly more fecal material during the exercise bout than the relevant control strains.

Discussion: We propose that exercise-­induced Colo-­Rectal Activation Phenotype test could be used as a simple, highly sensitive, non­invasive biomarker to determine efficacy of dystrophin replacement therapies.

Are Soy Products Effective in DMD?

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INTRODUCTION: 

In addition to their nutritional value, processed soy bean extracts contain several activities with potential therapeutic benefits. These include anti-oxidants, and tyrosine kinase and protease inhibitory activity. There are also anecdotal reports of health benefits of soy products in alleviating DMD symptoms.

METHODS: 

Mdx mice were fed a control soy-free diet or the same diet containing either a proprietary soy preparation (Haelan 951), purified soy isoflavones, purified Bowman-Birk protease inhibitor or a combination of isoflavones and Bowman-Birk inhibitor. Mice were tested for their wire hanging ability at the start of the diet regimen and every 4 weeks until week 12 of treatment.

RESULTS AND DISCUSSION: 

The diet containing Bowman-Birk inhibitor was the only one to show a significant and sustained improvement over the 12 weeks of the study. All other dietary additions; Haelan 951, isoflavones and isoflavones with Bowman-Birk inhibitor, were not significantly different from each other or from control. The effectiveness of Bowman-Birk inhibitor in mdx mice clearly warrants further study.

The Relationship Between Bone Mineral Density and Cardiovascular Function in Duchenne Muscular Dystrophy: A Retrospective Cohort Study

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INTRODUCTION: Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder that causes progressive skeletal and cardiac muscle weakness in boys. Cardiac dysfunction is a frequent cause of death in DMD. Glucocorticoids are the standard of care in DMD. The long-term use of oral glucocorticoids in DMD is complicated by poor bone health. Epidemiological studies suggest a biological link between the loss of bone mineral density (BMD) and cardiovascular disease, including coronary artery and cerebrovascular diseases. Whether an association between low BMD and cardiac dysfunction occurs in DMD boys has not yet been studied. The objective of this retrospective cohort study was to examine the relationship between BMD and cardiovascular health in DMD.

METHODS: Retrospective data analyses was performed from de-identified medical records from a tertiary academic medical center. Whole body BMD was measured using dual-energy xray absorptiometry (DEXA) scan and left ventricular ejection fraction (LVEF) was measured using echocardiogram. Linear regression was used to evaluate the relationship between BMD and LVEF.

RESULTS: Data was analyzed from a total of 32 boys with DMD. The mean age at which baseline BMD measurements was obtained of 11±3 (SD) years. The worst LVEF was measured at a mean of 23.7±21.8 (SD) months after the baseline BMD measurement. The final adjusted linear regression of the relationship between baseline BMD z-score and worst LVEF was not statistically significant (ß=0.41, p‑value=0.6455).

DISCUSSION: In this cohort of boys with DMD, BMD was not associated with LVEF dysfunction up to 79 months later. Future research with a longer longitudinal follow-up period is warranted to evaluate the relationship between BMD and cardiovascular disease in DMD. 

Collective Statement Regarding Patient Access to Approved Therapies from the Center Directors of Parent Project Muscular Dystrophy’s Certified Duchenne Care Centers

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The dystrophinopathies (Duchenne [DMD] and Becker muscular dystrophy) are progressive diseases that until recently had no specific treatments. New FDA pathways to drug approval in rare diseases have resulted in a dramatic increase in the number of treatment trials for DMD and recently, two approved drugs. Health insurance policies for DMD products have been constructed with limited input from neuromuscular specialists directly involved in patient care and without patient input. These policies often reflect a lack of understanding of the disease, clinical population or the treatment. To ensure that policy determinations reflect best clinical practice, we recommend insurers work with neuromuscular specialists with expertise in care for patients with dystrophinopathy, as well as patients and families, and prominent advocacy organizations, such as Parent Project Muscular Dystrophy, in developing policies.

A Review of Mathematical Models for Muscular Dystrophy: A Systems Biology Approach

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Muscular dystrophy (MD) describes generalized progressive muscular weakness due to the wasting of muscle fibers. The progression of the disease is affected by known immunological and mechanical factors, and possibly other unknown mechanisms. These dynamics have begun to be elucidated in the last two decades. This article reviews mathematical models of MD and models that could be used to study molecular and cellular components implicated in MD progression. A biological background for these processes is also presented. Molecular effectors that contribute to MD include mitochondrial bioenergetics and genetic factors; both drive cellular metabolism, communication and signaling. These molecular events leave cells vulnerable to mechanical stress which can activate an immunological cascade that weakens cells and surrounding tissues. This review article lays the foundation for a systems biology approach to study MD progression. 

Epigenetic Regulators Modulate Muscle Damage in Duchenne Muscular Dystrophy Model

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Histone acetyl transferases (HATs) and histone deacetylases (HDAC) control transcription during myogenesis. HDACs promote chromatin condensation, inhibiting gene transcription in muscle progenitor cells until myoblast differentiation is triggered and HDACs are released. HATs, namely CBP/p300, activate myogenic regulatory and elongation factors promoting myogenesis. HDAC inhibitors are known to improve regeneration in dystrophic muscles through follistatin upregulation. However, the potential of directly modulating HATs remains unexplored. We tested this possibility in a well-known zebrafish model of Duchenne muscular dystrophy. Interestingly, CBP/p300 transcripts were found downregulated in the absence of Dystrophin. While investigating CBP rescuing potential we observed that dystrophin-null embryos overexpressing CBP actually never show significant muscle damage, even before a first regeneration cycle could occur. We found that the pan-HDAC inhibitor trichostatin A (TSA) also prevents early muscle damage, however the single HAT CBP is as efficient even in low doses. The HAT domain of CBP is required for its full rescuing ability. Importantly, both CBP and TSA prevent early muscle damage without restoring endogenous CBP/p300 neither increasing follistatin transcripts. This suggests a new mechanism of action of epigenetic regulators protecting dystrophin-null muscle fibres from detaching, independent from the known improvement of regeneration upon damage of HDACs inhibitors. This study builds supporting evidence that epigenetic modulators may play a role in determining the severity of muscle dystrophy, controlling the ability to resist muscle damage. Determining the mode of action leading to muscle protection can potentially lead to new treatment options for muscular dystrophies in the future.