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L-carnitine supplementation in duchenne muscular dystrophy steroid-naïve patients: A pilot study

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Abstract

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder characterized by progressive weakness leading to disability. Steroid administration and physiotherapy are the most useful medical interventions in ambulant patients; In DMD, muscles present a significant deficiency of L-carnitine compared to normal subjects. Nutritional supplements are used to support management. We evaluated the effect of L-carnitine supplementation in patients that were not under steroid treatment. A double blind, controlled trial was performed in 20 patients assigned to L-carnitine or placebo treatment for one year, dose of (50 mg/ kg) twice daily. Evaluations were performed every 4 months and results were analyzed using ANOVA. Variables such as age, weight, and disease onset were similar in both groups. L-carnitine supplementation was well tolerated; no significant side effects were reported during and after treatment. Clinical evaluations showed no differences between groups (p>0.05). L-carnitine supplementation does not significantly improve the function of upper and lower extremities of DMD steroid-naïve patients
... More specifically, both palmitoyl carnitine transferase and palmitoyl coenzyme A hydrolase are increased, whereas palmitoyl carnitine hydrolase is absent in DMD. The latter is an important component in carnitine metabolism and could explain the results obtained in a pilot study conducted in 2013 on a small number of steroid-naïve DMD boys with Lcarnitine supplementation, showing no difference in the function of the upper and lower extremities [29,30]. An inhibitor of p38 named SB203580 provided contradictory results in mdx myotubes during in vitro experiments and in mdx mice tissue and seems to be of lesser value as a therapeutic molecule. ...
... miR-206 is known for activating a large array of proteins such as HDAC4, PTB, utrophin, Fstl1, Cx43, and TIMP3 and for inhibiting IGF-1, Pax3, and Pax7 [25]. Despite promising results in mdx mice with (ALA)/L-carnitine (L-car) and its FDA approval, the absence of palmitoyl carnitine hydrolase in DMD muscle and its essential role in carnitine metabolism, makes this molecule uninteresting to consider as a stabilizing agent as it did not show any difference in function of extremities in DMD patients [29][30][31]. Considering the JNK inhibitor JIP1 is less interesting as it is generally administered through adenoviral infection, which makes it less suitable. The NF-ƘB inhibitors PDTC and IRFI-042 and the AP-1 inhibitor batimastat (Table 3) can all be orally ingested. ...
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In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.
... As it acts by transporting long-chain fatty acids into the mitochondrial matrix, its bioavailability is directly related to the rate of ß-oxidation, which was found to be slow in DMD muscle [57], as were reduced carnitine levels [58]. With 95% of carnitine residing in skeletal muscle and since this tissue largely depends on fatty acids as an energy source, its use has been tried in DMD (50mg/kg/day) in an unsuccessful trial [59]. In Becker muscular dystrophy (BMD), a low level of carnitine was found and supplementation has been observed to be beneficial in some cases [60]. ...
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In Duchenne muscular dystrophy (DMD), the absence of dystrophin from the dystrophin-associated protein complex (DAPC) causes muscle membrane instability, which leads to myofiber necrosis, hampered regeneration, and chronic inflammation. The resulting disabled DAPC-associated cellular pathways have been described both at the molecular and the therapeutical level, with the Toll-like receptor nuclear factor kappa-light-chain-enhancer of activated B cells pathway (NF-ƘB), Janus kinase/signal transducer and activator of transcription proteins, and the transforming growth factor-β pathways receiving the most attention. In this review, we specifically focus on the protein kinase A/ mitogen-activated protein kinase/nuclear factor of activated T-cells 5/organic osmolytes (PKA-p38MAPK-NFAT5-organic osmolytes) pathway. This pathway plays an important role in osmotic homeostasis essential to normal cell physiology via its regulation of the influx/efflux of organic osmolytes. Besides, NFAT5 plays an essential role in cell survival under hyperosmolar conditions, in skeletal muscle regeneration, and in tissue inflammation, closely interacting with the master regulator of inflammation NF-ƘB. We describe the involvement of the PKA-p38MAPK-NFAT5-organic osmolytes pathway in DMD pathophysiology and provide a clear overview of which therapeutic molecules could be of potential benefit to DMD patients. We conclude that modulation of the PKA-p38MAPK-NFAT5-organic osmolytes pathway could be developed as supportive treatment for DMD in conjunction with genetic therapy.
