What is Muscular Dystrophy?

The term “muscular dystrophy” refers to a group of different genetic diseases that all result in muscular deterioration over time. Most commonly, the muscles in the arms and legs are weakened initially, but sometimes weakening of the heart muscles (cardiomyopathy) or other muscles occurs as well. Respiratory failure is common in late-stage muscular dystrophy and is a frequent cause of death.

There is currently no cure for muscular dystrophy. However, new research is uncovering particular genetic mutations associated with different types of muscular dystrophy; these not only help diagnose the different forms of the disease, but also with potential emerging therapies.

Several natural interventions such as coenzyme Q10 and creatine may help complement conventional treatments and improve quality of life.

What are the Signs and Symptoms of Muscular Dystrophy?

Note: There are many types of muscular dystrophy, and they can present different symptoms and appear at different stages in life. The following are some common symptoms:

• Difficulty walking or getting up from a seated position
• Walking on tiptoes (in children learning to walk)
• Enlarged calf muscles
• Waddling gait
• Learning disabilities
• Gastrointestinal complaints
• Weakening muscles (different diseases will affect different muscles)
• In certain forms of the disease, difficulty swallowing and keeping eyes open/closed
• Hearing loss beginning in infancy
• Abnormal heart rhythm

What are the Conventional Medical Treatments for Muscular Dystrophy?

Note: There is currently no cure for muscular dystrophy. However, certain therapies described below may help delay symptoms and improve muscle function.

• Physical therapy
• Corticosteroids
• Other treatments are also available to help manage the side effects of muscular dystrophy, including drugs to block muscle spasms, antiepileptics, surgery for scoliosis, and other supportive care.

What are Emerging Therapies to Treat Muscular Dystrophy?

• Exon skipping is an investigational technique that can help compensate for the mutations in the dystrophin gene that cause dysfunctional muscle proteins
• Proteasome inhibitors to prevent breakdown of muscle proteins

What Dietary and Lifestyle Changes Can Help Manage Muscular Dystrophy?

Dietary and lifestyle changes cannot directly impact muscular degradation. However, many people with muscular dystrophy have limited mobility, which makes proper nutrition essential. A high-fiber, high-protein, low-calorie diet with proper fluid intake is recommended for many patients with muscular dystrophy.

What Natural Interventions Can Help Manage Muscular Dystrophy?

• Coenzyme Q10. Coenzyme Q10, in combination with corticosteroid treatment, may help increase muscle strength.
• Resveratrol. In animal models of muscular dystrophy, resveratrol treatment decreased inflammation and protected the hearts against enlargement and fibrosis.
• Creatine. Treatment with creatine, alone or in combination with corticosteroids, lengthened the time for patients to fatigue and increased muscle strength.
• Omega-3 fatty acids. In animal models of muscular dystrophy, a diet rich in omega-3 fatty acids prevented degeneration of skeletal muscle.
• Vitamin D and calcium. Vitamin D and calcium are essential for muscle and bone function. Decreased bone density is common in some forms of muscular dystrophy, and increasing vitamin D and calcium levels improved bone mass in some patients.
• Taurine. Taurine, alone or in combination with corticosteroids, improved functional measures of muscle health in an animal model.
• Glutamine. Glutamine supplementation in patients with the most common form of muscular dystrophy was associated with inhibition of protein degradation.
• Other promising natural interventions for muscular dystrophy include L-carnitine, melatonin, green tea, vitamin E and selenium, and N-acetylcysteine.

“Muscular dystrophy” refers to a large group of clinically diverse genetic diseases that lead to deterioration of muscle structure and function over time (Mercuri 2013). While weakness and functional decline in peripheral muscles, such as those of the arms and legs, are common in muscular dystrophies, function of the heart muscle (myocardium) can be affected as well, a condition called cardiomyopathy. Respiratory failure is also common in late-stage muscular dystrophy and represents a frequent cause of death (Mayo Clinic 2012). In some forms of muscular dystrophy, weakness may be evident at birth or during childhood, while in other forms signs and symptoms of progressive weakness do not emerge until later in adulthood (Amato 2011).

As research continues to identify the particular genes associated with the various types of muscular dystrophy, the medical community is transitioning from a classic characterization system based on physical symptoms (such as the pattern of muscle weakness) to a system based on the detection of mutations in specific genes. In addition to diagnosis, treatment methods are evolving along with the increased understanding of the genetic background of muscular dystrophies. The hope is that new therapies can be designed to target the underlying biology of these devastating diseases (Amato 2011; Mayo Clinic 2012; Chatterjee 2003).

