mitigates Duchenne muscular dystrophy via metabolic and angiogenic
reprogramming
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2013 NEWS
DECEMBER
Modifiers of Heart and Muscle Function: Where Genetics Meets Physiology
NOVEMBER
30 - (Clinical Rehabilitation, 2013) Effects of respiratory muscle training on pulmonary functions in patients with slowly progressive neuromuscular disease: a randomized controlled trial
Goksen Kuran Aslan, H Nilgun Gurses, Halim Issever and Esen Kiyan - Turkey
Abstract
Objective: To investigate the effects of inspiratory and expiratory muscle training on pulmonary functions in patients with slowly progressive neuromuscular disease.
Design: Prospective randomized controlled double-blinded study.
Setting: Chest diseases clinic of university hospital.
Subjects: Twenty-six patients with slowly progressive neuromuscular disease followed for respiratory problems were included in the study. Patients were randomly divided into two groups; experimental (n = 14; age 31.6 ±12.3 years) and sham (n = 12; age 26.5 ±8.6 years) groups.
Methods: Spirometry, peak cough flow, maximal inspiratory pressure, maximal expiratory pressure, and sniff nasal inspiratory pressure were measured before the eighth week of study, and subsequently at end of it. Respiratory muscle training was performed by inspiratory (Threshold Inspiratory Muscle Trainer) and expiratory (Threshold Positive Expiratory Pressure) threshold loading methods. Training intensities were increased according to maximal inspiratory and expiratory pressures in the experimental group, while the lowest loads were used for training in the sham group. Patients performed 15 minutes inspiratory muscle training and 15 minutes expiratory muscle training, twice a day, five days/week, for a total of eight weeks at home. Training intensity was adjusted in the training group once a week.
Results: Maximal inspiratory and expiratory pressures (cmH2O, % predicted) (respectively p = 0.002, p = 0.003, p = 0.04, p = 0.03) and sniff nasal inspiratory pressure (p = 0.04) were improved in the experimental group when compared with the sham group. However, there was no improvement in spirometric measurements when groups were compared (p > 0.05).
Conclusions: As a conclusion of our study, we found that respiratory muscle strength improved by inspiratory and expiratory muscle training in patients with slowly progressive neuromuscular disease.
15 - Abstracts From the American Heart Association 2013
10 - (ASCB, 2013) Effects of omega-3 at later stages of dystrophinopathy in the mdx mice
A. F. Mauricio, H. Santo Neto, M. Marques -
Department of Structural and Functional Biology, Unicamp, Campinas, Brazil
In Duchenne muscular dystrophy (DMD) and in the mdx mice model of DMD, lack of dystrophin results in sarcolemma
instability, increased calcium influx and myonecrosis. At later stages of the disease, fibrosis deposition, mainly in
respiratory muscles such as the diaphragm, is responsible for the loss of muscle function with consequent respiratory
failure seen in DMD patients. Previously, we demonstrated that omega-3 protected dystrophic skeletal muscles against
myonecrosis at early stages of disease, in the young mdx. In the present study we investigated whether omega-3 therapy
would benefit dystrophy at later stages of the disease, in old (13 months of age) mdx. Mdx mice received fish oil
containing eicosapentaenoic acid and docosahexanoic acid (300mg/kg via gavage 3 days a week) or linseed (via oral,
3g/mice, per day). Control mdx received nujol in an equivalent dosage to the animals treated with fish oil. Omega-3
therapy started at 8 months of age, for 5 months. Functional analysis (grip strength) showed that omega-3 therapy
improved forelimb muscle strength over the time period studied. The serum levels of creatine kinase (CK), an indicative of
muscle degeneration, were 7.4 times higher in mdx-nujol in comparison to normal C57BL/10 mice. Fish oil and linseed
significantly reduced (40% reduction) CK. In the diaphragm muscle, both omega-3 therapies resulted in a significant
increase in the number of fibers with peripheral nuclei (PN), indicative of fibers that had not undergone muscle
degeneration, compared to mdx-nujol (59±1.5% of PN fibers in mdx-nujol vs. 77.6±4.5% of PN fibers in mdx-omega-3).
Central nucleated (CN) fibers, indicative of muscle degeneration-regeneration, were significantly reduced by omega-3 in
comparison to mdx-nujol (41±1.5% of CN fibers in mdx-nujol vs. 24±4.5% of CN fibers in mdx-omega-3). At this later
stage of the disease, the diaphragm showed extensive area of fibrosis (43.6±2.6% of fibrosis in relation to the total cross
sectional area). Both therapies reduced 20% the fibrosis area (34.7±1.2% of fibrosis in relation to the total cross sectional
area in mdx-omega-3). Western blot analysis of the diaphragm indicated that the levels of TGF-β1, a mediator of fibrosis,
were significantly reduced by omega-3 (2.7±0.4% of TGF-β1 in mdx-nujol vs. 2.2±0.3% of TGF-β1 in mdx-omega-3). The
levels of TNF-α, a mediator of inflammation, were not affected by omega-3 therapy, at this later stage of the disease. In
conclusion, we demonstrated that omega-3 therapy is able to benefit dystrophy at later stages of the disease, by reducing
myonecrosis and fibrosis in the diaphragm muscle of old mdx mice. The beneficial effects of omega-3 may be related, at
least in part, to its ability to decrease TGF-β1, a key mediator of fibrosis formation in dystrophic muscles.
10 - (ASCB, 2013) N-Acetylcysteine and Deferoxamine improve diaphragm muscle pathophysiology in mdx mice.
L. H. R. Moraes
, F. R. M. Dos Santos
, A. B. Macedo
, T. D. Hermes
, E. Minatel - Brazil
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease that affects 1 in 3,500 male births. Reactive oxygen
species (ROS) and exacerbate inflammatory response play a key role in the pathogenesis of DMD. The present study
investigates the effects of the combination of antioxidant N-acetylcysteine (NAC) with the iron chelator Deferoxamine
(DFX) on dystrophic diaphragm muscle. Mdx mice (14 days old) received NAC (150mg/kg) plus DFX (150mg/kg) or saline
solution for 14 days. C57BL/10 mice were used as control. Grip strength measurement was used for functional evaluation.
Creatine kinase (CK) levels were determined for biochemical evaluation of muscle fiber degeneration. The extent of
inflammatory process was assessed by TNF-¦Á and NF-¦ÊB levels by western blotting. 4-HNE analysis was used as a
lipid peroxidation marker. NAC plus DFX protect against the loss of muscle strength in mdx mice (p¡Ü 0.0001; Anova).
The levels of CK significantly increased in saline-treated mdx mice when compared to control mice, and NAC plus DFX
significantly reduced this increase (58%). Higher levels of TNF-¦Á, NF-¦ÊB and 4-HNE were observed in the dystrophic
diaphragm muscle, compared to control mice. NAC plus DFX significantly reduced the levels of TNF-¦Á, NF-¦ÊB and 4-
HNE in dystrophic diaphragm muscle (66%, 64% and 43%, respectively). The results suggest that NAC plus DFX play a
protective role in dystrophic muscle and support further investigations as a potential therapy for dystrophinopathies.
10 - (ASCB, 2013) Arbekacin suppress nonsense mutations in mouse model and human cells of Duchenne muscular dystrphy
M. Shiozuka, A. Nishida, Y. Takeshima, M. Yagi
, T. Lee
, M. Matsuo A. Wagatsuma
, M. Yoshida, M. Date
, Y.