... These results suggest that carnitine supplementation could improve muscle membrane stability in DMD. Escobar-Ceclillo and colleagues [ 59 ] performed a double-blinded, controlled trial in DMD patients assigned to L -carnitine (50 mg/kg, twice daily) or placebo treatment for 1 year. Overall, L -carnitine was well tolerated but did not improve muscle function in steroid-naïve boys. ...
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Appropriate nutrition is a fundamental contributor to the health and quality of life of boys with Duchenne muscular dystrophy (DMD), yet there are few nutrition guidelines. DMD is an X-linked disease caused by mutations in the gene encoding the dystrophin protein resulting in its absence from a number of tissues. Striated and smooth muscles are essential to digestion, and both are dysfunctional in the absence of dystrophin. Obesity and underweight are prevalent within the condition. Nutritional assessment involves determining nutrient needs and reviewing anthropometric and biochemical data, physical findings, nutritional implications of medications, and the client history. The purpose of this chapter is to provide guidance to the members of the multidisciplinary healthcare team, but especially the physician and registered dietitian. Herein, we review existing research and make recommendations for nutritional assessment, including strategies to counter fundamental nutrition concerns for DMD boys. In addition, common nutrient constituents and supplements, reported to alleviate some deleterious aspects of DMD, and potential drug-nutrient interactions are reviewed.
Article
Purpose To provide evidence-based guidance specific to allied health and nursing practice for the assessment and management of individuals with Duchenne muscular dystrophy (DMD). Materials and methods Thirteen key focus areas were identified in consultation with health professionals and consumer advocacy groups. A series of systematic literature reviews were conducted to identify assessment and management strategies for each key focus area. A consensus process using modified Delphi methodology, including an Australia-New Zealand expert consensus meeting, was conducted. Recommendations underwent consultative review with key groups before being finalised and prepared for dissemination. Results This clinical practice guideline (CPG) generated 19 evidence-based recommendations, 117 consensus-based recommendations and five research recommendations across the 13 focus areas to inform allied health assessment and management of individuals with DMD. Conclusions The resulting recommendations can be used in conjunction with existing medical CPGs to improve, standardise and advocate for allied health and rehabilitation care in DMD. The process used here may be useful for the development of CPGs in other rare diseases. • Implications for rehabilitation • Implementation-ready evidence-based statements to guide clinical care of individuals with DMD are provided with the potential to improve participation, function in the community and quality of life. • A model for developing best practice statements for other rare neurological diseases is described. • Allied health and nursing health professionals should focus research efforts to generate quality evidence to support rehabilitation practice.
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Duchenne muscular dystrophy (DMD) arises as a consequence of mutations in the dystrophin gene. Dystrophin is a membrane-spanning protein that connects the cytoskeleton and the basal lamina. The most distinctive features of DMD are a progressive muscular dystrophy, a myofiber degeneration with fibrosis and metabolic alterations such as fatty infiltration, however, little is known on lipid metabolism changes arising in Duchenne patient cells. Our goal was to identify metabolic changes occurring in Duchenne patient cells especially in terms of L-carnitine homeostasis, fatty acid metabolism both at the mitochondrial and peroxisomal level and the consequences on the membrane structure and function. In this paper, we compared the structural and functional characteristics of DMD patient and control cells. Using radiolabeled L-carnitine, we found, in patient muscle cells, a marked decrease in the uptake and the intracellular level of L-carnitine. Associated with this change, a decrease in the mitochondrial metabolism can be seen from the analysis of mRNA encoding for mitochondrial proteins. Probably, associated with these changes in fatty acid metabolism, alterations in the lipid composition of the cells were identified: with an increase in poly unsaturated fatty acids and a decrease in medium chain fatty acids, mono unsaturated fatty acids and in cholesterol contents. Functionally, the membrane of cells lacking dystrophin appeared to be less fluid, as determined at 37°C by fluorescence anisotropy. These changes may, at least in part, be responsible for changes in the phospholipids and cholesterol profile in cell membranes and ultimately may reduce the fluidity of the membrane. A supplementation with L-carnitine partly restored the fatty acid profile by increasing saturated fatty acid content and decreasing the amounts of MUFA, PUFA, VLCFA. L-carnitine supplementation also restored muscle membrane fluidity. This suggests that regulating lipid metabolism in DMD cells may improve the function of cells lacking dystrophin.