Currently, no cure is available for muscular dystrophy. However, corticosteroid medications may help delay onset of certain symptoms and increase muscle strength in some patients (Beytía 2012). Also, a variety of interventions, such as physical therapy and speech therapy, can help delay some aspects of functional decline for individuals with muscular dystrophy.

Several natural interventions, such as coenzyme Q10 and creatine, may complement conventional treatment modalities and enhance quality of life for muscular dystrophy patients. For instance, creatine, a natural compound found in muscle tissue, has been studied in the context of neuromuscular disorders for nearly 20 years, with several human clinical trials of creatine supplementation showing benefit in neuromuscular diseases (Chung 2007; Klopstock 2000; Louis 2003). Moreover, breakthroughs in genetic technologies continue to inch us closer to a method of overcoming challenges that have historically made muscular dystrophies so daunting. For example, a cutting-edge technology called exon skipping, which allows scientists to “bypass” defective regions in genes, is currently making its way from preliminary clinical trials to phase II and III trials (Iftikhar 2020; Dzierlega 2020). It is hoped that within the not-to-distant future, innovations in technology will deliver effective treatments for the muscular dystrophies.

This protocol will outline some of the basic features of the various types of muscular dystrophies, and touch on the growing knowledge about the genetics underlying these complex diseases. The diagnosis and conventional treatment of muscular dystrophies will be discussed, as will some emerging therapeutic strategies that may one day improve outlook for patients with these diseases. Finally, several important dietary and lifestyle considerations will be discussed, and a number of scientifically evaluated natural therapies will also be reviewed.

There are several types of muscular dystrophy; some form of genetic mutation is responsible for them all. Between the various types of muscular dystrophy, mutations in different genes lead to dysfunction in one or more of the many proteins responsible for normal muscle cell function. Gene mutations can lead to alterations in normal cellular activity, contribute to increased oxidative stress, cause mitochondrial dysfunction, and increase the rate of cell death. As an increasing quantity of muscle cells die over time, they are replaced by fibrotic, adipose (fat), and connective tissue, and the patient’s functional capacity declines (Mayo Clinic 2012; Tidball 2007).

Genetic mutations may be inherited from the parents or may occur spontaneously during reproduction. In the latter case, clinical disease may arise even in children whose parents do not carry a genetic mutation associated with muscular dystrophy (NINDS 2011; Mayo Clinic 2012).

Incidence of muscular dystrophy is dependent upon the specific type of disorder. Duchenne muscular dystrophy (DMD) is the most common type, and the inheritance pattern is sex-linked, occurring at a rate of 1 case per 3500 male births (Dubowitz 1995). Also, people who are born into families with a history of muscular dystrophies have a higher risk of developing them or passing them on to their children (Mayo Clinic 2012).

Duchenne Muscular Dystrophy (DMD)

Mutations in a gene called dystrophin are responsible for the most common form of muscular dystrophy—Duchenne muscular dystrophy (Briguet 2008; Wang 2009; Muir 2009; Pilgram 2010). The dystrophin protein is responsible for maintaining muscle strength, so when the dystrophin gene is mutated in a way that prevents the dystrophin protein from being produced or functioning normally, muscles become weak (CDC 2012).

DMD occurs more frequently in young males, and accounts for approximately half of all muscular dystrophies (CDC 2012; Mayo Clinic 2012). In DMD, muscle weakness typically starts in the pelvis and legs, but can also occur in the arms, neck, and other regions of the body (PubMed Health 2013), while muscles of the face are normally spared. Calf muscles are also enlarged due to an accumulation of fatty tissue (NINDS 2011). People with DMD usually lose their ability to walk sometime between 7 and 13 years of age (CDC 2012), and they often die of respiratory failure before reaching age 40 as a result of damage to muscles that control breathing. About two-thirds of DMD cases run in families and one-third are caused by spontaneous mutations (NINDS 2011).

Females who carry the mutation usually do not display any symptoms, but about 8–10% of them will show some manifestation of the disease. When these symptoms do occur, they are typically more minor than the severe muscle weakness seen in males (Bushby 2005).

Signs and symptoms usually become evident when the child starts walking and may include (NINDS 2011; CDC 2012; Mayo Clinic 2012):

• Clumsiness and falling more often than other children of the same age
• A delay in walking
• Difficulty getting up from the sitting or lying position
• Difficulty running and jumping
• Walking on tip toes
• Large calf muscles
• A waddling gait
• A delay in using language
• Learning disabilities

Approximately 90% of patients with DMD die from cardiomyopathy (a chronic heart disease in which the heart muscle is thickened, abnormally enlarged, or stiffened) or muscular respiratory failure (Finsterer 2006). Endocrine (hormonal) problems also appear in DMD (as well as some other muscular dystrophies), and the glucocorticoid medications frequently used for treatment can have additional adverse effects on the hormonal system (Ashizawa 2011). Furthermore, some studies have reported that DMD patients have problems with blood clotting, which can complicate surgery (Morrison 2011).