Nonomura
, R. Matsuda- Japan
Translational readthrough of a premature termination codon is a promising therapeutic method in more than 2,400
distinctly inherited human diseases caused by respective single genes. In order to investigate potent readthrough inducer
with fewer toxicity than known readthrough-inducing drug such as gentamicin, we screened from kanamycin-related
antibiotics using the novel transgenic mouse strain for detection of readthrough activity, named READ (Readthrough
Evaluation and Assessment by Dual reporter). In consequence, we discovered that the arbekacin induced the in vivo
nonsense suppression dose-dependently in READ mice. We found that arbekacin promoted the accumulation of
dystrophin, the reduction of serum creatine kinase activity and the improvement of contractile function in mdx mice which
carried nonsense mutation in dystrophin gene. Moreover, arbekacin exhibited the restoration of dystrophin expression on
human muscle cells obtained by biopsies from Duchenne muscular dystrophy (DMD) patients with nonsense mutation of
dystrophin gene. These results demonstrate the feasibility of these investigational drugs to DMD and suggest that
arbekacin represents an important chemical entity for the potential treatment of genetic disorders caused by nonsense
mutations. Arbekacin is a breakthrough readthrough-inducing drug for muscular dystrophy patients harboring nonsense
mutations, and can be use as “Off-label use”. Now, we are preparing "investigator-initiated clinical trial" supported by the
Japan Medical Association Center of Clinical Trials. It is our hope that arbekacin will contribute towards the teatment for
DMD
10 - (ASCB, 2013) Suramin decreases cardiomyocyte necrosis and cardiac muscle total calcium in the mdx mice
D. O. Moreira, H. Santo Neto, M. Marques -
Department of Structural and Functional Biology, Unicamp, Campinas, Brazil
Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease that causes respiratory failure that results
in death at about 30 years of age. The lack of dystrophin in mdx mice, the experimental model of DMD, causes
sarcolemma breakdown and increased calcium influx followed by necrosis and fibrosis. At later stages of disease, cardiac
muscle is also affected and the dystrophic cardiomyopathy is characterized by cardiomyocyte hypertrophy, necrosis,
myocardial fibrosis and ECG abnormalities. Previously, we demonstrated that suramin, an antifibrotic agent and purinergic
P2 receptor antagonist, decreased fibrosis and improved cardiac function in mdx mice. In this study we add further
information about the effects of suramin on cardiac muscle total calcium and on β-dystroglycan, a main component of the
dystrophin-protein complex. Mdx mice (n=18; 8 months old) received intraperitoneal injections of suramin (60 mg/kg body
weight), twice a week for 3 months. Control mdx mice (n=18; 8 months old) were injected with saline. Blood was obtained
to determine cardiac creatine-kinase (CK-cardiac). Suramin decreased (61%) the total amount of cardiac calcium
(determined by inductively coupled plasma-optical emission spectrometry) and there was a tendency to suramin to
increase β-dystroglycan levels (12.5±3% in control vs 13.7±2.7% in suramin-mdx). Western blot analysis showed that
suramin decreased the levels of the transient receptor potencial canonical channel 1 (3.1±0.1% in control vs 2.4±0.3% in
suramin-mdx, p<0.05), a component of the stretch-activated calcium channel. Overall, we demonstrate that
suramin decreases cardiomyocyte necrosis, possibly by its ability to affect cardiac muscle total calcium and a calcium
channel-related protein. Furthermore, suramin may have potential benefits in maintaining the strucutre of dystrophin-protein complex.
OCTOBER
26 - (Human Molecular Genetics, 2013) Restoration of muscle strength in dystrophic muscle by Angiotensin-1-7 through inhibition of TGF-β signaling
María José Acuña, Patrizia Pessina, Hugo Olguin, Daniel Cabrera, Carlos P. Vio, Michael Bader, Pura Muñoz-Canoves, Robson A. Santos, Claudio Cabello-Verrugio, and Enrique Brandan - Chile
Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease, and is characterized by the lack of dystrophin, muscle wasting, increased transforming growth factor (TGF)-β Smad dependent signaling and fibrosis. Acting via the Mas receptor, Angiotensin-1-7 (Ang-(1-7)) is part of the renin–angiotensin system, with the opposite effect to that of angiotensin II. We hypothesized that the Ang-(1-7)/Mas receptor axis might protects chronically damaged tissues as in skeletal muscle of the DMD mouse model mdx. Infusion or oral administration of Ang-(1-7) in mdx mice normalized skeletal muscle architecture, decreased local fibrosis and improved muscle function in vitro and in vivo. These positive effects were mediated by the inhibition of TGF-β Smad signaling, which in turn, led to reduction of the pro-fibrotic microRNA miR-21 concomitant with a reduction in the number of TCF4 expressing fibroblasts. Mdx mice infused with Mas antagonist (A-779) and mdx deficient for the Mas receptor showed highly deteriorated muscular architecture, increased fibrosis and TGF-β signaling with diminished muscle strength. These results suggest that this novel compound Ang-(1-7) might be used to improve quality of life and delay death in individuals with DMD and this drug should be investigated in further pre-clinical trials.
16 - (Pediatric Neurology, 2013) Corticosteroid Therapy for Duchenne Muscular Dystrophy: Improvement of Psychomotor Function
Of the numerous clinical trials for Duchenne muscular dystrophy, only the corticosteroid prednisolone has shown potential for temporal improvement in motor ability. In this study, the effects of prednisolone on intellectual ability are examined in 29 cases of Duchenne muscular dystrophy because little information has been reported. And also, motor functions and cardiac functions were evaluated.
The treated group was administered prednisolone (0.75 mg/kg) orally on alternate days and the compared with the untreated control group. Gene mutations were investigated. The patients were examined for intelligence quotient adequate for age, brain natriuretic peptide, creatine kinase, and manual muscle testing before treatment and after the period 6 months to 2 years.
Results
Intelligence quotient scores of the treated increased to 6.5 ± 11.9 (mean ± standard deviation) were compared with the controls 2.1 ± 4.9 (P = 0.009). Intelligence quotient scores of the patients with nonsense point mutations improved significantly (21.0 ± 7.9) more than those with deletion or duplication (1.9 ± 9.0; P = 0.015). Motor function, such as time to stand up, of those treated improved significantly and brain natriuretic peptide level was reduced to a normal level after treatment in 15 patients (73%).
Our results demonstrate the effectiveness of prednisolone in improving intellectual impairment as well as in preserving motor function and brain natriuretic peptide levels. We presume that prednisolone has a read-through effect on the stop codons in the central nervous systems of Duchenne muscular dystrophy because intelligence quotient of point mutation case was improved significantly
SEPTEMBER
21 - GSK-Prosensa DMD Candidate Drisapersen Flops in Phase III Trial
7 - (Eur. Respir. J., Sep 2013; 42: 671 - 680) Sniff nasal inspiratory pressure in the longitudinal assessment of young Duchenne muscular dystrophy children
Véronique Nève, Jean-Marie Cuisset, Jean-Louis Edmé, Alain Carpentier, Mike Howsam, Olivier Leclerc, and Régis Matran
Abstract
Traditional measures of respiratory function in children with Duchenne muscular dystrophy (DMD) are based on maximal inspiratory pressure (PImax) and vital capacity (VC). Sniff nasal inspiratory pressure (SNIP) measurements are easily performed by young children with neuromuscular disorders. The clinical value of SNIP in the longitudinal assessment of respiratory weakness remains to be assessed. The objective of the present study was to assess longitudinally the changes in SNIP, PImax and VC with age in DMD children. We hypothesised that their longitudinal assessment would show an earlier decline in SNIP than VC.
A 3-year, prospective follow-up, at 6-month intervals of, 33 steroid-naïve, 5–20-year-old DMD patients was analysed using a linear mixed model.
