From 16th to 18th March 2018 a workshop about nutrition in Duchenne muscular dystrophy (DMD) was held in Zaandam, the Netherlands, organized by Parent Project The Netherlands. During the workshop researchers, clinicians, patient representatives and industry discussed the role of nutrition and metabolism in the disease process, the need for further research and the importance of guidelines for patients and their caretakers.
The absence of dystrophin also has an effect on metabolic processes (processes occurring in the body to convert food into energy). These disturbances play a role in the disease process. Also corticosteroids that are used by most patients, can cause side effects like obesity. Furthermore food intake is often altered in patients due to chewing and swallowing problems and the use of energy is often decreased, especially in non-ambulant patients. All these changes may worsen the disease and have an impact on the quality of life. The importance of nutrition, however, is often neglected. Little is known about the precise role and good guidelines are lacking.
Over-the-counter nutritional supplements are widely taken by patients, but exact numbers are not known, since they are often used on their own initiative. The only two supplements that are currently widely recommended are vitamin D and calcium if intake via food is insufficient. Supplements might potentially have beneficial effects, but might also have deleterious effects or interact with other medication. Therefore caution should be taken and it is wise to discuss this with a dietitian/pharmacist.
Why are nutritional guidelines and research important for DMD?
During this first session was discussed what is currently known about nutrition in DMD. One of the problems is that there is not much scientific evidence to support the clinical practice.
Obesity is a major problem in DMD, requiring better approaches for weight management. That is one of the reasons why it is important that dietitians are part of the care team from the beginning of the disease process. They can explain the importance of healthy eating habits and monitor if vitamin D and calcium intake is sufficient. Vitamin D and calcium are both important for maintaining healthy bones. It was discussed which would be the key moments in the life of a Duchenne patients that advice should be given. For example if major changes take place, like the loss of ambulation.
Many patients use corticosteroids. It is currently unclear what is the best strategy if the patient gains a lot of weight. Stopping with corticosteroids might not necessarily be the best choice, since it is proven they also have many beneficial effects.
The life expectancy of Duchenne boys has increased a lot over the recent years. However, care guidelines are still mainly for children. New guidelines should also take adult patients into account, since malnutrition is often observed and gastrointestinal problems (e.g. constipation and bloating). An adult patient was present to share his experiences and views. He knows it is important to maintain a healthy weight, but indicated there is a lack of information where especially to pay attention to in his diet. He also discussed the challenges he is facing in daily life, especially now he becomes older.
The main action points of the day were that easier ways to measure weight in non-ambulant patients are needed. Furthermore dietitians should play a larger role in the treatment of DMD, whereby it is important that dietary advices are easily implementable in daily life.
Preclinical and clinical research on nutritional aspects
The next session focused on nutrition-related research, both preclinical (experiments in cells and animal models) and clinical (experiments involving patients).
One of the major problems with preclinical experiments is that there is too much variability in experimental procedures between different labs. This hampers the reproducibility of experiments, since sometimes completely different results are obtained between labs. Therefore a taskforce has been established that aims to standardise experimental procedures. This would hopefully lead to more reproducible results and increase the chance of positive results if medicines are later tested clinically.
Several mouse models exist for DMD of which the mdxmouse is most widely used. Studies have been performed testing the effect of diet on these mdxmice and healthy (wildtype) mice, whereby different effects in mdxversus wildtype mice were seen, which indicates diet may have an effect on the disease severity and progression. In humans the protein intake is usually skewed (protein intake is usually low at breakfast and lunch compared to dinner), which does not support optimal muscle synthesis. In mice was noticed that the intervals at which meals are fed has an impact on muscle mass and weight. Mice fed at specific intervals had an improved body composition. A better spreading of protein intake over the day could be beneficial.
The role of mitochondria in DMD was also discussed. Mitochondria are the energy suppliers of cells. There are indications that absence of dystrophin also has an impact on the mitochondria. Therefore medicines that try to improve the mitochondrial function may also be beneficial for DMD.