Becker muscular dystrophy (BMD)

Becker muscular dystrophy (BMD) is also caused by mutations to the dystrophin gene. Together, DMD and BMD are collectively known as “dystrophinopathies,” since they both arise as a consequence of dystrophin mutations.

While similar to DMD, BMD has significantly milder symptoms (Mayo Clinic 2012). These differences are attributed to the type of mutation that arises in the dystrophin gene. If the dystrophin gene is mutated in a way that leads to very little or no dystrophin protein, then the patient has more severe symptoms and is diagnosed with DMD. However, if the gene is mutated in a way that simply lowers the production of dystrophin protein, then the effect is less severe and those people are diagnosed with BMD (CDC 2012).

The incidence of BMD is approximately one-tenth that of DMD (Finsterer 2008; CDC 2012). Clinical disease also starts later, from as young as age 11 to as late as age 25, and patients typically live into middle age or later (NINDS 2011; Mayo Clinic 2012). In BMD, cardiac involvement usually starts later, in the third decade of life.

Myotonic dystrophy (DM)

Myotonic dystrophy (DM) usually has a late onset, between ages 20 and 30, and has a slowly progressive course. Thus, patients typically live longer than those with more severe forms of muscular dystrophy (Schara 2006; NINDS 2011). Two forms of DM are described (DM1 and DM2), and they share certain features, though they are caused by two different genetic mutations (DMPK for DM1 and CNBP for DM2). DM2 is usually less severe than DM1 (NHGRI 2012). About 1 in 8000 people are affected by DM worldwide, and DM1 is more common in most populations, although the frequency of DM1 and DM2 is similar in people from Germany (NIH Genetics Home Reference 2013A; NHGRI 2012). In the majority of populations, DM1 (also called Steinert’s disease) appears to be more common (NIH Genetics Home Reference 2013A). DM1 is also the most common form of adult-onset muscular dystrophy (NINDS 2011; Romeo 2012). DM1 affects both men and women and typically becomes more severe with progressive generations, a phenomenon known as “anticipation” (Ekström 2010; NINDS 2011; Romeo 2012; Sahenk 2011).

A genetic diagnosis for DM became available in 1992 after researchers came to understand that both DM1 and DM2 are caused by a genetic phenomenon called a “triplet repeat.” For this type of mutation, a certain 3 “letter” section of the genetic code is erroneously repeated many times (eg, CTG-CTG-CTG-CTG…); the more times the triplet is repeated, the greater the likelihood of disease occurrence and severity (Brook 1992; NINDS 2011). An interesting finding in DM1 is that the levels of serum coenzyme Q10 (CoQ10) are significantly and inversely related to the degree of the triplet repeat expansion; in other words, lower CoQ10 levels are associated with a greater number of triplet repeats (Siciliano 2001).

Myotonia—the inability to quickly relax muscles after a sudden contraction—is characteristic of DM (NINDS 2011). Cataracts and retinal or corneal changes are a few of the main eye problems in patients with DM1. Heartburn, regurgitation, bloating, and abdominal pain are some gastrointestinal complaints that have been reported (Ekström 2010; Ashizawa 2011).

Distal Muscle Dystrophy

Distal muscle dystrophy refers to a group of at least six muscle diseases that affect both males and females, usually between the ages of 40 and 60. As the name implies, distal muscle dystrophy affects distal muscle groups, which are muscle groups located furthest from the core of the body (eg, forearms, hands, lower legs, and feet). Often, diseases in this group affect fewer muscles, are less severe, and progress more slowly than other forms of MD (NINDS 2011). Although the molecular genetics of the various types of distal muscular dystrophy are still being delineated, mutations in the dysferlin gene, which codes for a protein of the same name thought to be involved in muscle repair, have been implicated (Kawai 2011).

Congenital Muscular Dystrophies (CMDs)

Congenital muscular dystrophies (CMDs) include a group of conditions that vary in severity and age of onset. Over 10 genes have been implicated in the formation of various congenital muscular dystrophies (Sparks 2011; Mercuri 2012).

In patients with CMD, muscle weakness and muscle tissue abnormalities are present from birth or before age 2 (Mayo Clinic 2012). Some CMD patients show normal intellectual development, while others have severely impaired cognition (NINDS 2011). It is anticipated that with developments in genetic technologies it will soon be easier to identify the different forms of CMD (Mercuri 2012).