SNIP measurements were reliable (within-session coefficient of variation 8%). SNIP and VC increased until 10.5 and 12.5 years of age, respectively, and declined thereafter, while PImax did not change with age.
SNIP was an earlier marker of decline in respiratory muscle strength (at 10.5 years) than VC (at 12.5 years) in young DMD patients. SNIP longitudinal assessment is useful in the detection of inspiratory strength decline in young DMD patients when VC values remain within normal values and as an outcome measure in clinical trials for emerging therapeutics in young DMD patients from the age of 5 years
AUGUST
31 - Abstracts that will be presented in 18th World Muscle Society Meeting in USA - October 2013
3 - (Pediatric Neurology, 2013) The Impact of Deflazacort on Puberty in Duchenne Muscular Dystrophy
Joseph M. Dooley, Susan A. Bobbitt, Elizabeth A. Cummings MD - Canada
The routine use of glucocorticoids has increased the longevity of patients with Duchenne muscular dystrophy. Long-term steroid therapy may have adverse effects on
endocrine function and could influence the onset of puberty. METHODS: We assessed the
pubertal development of our patients who were 14 years of age or older and had been
treated with deflazacort as their only glucocorticoid. RESULTS: Half (6 of 12) of the boys who
were treated with deflazacort had pubertal delay. There was no difference in the age of
onset, dose, or duration of deflazacort therapy between those who did and did not have
delayed puberty. CONCLUSIONS: This pilot study suggests that delayed puberty should be
studied in future trials that address different doses and schedules of deflazacort therapy in
Duchenne muscular dystrophy.
3 - Eteplirsen for the treatment of duchenne muscular dystrophy.
3 - Why short stature is beneficial in duchenne muscular dystrophy
JULY
24 - (The International Journal of Biochemistry & Cell Biology, 2013)Treatment with the cysteine precursor L-2-Oxothiazolidine-4-Carboxylate (OTC) implicates taurine deficiency in severity of dystropathology in mdx mice
Jessica R. Terrill, Amber Boyatzis, Miranda D. Grounds, Peter G. Arthur - Australia
24 - (Neurorehabil Neural Repair, Jul 2013) Assisted Bicycle Training Delays Functional Deterioration in Boys With Duchenne Muscular Dystrophy: The Randomized Controlled Trial "No Use Is Disuse"
Merel Jansen, Nens van Alfen, Alexander C. H. Geurts, and Imelda J. M. de Groot - Netherlands
Background. Physical training might delay the functional deterioration caused by disuse in boys with Duchenne muscular dystrophy (DMD). The “No Use Is Disuse” study is the first explorative, randomized controlled trial in boys with DMD to examine whether assisted bicycle training is feasible, safe, and beneficial. Methods. Ambulatory and recently wheelchair-dependent boys with DMD were allocated to the intervention or control group. The intervention group received assisted bicycle training of the legs and arms during 24 weeks. The control group received the same training after a waiting period of 24 weeks. The primary study outcomes were the Motor Function Measure (MFM) and the Assisted 6-Minute Cycling Test (A6MCT). Group differences were examined by an analysis of covariance. Results. Thirty boys (mean age 10.5 ± 2.6 years, 18 ambulant and 12 wheelchair-dependent) were allocated to the intervention (n = 17) or the control (n = 13) group. All boys in the intervention group (except one) completed the training. After 24 weeks, the total MFM score remained stable in the intervention group, whereas it had significantly decreased in the control group (Δ = 4.9, 95% confidence interval = 2.2-7.6). No significant group differences were found for the A6MCT. No serious adverse events were observed. Conclusions. Our results suggest that assisted bicycle training of the legs and arms is feasible and safe for both ambulant and wheelchair-dependent children and may decline the deterioration due to disuse. Progressive deterioration, however, may compromise the design of trials for DMD.
20 - (J Pediatr 2013) Oral Corticosteroids and Onset of Cardiomyopathy in Duchenne Muscular Dystrophy
Brent J. Barber, Jennifer G. Andrews, Zhenqiang Lu, Nancy A. West, F. John Meaney, Elinora T. Price, Ashley Gray, Daniel W. Sheehan, Shree Pandya, Michele Yang and Christopher Cunniff
Objective
To estimate the age when cardiomyopathy develops in boys with Duchenne muscular dystrophy (DMD) and to analyze the effect of corticosteroid treatment on the age of cardiomyopathy onset.
Study design
We identified a population-based sample of 462 boys with DMD, born between 1982 and 2005, in 5 surveillance sites in the US. Echocardiographic and corticosteroid treatment data were collected. Cardiomyopathy was defined by a reduced fractional shortening (<28%) or ejection fraction (<55%). The age of cardiomyopathy onset was determined. Survival analysis was performed to determine the effects of corticosteroid treatment on cardiomyopathy onset.
Results
The mean (SD) age of cardiomyopathy onset was 14.3 (4.2) years for the entire population and 15.2 (3.4) years in corticosteroid-treated vs 13.1 (4. in non-treated boys. Survival analysis described a significant delay of
cardiomyopathy onset for boys treated with corticosteroids (P< .02). By 14.3 years of age, 63% of non-treated boys had developed cardiomyopathy vs only 36% of those treated. Among boys treated with corticosteroids, there is a significant positive effect of duration of corticosteroid treatment on cardiomyopathy onset (P< .0001). For every year of corticosteroid treatment, the probability of developing cardiomyopathy decreased by 4%.
Conclusions
Oral corticosteroid treatment was associated with delayed cardiomyopathy onset. The duration of corticosteroid treatmentalsocorrelated positively with delayed cardiomyopathy onset.Our analysis suggests that a boy with DMD treated for 5 years with corticosteroids might experience a 20% decrease in the likelihood of developing cardiomyopathy compared with untreated boys.
20 - (Pediatric Pulmonology,2013, 48(8):824–29) Changes in gastric pressure and volume during mechanical in-exsufflation
Laura J. Miske, Joseph M. McDonough, Daniel J. Weiner and Howard B. Panitch
Background/Purpose
A mechanical insufflator–exsufflator (MI–E) is used to replicate spontaneous cough in weak or neurologically impaired patients. Its use is often withheld after abdominal surgery because of concerns for potential wound dehiscence from abdominal distension or development of excessive abdominal positive pressure. We hypothesized that gastric pressure during MI–E use would not exceed usual pressures generated during a spontaneous cough.
Methods
Thirteen subjects 0.8–23.1 years (mean 10.5 years) with neuromuscular weakness, pre-existing gastrostomy tube, and established MI–E routine were studied. A pressure transducer through the gastrostomy tube measured gastric pressure (Pgas) during MI–E treatment. Chest and abdominal volume change was assessed by respiratory inductance plethysmography. In three subjects, the same measurements were made during spontaneous cough
Results
The maximum Pgas was 24 cm with applied pressures of 20–40 cm. In the three subjects able to cough, the maximum Pgas achieved during the spontaneous maneuver was 25 cm, a value higher than they achieved with MI–E treatment.
Conclusion
MI–E resulted in less positive abdominal pressure than has been described in healthy subjects during spontaneous coughing. As such, use of an MI–E device should be considered safe to use in the post-operative period following abdominal surgery in patients with neuromuscular weakness.
10 - Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy.
10 - (Muscle & Nerve, 2013) Bone density and alendronate effects in Duchenne muscular dystrophy patients
Caroline Houston, Katherine Mathews and Amal Shibli-Rahhal - USA
Abstract
Introduction: Patients with DMD have low bone mineral density (BMD) and are at high risk for fractures. We examined changes in BMD and the effects of alendronate in DMD patients treated at our institution in the last decade.
Methods: Retrospective cohort study of 39 DMD patients.