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The purpose of this study was to evaluate the quality of life (QoL) of patients with Duchenne muscular dystrophy (DMD) in different stages of the disease, by means of the Life Satisfaction Index for Adolescents (LSI-A). The practicality of this scale was also verified. The LSI-A was applied four times to 95 patients with DMD who were undergoing steroid therapy, at three-month intervals. The patients were divided into four groups according to age. The results from the four applications and the inter and intra-examiner concordance were treated statistically. Comparing the different age groups, patients with DMD did not lose QoL, even with disease progression. We concluded that, in spite of the progressive course of the disease, the QoL in patients with DMD does not get worse. The use of a scale that embraces a great diversity of circumstances in patients' lives, without considering clinical aspects excessively, is a good alternative for assessing the QoL of these patients.
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The recent development of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify clinical outcome measures for planned efficacy studies. Although several studies have reported the value of functional scales, timed tests, and measures of endurance aimed at ambulant individuals, less has been done to identify reliable measures of function in individuals who have lost ambulation. The aim of this paper is to provide a critical review of the existing literature on functional measures assessing upper extremity function in DMD. Four observer-rated, performance-based measures and four self-reported scales have been previously used in DMD. Each scale provides useful information but none reflects all the different levels of functional ability in activities of daily living observed in individuals with DMD at different ages.
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Randomized, placebo-controlled single blinded study was carried out to evaluate the effect of oral creatine supplementation on cellular energetics, manual muscle test (MMT) score and functional status in steroid-naive, ambulatory boys suffering with Duchenne muscular dystrophy (DMD; n=33). Eighteen patients received creatine monohydrate (Cr; 5 g/day for 8 weeks), while 15 received placebo (500 mg of vitamin C). Phosphorus metabolite ratios were determined from the right calf muscle of patients using phosphorus magnetic resonance spectroscopy ((31)P MRS) both prior to (baseline) and after supplementation of Cr or placebo. In addition, metabolite ratios were determined in normal calf muscle of age and sex matched controls (n=8). Significant differences in several metabolite ratios were observed between controls and DMD patients indicating a lower energy state in these patients. Analysis using analysis of covariance adjusted for age and stature showed that the mean phosphocreatine (PCr)/inorganic phosphate (Pi) ratio in patients treated with Cr (4.7; 95% CI; 3.9-5.6) was significantly higher (P=.03) compared to the placebo group (3.3; 95% CI; 2.5-4.2). The mean percentage increase in PCr/Pi ratio was also more in patients <7 years of age compared to older patients after Cr supplementation indicating variation in therapeutic effect with the age. In the placebo group, significant reduction in PCr/Pi (P=.0009), PCr/t-ATP (P=.05) and an increase in phosphodiester (PDE)/PCr ratios was observed after supplementation. Further, in the placebo group, patients <7 years showed reduction of PCr/t-ATP and Pi/t-ATP compared to older patients (>7 years), after supplementation. These results imply that the significant difference observed in PCr/Pi ratio between the Cr and the placebo groups after supplementation may be attributed to a decrease of PCr in the placebo group and an increase in PCr in the Cr group. Changes in MMT score between the two groups was significant (P=.04); however, no change in functional scale (P=.19) was observed. Parents reported subjective improvement on Cr supplementation versus worsening in placebo (P=.02). Our results indicated that Cr was well tolerated and oral Cr significantly improved the muscle PCr/Pi ratio and preserved the muscle strength in short term. However, this study provides no evidence that creatine will prove beneficial after long-term treatment, or have any positive effect on patient lifespan.
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Duchenne muscular dystrophy (DMD) is a severe, progressive disease that affects 1 in 3600-6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation-University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.