Limb-girdle Muscular Dystrophy (LGMD)

Limb-girdle muscular dystrophy (LGMD) was, for many years, diagnosed based on the exclusion of other dystrophies. In recent years, however, several genetically-distinct subtypes have been discovered and over 12 forms can now be specifically identified. This group includes muscular dystrophies characterized by weakness, wasting, and impaired reflexes in proximal muscles, or muscles closest to the core of the body (eg, shoulder and hip reflexes) (Rocha 2010; NINDS 2011), while facial muscles are generally spared. In addition, intelligence is unaffected, and cardiomyopathy occurs in some LGMD patients (NINDS 2011).

Emery-Dreifuss Muscular Dystrophy

Emery-Dreifuss muscular dystrophy is another progressive neuromuscular degenerative disease. Three genes have been associated with this condition (Walter 2007; Bonne 2010). It is characterized by the triad of early-onset contractures (which describe an abnormal shortening of tissue at joints including the elbows and ankles), slowly progressive muscle weakness, and cardiac involvement (Ellis 2006; Bonne 2010; NINDS 2011).

Almost all patients have to use pacemakers for their heart problems by the age of 30, and females can develop heart problems without having any signs of muscle weakness (NINDS 2011). Furthermore, the involvement of respiratory muscles may cause respiratory difficulties and respiratory failure (Simonds 2002), with pneumonia as a possible complication (Amato 2011).

Fascioscapulohumeral Muscular Dystrophy (FSHD)

Fascioscapulohumeral muscular dystrophy (FSHD) affects approximately 1 in 20 000 individuals worldwide (Tawil 2008; Scionti 2012). As the name suggests, it leads to a progressive weakness in the muscles of the face (generally being more severe for the lower muscles of the face), shoulders, and upper arms. Muscles of the eyes and mouth are often the first ones affected (NINDS 2011). As a result, patients often cannot close their eyes completely and are unable to smile, which gives them a flat affect (Sahenk 2011; NINDS 2011). Muscles of the lower shoulders, chest, and abdomen may also be affected (NINDS 2011), and one of the earliest telltale signs of this disease is the inability to reach above shoulder level, due to the weakness of the muscles that stabilize the shoulder blade (Tawil 2008).

Extramuscular involvement includes high-frequency hearing loss that usually starts in early infancy (NIH 2011), irregularities in the capillaries of the eyes (Paunescu 2006), and an abnormal heart rhythm (Tawil 2008).

Oculopharyngeal Muscular Dystrophy (OPMD)

Oculopharyngeal muscular dystrophy (OPMD) includes conditions that affect both males and females and do not appear until the fourth or fifth decade of life. This type of muscular dystrophy is distributed worldwide. In the United States, it mostly affects people of French-Canadian descent and Hispanic individuals from northern New Mexico. The earliest symptom of OPMD is ptosis (or drooping eyelids), which affects both eyes, but asymmetrically. This symptom is sometimes so severe that people have to compensate by tilting back their head and raising their eyebrows (Abu-Baker 2007; NINDS 2011). Additional weakness in the facial and pharyngeal muscles often makes swallowing difficult. Initially, this is apparent for solid foods but, as the disease progresses, it also occurs for liquids (Abu-Baker 2007; NIH Genetics Home Reference 2013B).

Several types of tests can be used to diagnose and monitor patients with muscular dystrophy (CDC 2012; NINDS 2011):

Enzyme testing

• Creatine kinase (CK) testing, also known as creatine phosphokinase (CPK), is the most specific test for muscular dystrophy. CK is an enzyme that helps regulate cellular energy and is particularly concentrated in muscle cells, where a lot of power needs to be produced. In patients with muscular dystrophy, the muscle cells become damaged and release creatine kinase into the blood stream. In DMD and BMD patients, blood creatine kinase levels are at least 10–20 times higher than in normal individuals, and often much higher (Bushby 2005). Early in the disease process, CK levels are 50–300 times greater than normal levels, but the levels tend to decrease as muscle mass decreases. All patients suffering from muscular dystrophy incur CK elevation during active disease, and the finding of 3 elevated levels obtained one month apart is diagnostic for the disease.
• Patients with muscular dystrophy also have higher blood levels of aldolase, another enzyme concentrated in muscle cells, which is involved in the cellular metabolism of fructose and glucose (GHR 2013).

Genetic testing

Genetic testing can confirm a diagnosis for muscular dystrophies in which an affected gene has been identified and a laboratory test exists. Specific methods used include the following.