Results: Patients had screening dual energy x-ray absorptiometry (DXA) at an average age of 12 years. The vast majority had low Z-scores at the total hip and lumbar spine. Patients treated with glucocorticoids had a significantly lower Z-score at the spine than those not treated with glucocorticoids. Z-scores at the hip trended down without alendronate (P= 0.07) and trended up with alendronate (P= 0.4).
Discussion: By age 12 years, most patients with DMD had low Z-scores. They may have benefitted from earlier screening. Z-score at the hip trended downward without alendronate and trended upward (stabilized) with alendronate, but these trends were not statistically significant
JUNE
30 - (Annals of Physical and Rehabilitation Medicine, 2013) Evolution of life expectancy of patients with Duchenne muscular dystrophy at AFM Yolaine de Kepper centre between 1981 and 2011
Retrospective study over the last 30 years of life expectancy in patients suffering from Duchenne muscular dystrophy (DMD). Analysis of the role of ventilatory assistance and causes of death.
One hundred and nineteen adult DMD patients were hosted during 1981 to 2011 at AFM Yolaine de Kepper centre, Saint-Georges-sur-Loire, France. Patients’ life expectancy was calculated using Kaplan-Meier model.
Life expectancy without or with ventilatory assistance was 22.16 and 36.23 years, respectively. Similarly, life expectancy of patients born from 1970 (mostly with ventilatory assistance) was 40.95 years old from 1970 and 25.77 years old before 1970. Causes of death changed. Cardiac origins of death have increased from 8% to 44%.
Ventilator assistance, in this study mostly through tracheotomy prolongs by more than 15 years life expectancy of DMD patients. It allows conservation of a satisfactory quality of life, and should be systematically proposed to patients
23 -
(FASEB J,
Jun 2013; 10.1096/fj.13-228296) Muscle
ERR
mitigates Duchenne muscular dystrophy via metabolic and angiogenic
reprogramming
Antonios Matsakas, Vikas Yadav, Sabina Lorca, and Vihang Narkar -USA
Treatment of Duchenne muscular dystrophy (DMD) by replacing
mutant dystrophin or restoring dystrophin-associated glycoprotein complex (DAG)
has been clinically challenging. Instead, identifying and targeting muscle
pathways deregulated in DMD will provide new therapeutic avenues. We report that
the expression of nuclear receptor estrogen-related receptor-γ (ERRγ), and its
metabolic and angiogenic targets are down-regulated (50–85%) in skeletal muscles
of mdx mice (DMD model) vs. wild-type mice. Corelatively, oxidative
myofibers, muscle vasculature, and exercise tolerance (33%) are decreased in mdx
vs. wild-type mice. Overexpressing ERRγ selectively in the dystrophic
muscles of the mdx mice restored metabolic and angiogenic gene expression
compared with control mdx mice. Further, ERRγ enhanced muscle oxidative
myofibers, vasculature, and blood flow (by 33–66%) and improved exercise
tolerance (by 75%) in the dystrophic mice. Restoring muscle ERRγ pathway
ameliorated muscle damage and also prevented DMD hallmarks of postexercise
muscle damage, hypoxia, and fatigue in mdx mice. Notably, ERRγ did not restore
sarcolemmal DAG complex, which is thus dispensable for antidystrophic effects of
ERRγ. In summary, ERRγ-dependent metabolic and angiogenic gene program is
defective in DMD, and we demonstrate that its restoration is a potential
strategy for treating muscular dystrophy.
.
16 - Steroids in Duchenne Muscular Dystrophy - Personal point of view of V. Dubowitz
16 - (JPEN J Parenter Enteral Nutr, Jun 2013) Vitamin D Deficiency in Patients With Neuromuscular Diseases With Chronic Respiratory Failure
Sridhar Badireddi, Anita J. Bercher, Jason B. Holder, and Eduardo Mireles-Cabodevila
Background: The prevalence and clinical implications of vitamin D deficiency have never been studied in patients with underlying neuromuscular diseases complicated with chronic respiratory failure. The aim of this study is to demonstrate the prevalence of vitamin D deficiency, its relationship with other bone markers, and mode of nutrition. Materials and Methods: Serum 25-hydroxyvitamin D (25[OH]D) levels along with calcium, serum albumin, and phosphorus levels were obtained from 57 patients with chronic respiratory failure due to underlying neuromuscular diseases. These levels were obtained during their first visit to a chronic respiratory diseases clinic. Data with regard to nutrition, respiratory muscle function, and level of mobility were also obtained at the same time. Results: Seventy-five percent of patients had serum 25(OH)D levels ≤30 ng/mL. There is a negative correlation between parathyroid hormone and 25(OH)D levels (P = .006) and corrected calcium levels (P = .066). Serum 25(OH)D levels varied with the mode of nutrition. Patients on enteral nutrition had the highest serum levels of 25(OH)D, whereas combined oral and tube feeds had the lowest 25(OH)D levels (P = .006). Conclusion: Low serum 25(OH)D levels are highly prevalent in patients with neuromuscular disease and chronic respiratory failure. The route of nutrition has an impact on these levels.
MAY
25 - (J Neurol Psychiatry, May 2013) Clinical characterisation of Becker muscular dystrophy patients predicts favourable outcome in exon-skipping therapy
J C van den Bergen, S M Schade van Westrum, L Dekker, A J van der Kooi, M de Visser, B H A Wokke, C S Straathof, M A Hulsker, A Aartsma-Rus, J J Verschuuren, and H B Ginjaar
Abstract
Objective Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD.
Methods Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD
Results Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6–67). Nine patients were wheelchair users (26–56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively
Conclusions This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a ‘skipped’ DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD
25 - (European Journal of Pharmacology, 2013) The Nitric Oxide-donor molsidomine modulates the innate inflammatory response in a mouse model of muscular dystrophy
Paola Zordan, Clara Sciorati, Lara Campana, Lucia Cottone, Emilio Clementi, Patrizia-Rovere Querini, Silvia Brunell
Inflammation plays a crucial role in muscle remodelling and repair after acute and chronic damage, in particular in muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration. Defect of nitric oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. We have investigated the immune-modulating effect of one of such drugs, molsidomine, able to slow the progression of muscular dystrophy in the α-Sarcoglican-null mice a model for the limb girdle muscular dystrophy 2D, sharing several hallmarks of muscle degeneration with other muscular dystrophies. α-Sarcoglican-null mice were treated with molsidomine and drug effects on the inflammatory infiltrates and on muscle repair, were assessed at selected time points. We found that molsidomine treatment modulates effectively the characteristics of the inflammatory infiltrate within dystrophic muscles, enhancing its healing function. Initially molsidomine amplified macrophage recruitment, promoting a more efficient clearance of cell debris and effective tissue regeneration. At a later stage molsidomine decreased significantly the extent of the inflammatory infiltrate, whose persistence exacerbates muscle damage: most the remaining macrophages displayed characteristics of transitional population, associated with reduced fibrosis and increased preservation of the muscle tissue. The dual action of molsidomine, the already known NO donation and the immunomodulatory function we now identified, suggests that it has a unique potential in tissue healing of chronic muscle damage. This, alongside its already approved use in human, make of molsidomine a drug with a significant therapeutic potential in muscular dystrophies.