Ongoing research in other fields
Research in other fields could be relevant to the Duchenne field too. Therefore speakers from other fields were invited to share their views.
Since most regular assessment methods for assessing height, weight and body composition are not suitable for wheelchair-dependent patients, alternative methods are needed. Several alternative methods have shown reliable and reproducible results; however, another complication is that the reference values for healthy individuals are not suitable. Therefore there is a need for DMD-specific reference charts.
There are already many medicines as well as nutriceuticals (food compounds that have proven to have a positive effect on health) on the market for other diseases. Some of these may also have a positive effect on DMD, so called repurposing. The advantage of these compounds is that they are already quite extensively tested in humans on safety and toxicity. A company that is specialised in repurposing drugs, uses computational models to find possible candidates. There is a lot known about the underlying disease mechanisms of DMD, which facilitates this approach. Candidates are first tested in cells and mouse models and when they show positive effects they may move to clinical research. Currently there are already several repurposed drugs tested in clinical trials, for example tamoxifen or green tea extract.
Current knowledge and clinical practice
The current knowledge and clinical advices around swallowing and dental problems, and bone health were discussed.
Swallowing and chewing can become problematic if the disease worsens. This is partly caused by weakening of the facial muscles, but also due to changes in the shape of the dental arches and thickening (and reduces motility) of the tongue. To make eating more easy, changes in food structure and intake are advised. Providing food in smaller pieces or using more liquid food could be an option. In advanced stages gastrointestinal tube feeding is an option. Drinking water after every meal is recommended.
Dental health is often neglected, while caries and loss of teeth impair eating abilities even more. It is advised to rinse well after eating, regularly brush the teeth, take preventive measures (such as fluoride and sealants) and avoid certain types of food and drinks (i.e. sticky, sugar rich, especially in combination with a low pH).
The bones are also affected in DMD, which is worsened by the use of corticosteroids. Due to the decrease of the bone density, there is an increased risk of fractures, which can lead to earlier loss of ambulation. Currently it is advised to take additional vitamin D, possibly in combination with calcium.
Working groups on need for further research and guidelines
At the final day working groups were formed to discuss strategies and set action points for future research and nutritional guidelines.
One group focused on the clinical research in the field of nutrition. They concluded that there is a need for research on the natural course of the disease, regarding body composition, glucose metabolism, dental involvement and supplement use. Therefore, a survey among DMD patients/caregivers would be a good tool to get inside in e.g.the extent of feeding-related problems, and measures that are currently taking and advices given to prevent or treat these problems. Also research is required to make reference charts specific for DMD and get insight in the changes in body composition occurring during the progression of the disease. The psychological aspect of eating should not be neglected. What are the barriers to change eating-related habits and reluctance to start gastrointestinal tube feeding, while patients could really benefit from this?
The second group discussed pre-clinical research. Since the currently mostly used animal model for DMD (mdxmouse) has several disadvantages, animal models that better reflect the human disease could better be used. However, good data on the natural course of the disease in these models is lacking, thereby hampering their use. Therefore, research into the natural course of the disease in these models is needed. This could be used to facilitate nutrition-related research (e.g.on body composition) and to evaluate the benefits of nutritional supplements. Furthermore, a major problem is the lack of reproducibility of research results between different labs. Therefore guidelines to get more standardised procedures will be made.
The last group focused on guidelines on nutrition for patients and their parents/caregivers. The current guidelines are very brief and general. New guidelines should be more detailed and address the different ages and stages of the disease. The guidelines should be simple, easily implementable and disseminated in easily accessible ways. It was agreed to make three videos and one-page information sheets for a) childhood, b) late childhood and adolescents (teens and twenties) and c) adults. The three videos will discuss 1) weight (over- and underweight), 2) the use of nutritional supplements and 3) gastrointestinal tube feeding. They should become available in different languages. Furthermore social media should be used to react on hypes and news related to nutrition.