25 - Inhibition of the angiotensin-converting enzyme decreases skeletal muscle fibrosis in dystrophic mice by a diminution in the expression and activity of connective tissue growth factor (CTGF/CCN-2)
25 - Cardiac Resynchronization Therapy in Becker Muscular Dystrophy
5 - (Pharmacological Research, 2013) Ibuprofen plus Isosorbide Dinitrate treatment in the mdx mice ameliorates dystrophic heart structure
Clara Sciorati, Lidia Staszewsky, Vanessa Zambelli, Ilaria Russo, Monica Salio, Deborah Novelli, Giuseppe Di Grigoli, Rosa Maria Moresco, Emilio Clementi, Roberto Latini
Abstract
Background
Co-administration of ibuprofen (IBU) and isosorbide dinitrate (ISDN) provides synergistic beneficial effects on dystrophic skeletal muscle. Whether this treatment has also cardioprotective effects in this disease was still unknown. Aims: to evaluate the effects of co-administration of IBU and ISDN (a) on left ventricular (LV) structure and function, and (b) on cardiac inflammatory response and fibrosis in mdx mice.
Methods
Three groups of mice were studied: mdx mice treated with IBU (50 mg kg−1) + ISDN (30 mg kg−1) administered daily in the diet, mdx mice that received standard diet without drugs and wild type aged-matched mice. Animals were analysed after 10-11 months of treatment. Structural and functional parameters were evaluated by echocardiography while histological analyses were performed to evaluate inflammatory response, collagen deposition, cardiomyocyte number and area.
Results
Treatment for 10-11 months with IBU + ISDN preserved LV wall thickness and LV mass. Drug treatment also preserved the total number of cardiomyocytes in the LV and attenuated the increase in cardiomyocyte size, when compared to untreated mdx mice. Moreover, a trend towards a decreased number of inflammatory cells, a reduced LV myocardial interstitial fibrosis and an enhanced global LV function response to stress was observed in treated mdx mice.
Conclusions
Treatment for 10-11 months with IBU + ISDN is effective in preventing the alterations in LV morphology of mdx mice while not reaching statistical significance on LV function and cardiac inflammation
APRIL
28 - Abstracts that will be presented in American Society of Gene and Cell Therapy Meeting, May 2013.
12 - GlaxoSmithKline measures 36-meter leap over placebo in Duchenne walking test
MARCH
30 - Role of vascular tone in the pathogenesis of DMD:
a)
(Experimental Biology, 2013) Phosphodiesterase 5 inhibition rescues
functional sympatholysis in Duchenne Muscular Dystrophy
Michael Nelson, Elizabeth A. Martin, Xiu Tang, Jimmy Johannes, Joshua Lewis,
Swaminatha V. Gurudevan, Stanley Nelson, Carrie Miceli, Ronald G. Victor.
We recently reported that functional sympatholysis (i.e., muscle
contraction-induced attenuation of reflex vasoconstriction) is impaired in
Becker Muscular dystrophy and rescued by phosphodiesterase (PDE)5 inhibition
with tadalafil. However, tadalafil failed to rescue sympatholysis in one BMD
patient with a rapidly progressive disease resembling Duchenne Muscular
Dystrophy. Thus, we tested the ability of two different phosphodiesterase
inhibitors, tadalafil and sildenafil, to rescue sympatholysis in DMD. In 6 boys
with DMD (ages 7-13) and 8 healthy controls, we measured reflex vasoconstriction
(decreased forearm muscle oxygenation [ΔHb02, near infrared spectroscopy] evoked
by lower body negative pressure) at rest and during rhythmic handgrip exercise.
First, we confirm that sympatholysis is impaired in DMD, because handgrip
greatly attenuated vasoconstriction in controls (ΔHb02:-22±6 vs. -9±5 %, p<.05;
rest vs. HG) but caused no attenuation in DMD (-17±2 vs. -15±3%). Then, in a
randomized single dose (0.5 mg/kg) cross-over trial of tadalafil vs. sildenafil,
we show that sympatholysis is rescued in DMD by either PDE5 inhibitor (tadalafil:
-21±3 vs. -11±4; sildenafil, -22±4 vs. -12±3%; ΔHb02 rest vs. HG). PDE5
inhibition therefore constitutes a putative therapeutic treatment option for
patients with either Becker or Duchenne Muscular Dystrophy.
Support: Parent Project Muscular Dystrophy
b)
(Experimental Biology, 2013) Tadalafil-sensitive impairment in muscle
blood flow during
exercise in Duchenne Muscular Dystrophy
Michael Nelson, Elizabeth A. Martin, Xiu Tang, Jimmy Johannes, Joshua Lewis,
Swaminatha V. Gurudevan, Ronald G.Victor
Out-of-frame mutations in the dystrophin gene cause Duchenne muscular
dystrophy (DMD)—a devastating X-linked muscle wasting disease for which there is
no treatment other than corticosteroids. In DMD, loss of the cytoskeletal
protein dystrophin impairs sarcoelmmal targeting of nNOS, which is the main
source of skeletal muscle-derived nitric oxide (NO). We
previously showed that loss of nNOS impairs the normal exercise-induced
attenuation of reflex vasoconstriction in dystrophic skeletal muscle, thus
implicating a putative vascular component to the pathogenesis of DMD. Here we
present data on a second phenotype, that muscle blood flow (BF, measured by
Doppler ultrasound of the brachial artery) fails to increase normally during
mild rhythmic handgrip exercise in 6 boys with DMD (7-13 years of age) compared
with 8 age-matched male controls (Ctrls): ΔBF:+13±5% vs. +81±10%, respectively
(p<.05). Moreover, we show that the phosphodiesterase 5 inhibitor Tadalafil,
restores active hyperemia in boys with DMD in a dose-dependent manner: 0.5
mg/kg, +56±13%; 1.0 mg/kg, +72+18% These data significantly advance the vascular
hypothesis of DMD and implicate PDE5 inhibition as a putative therapeutic
treatment
option. Support: Parent Project Muscular Dystrophy, Heart and Stroke
Foundation of Canada (MN)
c) (Experimental Biology, 2013) Chronic tadalafil treatment ameliorates functional muscle ischemia and exercise-induced muscle injury in dystrophin- deficient mdx mice
Liang Li, Nancy Zepeda, Ronald G Victor,
Gail D Thomas. The
Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
The dystrophin-deficient muscles of
patients with Duchenne or Becker muscular dystrophy and mdx mice are
susceptible to ischemia during exercise due to loss of sarcolemmal neuronal
nitric oxide synthase (nNOS). We showed that functional muscle ischemia is
alleviated in patients and mice by acute treatment with the phosphodiesterase 5A
(PDE5A) inhibitor tadalafil to boost NO-cGMP signaling in the diseased muscles.
We now asked if this anti-ischemic effect is sustained during chronic PDE5A
inhibition. We fed mdx mice control or medicated diets (tadalafil, 4 mg/kg)
for 3 months and then evaluated norepinephrine (NE)-induced hindlimb
vasoconstriction. NE evoked similar decreases in femoral vascular conductance (FVC)
in resting and contracting hindlimbs of untreated mdx mice, indicating
functional muscle ischemia (ΔFVC contraction/rest, 1.07 ± 0.13; n=10).
NE-induced ischemia was attenuated in tadalafil-treated mice (ΔFVC
contraction/rest, 0.61 ± 0.06; n=9; P<0.05 vs untreated) and was similar to
C57BL10 controls (ΔFVC contraction/rest, 0.50 ± 0.08; n=10).
Serum creatine kinase activity was elevated 6-fold post-exercise in untreated
mice, but only 2.5-fold in treated mice (P<0.05). These findings indicate that
chronic PDE5A inhibition counteracts functional muscle ischemia in mdx mice,
which may reduce injury of the vulnerable dystrophin-deficient muscles during
exercise. Supported by MDA, 158944.
30 -
Suramin
attenuates dystrophin-deficient cardiomyopathy in the mdx mouse model of
Duchenne muscular dystrophy
23 - (Pharmacological Research, 2013) GLPG0492, A NOVEL SELECTIVE ANDROGEN RECEPTOR MODULATOR, IMPROVES MUSCLE PERFORMANCE IN THE EXERCISED-MDX MOUSE MODEL OF MUSCULAR DYSTROPHY
Anna Cozzoli, Roberta Francesca Capogrosso, Valeriana Teresa Sblendorio, Maria Maddalena Dinardo, Catherine Jagerschmidt, Florence Namour, Giulia Maria Camerino, Annamaria De Luca
Anabolic drugs may counteract muscle wasting and dysfunction in Duchenne Muscular Dystrophy (DMD); however, steroids have unwanted side effects. We focused on GLPG0492, a new non-steroidal selective androgen receptor modulator that is currently under development for musculo-skeletal diseases such as sarcopenia and cachexia. GLPG0492 was tested in the exercised mdx mouse model of DMD in a 4-week trial at a single high dose (30 mg/kg, 6 day/week s.c.), and the results were compared with those from the administration of (-methylprednisolone (PDN; 1 mg/kg, i.p.) and nandrolone (NAND, 5 mg/kg, s.c.). This assessment was followed by a 12-week dose-dependence study (0.3-30 mg/kg s.c.). The outcomes were evaluated in vivo and ex vivo on functional, histological and biochemical parameters. Similar to PDN and NAND, GLPG0492 significantly increased mouse strength. In acute exhaustion tests, a surrogate of the 6-min walking test used in DMD patients, GLPG0492 preserved running performance, whereas vehicle- or comparator-treated animals showed a significant increase in fatigue (30-50%). Ex vivo, all drugs resulted in a modest but significant increase of diaphragm force. In parallel, a decrease in the non-muscle area and markers of fibrosis was observed in GLPG0492- and NAND-treated mice. The drugs exerted minor effects on limb muscles; however, electrophysiological biomarkers were ameliorated in extensor digitorum longus muscle. The longer dose-dependence study confirmed the effect on mdx mouse strength and resistance to fatigue and demonstrated the efficacy of lower drug doses on in vivo and ex vivo functional parameters. These results support the interest of further studies of GLPG0492 as a potential treatment for DMD.
20 - (Neurology, 2013) FAT embolism syndrome in patients with Duchenne muscular dystrophy
Milton O. Medeiros, Caleb Behrend, Wendy King, James Sanders, John Kissel, Emma Ciafaloni - USA
Fat embolization is common after long bone fractures. Presentations range from asymptomatic to the potentially fatal fat embolism syndrome (FES), a clinical triad of respiratory distress, neurologic changes, and a petechial rash.1 FES is not a well-recognized complication in Duchenne muscular dystrophy (DMD). We report 8 patients with DMD with FES after low-energy trauma, and discuss presenting features unique to this patient population.
9 - (Journal of the American College of Cardiology, Volume 61, Issue 10, Supplement, 12) Autonomic Dysfunction by Heart Rate Variability Analyses Correlates with Myocardial Fibrosis in Pediatric Duchenne Muscular Dystrophy
Tamara O. Thomas, John Jefferies, Angela Lorts, Jeffrey Anderson, Kan Hor, Zhiqian Gao, Elaine Urbina
Background: An elevated resting
heart rate and cardiac failure are frequently observed
during the natural history of Duchenne Muscular Dystrophy (DMD). We hypothesize
that the elevated resting heart rate reflects autonomic dysfunction that can be
identified by heart rate variability (HRV) analyses and this abnormal HRV
correlates with abnormal cardiac magnetic resonance imaging (cMR) findings.
Methods: DMD patients (N=74) and controls (N=19) had anthropometric and blood
pressure data collected with heart rate and HRV analyses via Holter monitoring.
Time and frequency domain HRV parameters were calculated. Imaging data was taken
from clinical cMR performed on DMD cases only. T-test was used to perform
pair-wise comparison between groups. A p-value of <0.05 was used for statistical
significance.
Results: DMD cases did not differ from controls in age, height, weight or blood
pressure, however, they did differ in body mass index (17.8 + 2.5 years controls,
23 + 6.8 years cases). DMD cases had higher resting average heart rate (83.0 +
9.4 controls, 99.4 + 8.9 cases, p< 0.001). Among HRV variables, decreases were
seen in: standard deviation of R to R intervals (p<0.001), the percent RR
intervals differing by >50 ms from previous RR interval (p<0.001), the
root-mean-square of successive differences of RR intervals (p<0.001), the
standard deviation of the mean R to R segment (SDANN, p<0.001), Very Low
Frequency (<0.04 Hertz), Low Frequency (0.04-0.15 Hertz) and High Frequency
(0.15-0.4 Hertz). Of the HRV variables, SDANN most significantly correlates with
positive late gadolinium enhancement on cMR (p 0.01). 19/74 DMD cases were on
beta blocker (ββ) and the average resting heart rate differed significantly from
those not on ββ (101.5 ± 6.9 no ββ, 93.5 ± yes ββ, p 0.009), however, there was
no difference between the groups in HRV analyses. There was no difference in
cardiac function by cMR between DMD cases with abnormal versus normal HRV or
those on ββ versus not on ββ.
Conclusions: In conclusion, DMD patients have decreased overall HRV which
correlates with early scar fibrosis by cMR. This autonomic dysfunction is
associated with increased mortality and may be helpful in early risk
stratification and medical therapy.
9 - (Journal of the American College
of Cardiology, Volume 61, Issue 10, Supplement, 12) A
Longitudinal Examination of Cardiac Dysfunction in Patients with Duchenne and
Becker Muscular Dystrophy via CMRI
Animesh Tandon, Michael Taylor, Stephanie Ware, John Jefferies, Joshua Sticka, Robert J. Fleck, Brenda L. Wong, Wojciech Mazur, Kan Hor - USA
Background: Duchenne and Becker muscular dystrophy (D/BMD) typically exhibit
cardiac dysfunction, but the temporal evolution is not well understood.
Evaluation of potential therapies for cardiac dysfunction in D/BMD patients
requires accurate, quantitative, longitudinal data; therefore, our study
examined the relationship of cardiac function, age, and myocardial fibrosis
longitudinally in a large group of D/BMD patients.
Methods: D/BMD patients who underwent serial cardiac magnetic resonance (CMR)
studies over 7.5 years were evaluated for left ventricular ejection fraction (EF)
and presence of late gadolinium enhancement (LGE), a marker for myocardial
fibrosis. The data were analyzed using linear mixed effects regression.
Results: A total of 336 CMR studies from 75 D/BMD patients with >=4 CMR were
analyzed. Patient age at time of CMR ranged from 6.6 to 28.6 yrs (median 12.2,
mean 13.1). Forty-one studies (12%) showed depressed EF (EF <55%) and 91 studies
were LGE+ (27%). The youngest patient with depressed EF was 6.9 yrs and the
oldest with normal EF was 28.6 yrs. The youngest LGE+ patient was 8.4 yrs and
the oldest LGE− patient was 28.2 yrs. Thirty-nine patients (52%) had >=1
abnormal CMR, including 18 patients (24%) with depressed EF; 37 patients (49%)
with LGE+; and 16 patients (21%) with both. Five patients (7%) were LGE+ on
their first study. Twenty-six patients (35%) developed LGE before depressed EF;
11 (15%) developed depressed EF before LGE; and 2 (2.7%) developed both on the
same CMR. The patients exhibited depressed EF at a median age of 14.9 yrs and
LGE at a median age of 13.1 yrs. Age was associated with an EF decline of 0.57%/yr
(p<0.0001) overall; however, multivariate analysis showed that EF declined
0.25%/yr when LGE is absent (p=NS) but the decline accelerated to 1.9%/yr when
LGE was present (p<0.0001).
Conclusion: These data show that the temporal characteristics of cardiac
function in D/BMD patients are highly variable. There is a strong association of
LV dysfunction with age, but dysfunction accelerates markedly when LGE is
evident. Therefore, therapeutic interventions targeting myocardial fibrosis may
be beneficial in slowing the progression of cardiac dysfunction in D/BMD
patients.
9 - Duchenne muscular dystrophy and epilepsy
FEBRUARY
24 - Arginine butyrate: a therapeutic candidate for Duchenne muscular dystrophy
JANUARY
25 - (Journal of the American College of Cardiology, 2013) All-Cause Mortality and Cardiovascular Outcomes With Prophylactic Steroid Therapy in Duchenne Muscular Dystrophy
Gernot Schram, Anne Fournier, Hugues Leduc, ,Nagib Dahdah, Johanne Therien, Michel Vanasse, Paul Khairy - Canada
Objectives The aim of this study was to determine the impact
of steroid therapy on cardiomyopathy and mortality in patients with Duchenne
muscular dystrophy (DMD).
Background DMD is a debilitating X-linked disease that afflicts as many as 1 in
3,500 boys. Although steroids slow musculo skeletal impairment, the effects on
cardiac function and mortality remain unknown.
Methods We conducted a cohort study on patients with DMD treated with
renin-angiotensin-aldosterone system antagonists with or without steroid therapy.
Results Eighty-six patients, 9.1 + 3.5 years of age, were followed for
11.3 + 4.1 years. Seven of 63 patients (11%) receiving steroid therapy
died compared with 10 of 23 (43%) not receiving steroid therapy (p <0.0010).
Overall survival rates at 5, 10, and 15 years of follow-up were 100%, 98.0%, and
78.6%, respectively, for patients receiving steroid therapy versus 100%, 72.1%,
and 27.9%, respectively, for patients not receiving steroid therapy (log-rank p<
0.0005). In multivariate propensity-adjusted analyses, steroid use was
associated with a 76% lower mortality rate (hazard ratio: 0.24; 95% confidence
interval: 0.07 to 0.91; p 0.0351). The mortality reduction was driven by fewer
heart failure–related deaths (0% vs. 22%, p 0.0010). In multivariate analyses,
steroids were associated with a 62% lower rate of new-onset cardiomyopathy (hazard
ratio: 0.38; 95% confidence interval: 0.16 to 0.90; p 0.0270). Annual rates of
decline in left ventricular ejection fraction ( 0.43% vs. 1.09%, p 0.0101) and
shortening fraction ( 0.32% vs. 0.65%, p 0.0025) were less steep in steroid
treated patients. Consistently, the increase in left ventricular end-diastolic
dimension was of lesser magnitude ( 0.47 vs. 0.92 mm per year, p 0.0105).
Conclusions In patients with DMD, steroid therapy is associated with a
substantial reduction in all-cause mortality and new-onset and progressive
cardiomyopathy.
Editorial: Steroid Therapy Effectively Delays Duchenne’s Cardiomyopathy
25 - (The Journal of Urology, 2013) Urologic Manifestations in Duchenne Muscular Dystrophy
Eric J. Askeland, Angela M. Arlen, Bradley A. Erickson, Katherine D. Mathews, Christopher S. Cooper - USA
Purpose: Duchenne muscular dystrophy (DMD) is a
dystrophinopathy affecting males, with multiple organ system complications. To
date, urologic complications of DMD have been described only anecdotally.
Materials and Methods: Medical charts of 135 DMD and Duchenne-Becker muscular
dystrophy (D/BMD) patients were reviewed for demographics and disease
progression, urologic
diagnoses, intervention and follow-up. Results: Of 135 patients, 67 (50%) had at
least one documented urologic diagnosis and
38 (28%) had multiple manifestations. Presence of lower urinary tract symptoms (LUTS)
was the most common urologic diagnosis (32%). Survival analysis revealed a
median onset of LUTS of 23 years (95% CI 17.7 – 23.9). Twelve patients (9%)
required intervention, most commonly due to nephrolithiasis. Urologic morbidity
increased with DMD progression when stratified by
markers of clinical progression. LUTS were more common in non-ambulatory
patients (40.7% vs. 19%, p = 0.007), those with a diagnosis of scoliosis (44% vs.
19.7%, p = 0.003) and/or scoliosis spine surgery (60% vs. 22%, p <0.001) and on
invasive respiratory support (53% vs. 29%, p = 0.046). Likewise, nephrolithiasis
was more common in non-ambulatory patients (10% vs. 0%, p = 0.017), those with
scoliosis (12% vs. 0%, p = 0.004) and/or scoliosis spine surgery (20% vs. 1%, p
<0.001) and those on invasive respiratory support (29% vs. 3%, p < 0.001). Only
28% of patients with a urologic manifestation were referred to urology.
Conclusions: As these patients transition into adolescence and adulthood, the
increased prevalence of urologic manifestations warrants increased awareness and
referral to urologists.
19 - (International Journal of Cardiology, 2013) Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy — Prospective multicenter
Koichi Kimura, Katsu Takenaka, Aya Ebihara, Kansei Uno, Hiroyuki Morita, Takashi Nakajima,Tetsuo Ozawa, Izumi Aida, Yosuke Yonemochi, Shinya Higuchi, Yasufumi Motoyoshi, Takashi Mikata, Idai Uchida, Tadayuki Ishihara, Tetsuo Komori, Ruriko Kitao, Tetsuya Nagata, Shin'ichi Takeda, Yutaka Yatomi, Ryozo Nagai, Issei Komuro - Japan
Background: The reported prevalence of left ventricular
noncompaction (LVNC) varies widely and its prognostic impact remains
controversial. We sought to clarify the prevalence and prognostic impact of LVNC
in patients with Duchenne/Becker muscular dystrophy (DMD/BMD).
Methods:We evaluated the presence of LNVC in patientswith DMD/BMD aged 4–64
years old at the study entry (from July 2007 to December 2008) and prospectively
followed-up their subsequent courses (n=186). The study endpoint was all-cause
death and the presence of LVNC was blinded until the end of the study (median
follow-up: 46 months; interquartile range: 41–48 months).
Results: There were no significant differences in baseline characteristics
between patients with LVNC (n=35) and control patientswithout LVNC (n=151),with
the exception of LV function. Patientswith LVNC showed, in comparison with
patients without LVNC, a significant negative correlation between age and LVEF
(R=−0.7 vs. R=−0.4) at baseline;andshowedasignificantly greater decrease in
absolute LVEF (−8.6±4.6 vs. −4.3±4.5, pb0.001) during the follow-up. A worse
prognosiswas observed in patientswith LVNC (13/35 died) than in patients without
LVNC (22/151 died, Log-rank pb0.001).Multivariate Cox analysis revealed that
LVNC is an independent prognostic factor (relative hazard 2.67 [95% CI:
1.19–5.96]).
Conclusion: LVNC was prevalent in patients with DMD/BMD.ThepresenceofLVNCissignificantly
associated with a rapid deterioration in LV function and higher mortality.
Neurologists and cardiologists should pay more careful attention to the presence
of LVNC.
19 - Microdystrophin Ameliorates Muscular Dystrophy in the Canine Model of Duchenne Muscular Dystrophy
15 - Tamoxifen Ameliorates Symptoms of Duchenne Muscular Dystrophy, Study Suggests
12 - (Neuromuscular Disorders, 2013) Imatinib attenuates dystrophic condition in severe mouse dystrophy and inhibits both proliferation and fibrosis-marker expression in muscle mesenchymal progenitors
Takahito Ito, Ryo Ogawa, Akiyoshi Uezumi, Takuji Ohtani, Yoko Watanabe, Kazutake Tsujikawa, Yuko Miyagoe-Suzuki, Shin’ichi Takeda, Hiroshi Yamamoto, So-ichiro Fukada - Japan
Imatinib mesylate inhibits signaling of tyrosine kinase
receptors, including PDGFRa, and has been used for human cancer therapy.
Recent studies have indicated that imatinib is also effective in treatment of
some chronic diseases with fibrosis. Fibrosis is the feature of Duchenne muscular
dystrophy. It has been reported that imatinib attenuates fibrosis in mdx mice.
Recently we revealed that PDGFRa is specifically expressed in muscle mesenchymal
progenitors, which are the origin of muscle fibrosis. Here, we show that imatinib
ameliorates the muscular pathology of DBA/2-mdx, a more severe mouse muscular
dystrophy. In addition, imatinib inhibits both the proliferation and fibrosis
marker expression induced by PDGF-AA in muscle mesenchymal progenitors in vitro.
Importantly, the effective dose of imatinib on muscle mesenchymal progenitors
did not inhibit myoblast proliferation. These results suggest that imatinib
targes mesenchymal progenitors, and that a therapeutic strategy targeting
mesenchymal progenitors could be a potential treatment for muscular dystrophies.
6 - (Developmental Medicine & Child Neurology, 2013) Neurobehavioural disorders in Duchenne muscular dystrophy
V.RICOTTI, M. SCOTO,WPL MANDY, KENTWISTLE, SAROBB,,E MERCURI,
DH SKUSE, F MUNTONI - UK
Background: Variable neurobehavioural disorders and intelligence quotient (IQ)
one SD below average are recognised comorbidities in Duchenne muscular dystrophy
(DMD), reflecting the disrupted expression of different length dystrophin
isoforms in the brain, based on the site of the dystrophin gene mutation.
Objective: Our objective was to assess the neurobehavioural profile of DMD
and its relation to genotype. Methods: Following a screening of 84 DMD
boys with validated questionnaires, we previously reported 15 with severe
learning disability and 41 with scores predictive of autistic spectrum disorder
(ASD). Attention deficit and hyperactivity disorder (ADHD) traits, conduct and
emotional problems were also described. Overall, a higher proportion of boys
affected had mutations towards the 3’ end of dystrophin. We performed targeted
neuropsychological assessments including: Wechsler Intelligence Scale for
Children-IV (WISC-IV), Developmental Dimensional and Diagnostic Interview (3Di),
Conners-3 Questionnaires, Child Behaviour Checklist (CBCL).Results: We
found marked unevenness of performance on the WISC-IV. Eight out of 12 boys had
significant difference between verbal comprehension (VCI) and perceptual
reasoning (PRI), with VCI more compromised. Eight out of 19 met criteria for ASD
on the 3Di. In five boys with ASD the CBCL showed higher scores for internalising
and externalising difficulties compared to non-ASD. There were associations
between lower IQ and autistic social communication difficulties. On the Conners
6/17 boys met criteria for hyperactivity and 7 for inattention problems. There
was a strong association between ASD and severe ADHD symptoms of hyperactivity (OR=22.5)
and inattention (OR=54). There was a trend towards children with mutations
towards the 3’ end of the gene, having a greater chance of ASD (OR=3.4).
Conclusions: In our on-going study, we confirmed ASD prevalence rates and
other neurobehavioural disorders much higher in DMD than the general population.
Children with DMD should be provided with neurobehavioural-targeted support.
6 - (Developmental Medicine & Child Neurology, 2013) Audit of unexpected weight loss in patients with Duchenne muscular dystrophy (also presented at UK Neuromuscular Translational Conference 2012)
R KULSHRESTHA, N SWIDERSKA, ,H STUART,S
SPINTY - UK
Background: Significant proportion of individuals affected by Duchenne muscular
dystrophy (DMD) are overweight, a number
are at risk of weight loss with disease progression. Poor nutrition can
potentially have a negative effect on every organ system and
can contribute to reduced life expectancy. Objective: To identify the causes for
weight loss in this patient group as a potential marker for deterioration in
organ systems that might be amenable to targeted intervention. Method: Included
in this retrospective observational study were individuals with DMD who were 10
years of age or older, who experienced weight loss in last 5 years. Descriptive
statistics used to analyse the data in view of small numbers. Results: We identified
19/77 (24.7%) patients (age 11–17yr) who experienced 30 episodes of weight loss.
The average weight loss was 6.29% (1.1–31%). Weight loss was attributed to
various reasons: respiratory deterioration (3), cardiovascular deterioration
(2), infections (2), combined problems of respiratory, cardiovascular and
gastroenterological deterioration (9), worsening scoliosis (1), post surgery (4)
and deliberate weight loss (2). No cause iden-tified in seven episodes (23.3%).
Paired data were available for left ventricular fractional shortening and
sitting forced vital capacity (FVC) 6 months prior and at the time of weight
loss in 10 and 14 episodes respectively. 6/14 (43%) had reduction of FVC by an
average of 7.7%. There was no change in fractional shortening. The average time
to regain weight was 7.6 months (2–12m). 13 (43%) episodes had weight loss of
>5% and 9 (47%) took longer than 6 months to regain weight.
Conclusion: Our study shows unexpected weight loss in patients with DMD might be
more frequent than expected. Combined
respiratory, cardiovascular and gastroenterological causes were responsible for
weight loss in majority. Unexpected weight loss
can be a marker for potential organ deterioration that should prompt a detailed
history, examination, targeted investigations
and supportive management.
6- (Stem Cells Trans Med, Dec 2012) Injection of Vessel-Derived Stem Cells Prevents Dilated Cardiomyopathy and Promotes Angiogenesis and Endogenous Cardiac Stem Cell Proliferation in mdx/utrn–/– but Not Aged mdx Mouse Models for Duchenne Muscular Dystrophy
Ju Lan Chun, Robert O'Brien, Min Ho Song, Blake F. Wondrasch, and Suzanne E. Berry - USA
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. DMD patients lack dystrophin protein and develop skeletal muscle pathology and dilated cardiomyopathy (DCM). Approximately 20% succumb to cardiac involvement. We hypothesized that mesoangioblast stem cells (aorta-derived mesoangioblasts [ADMs]) would restore dystrophin and alleviate or prevent DCM in animal models of DMD. ADMs can be induced to express cardiac markers, including Nkx2.5, cardiac tropomyosin, cardiac troponin I, and α-actinin, and adopt cardiomyocyte morphology. Transplantation of ADMs into the heart of mdx/utrn−/− mice prior to development of DCM prevented onset of cardiomyopathy, as measured by echocardiography, and resulted in significantly higher CD31 expression, consistent with new vessel formation. Dystrophin-positive cardiomyocytes and increased proliferation of endogenous Nestin+ cardiac stem cells were detected in ADM-injected heart. Nestin+ striated cells were also detected in four of five mdx/utrn−/− hearts injected with ADMs. In contrast, when ADMs were injected into the heart of aged mdx mice with advanced fibrosis, no functional improvement was detected by echocardiography. Instead, ADMs exacerbated some features of DCM. No dystrophin protein, increase in CD31 expression, or increase in Nestin+ cell proliferation was detected following ADM injection in aged mdx heart. Dystrophin was observed following transplantation of ADMs into the hearts of young mdx mice, however, suggesting that pathology in aged mdx heart may alter the fate of donor stem cells. In summary, ADMs delay or prevent development of DCM in dystrophin-deficient heart, but timing of stem cell transplantation may be critical for achieving benefit with cell therapy in DMD cardiac muscle.