• The polymerase chain reaction (PCR) is a method that examines a patient’s DNA to identify mutations in the affected genes. PCR can be used to detect more than 98% of existing genetic deletions, and it can be performed within 24 hours.
• If a PCR test detects a genetic defect, another type of test, called Southern blot, may be used for confirmation (Bakker 2013).

Muscle biopsy

A small piece of muscle is removed and analyzed to help distinguish muscular dystrophy from other muscle diseases. Until the advent of molecular biology techniques, muscle biopsy was the definitive test for diagnosing and confirming muscular disease.

• Immunofluorescence is a technique used to stain proteins of interest (ie, dystrophin) in thin sections of tissue, usually collected from a muscle biopsy. 
• Electron microscopy can visualize changes in the integrity of cellular structures inside muscle cells (Kyriacou 1997; NINDS 2011).

Neurophysiology studies

• In electromyography (EMG), a tiny needle containing an electrode is used to record the electrical activity between a nerve and its muscle.
• Nerve conduction velocity studies measure how quickly electrical impulses are communicated in nerves.
• Repetitive stimulation studies measure how well a muscle responds to electrical stimulation, a measurement of muscle function (NINDS 2011).

Additional testing

• Muscle ultrasound can examine damaged muscles, but not all the muscles can be evaluated using ultrasound techniques. Alternatively, magnetic resonance imaging (MRI), a noninvasive, painless procedure, allows the visualization of all muscles. In recent studies, magnetic resonance spectroscopy (MRS), another noninvasive approach, has shown promise for the evaluation of skeletal muscle involvement in DMD (Finanger 2012).
• Exercise tests help to track functional decline over time.
• Cardiac MRI can evaluate heart complications that accompany most muscular dystrophies. It has become the gold standard for characterizing heart anatomy and function (Otto 2012).
• Audiograms are necessary in patients diagnosed with the infantile form of fascioscapulohumeral muscular dystrophy for the early detection of hearing loss (Tawil 2008).
• Surveillance by ophthalmoscopy is needed in patients with fascioscapulohumeral muscular dystrophy to detect the presence of fluid in the eye caused by retinal telangiectasias (Tawil 2008).
• Periodic electrocardiography is recommended, usually every 2 years, because patients with certain forms of muscular dystrophies develop heart defects like cardiomyopathy (Amato 2011; Rocha 2010).

Genetic Counseling Genetic counseling is helpful for muscular dystrophy patients and their family members (NINDS 2011; Morrison 2011). A genetic counselor helps family members and/or patients understand these diseases, and can help guide decision making regarding genetic testing. Two tests can be performed in pregnant mothers who want to know whether their baby has the disease: An amniocentesis removes a small bit of amniotic fluid that surrounds the fetus and contains fetal DNA. This DNA can then be tested for the presence of the mutation. Chorionic villus sampling involves the collection of a very small portion of the placenta, which also has fetal DNA that can be tested.

No cure is currently known for muscular dystrophy, but physical therapy may help patients retain muscle function and strength (NIH 2012). A multidisciplinary approach involving neurologists, psychiatrists, physical and occupational therapists, speech and respiratory therapists, dietitians, psychologists, and genetic counselors is ideal. These professionals have to work together to meet the needs of each individual patient (Amato 2011).

Physical and Speech Therapy

Physical therapy is recommended as a general principle to prevent deformities and promote walking (Rocha 2010; NINDS 2011). Some scientists recommend active and/or passive stretching 4–6 days a week for specific joints or muscle groups to prevent or decrease the extent of contractures (Bushby 2010B). However, others have pointed out that stretching programs can often be painful and ineffective. Furthermore, in animal models, some forms of exercise were shown to cause a more rapid deterioration of muscle function; professional guidance is ultimately recommended when considering exercise programs (Morrison 2011).

Speech therapy is particularly useful for patients with weakened facial and throat muscles. Special communication devices, such as voice synthesizers, are also sometimes required (NINDS 2011).

Medications

Pharmacologic treatments for dystrophinopathies were deemed ineffective until 1974, when corticosteroids were demonstrated to provide a short-term increase in muscle strength (Griggs 2011; Morrison 2011). Some additional interventions have been developed since then that have improved muscular dystrophy treatment outcomes.

• Corticosteroids have been shown to prolong the time that DMD patients can walk (by 2 years) and to prevent scoliosis (curvature of the spine). They are the only therapeutic strategy that has been consistently shown to be effective for the treatment of DMD (Malik 2012). Moreover, corticosteroids are the preferred therapy to increase muscle strength (Beytía 2012). While effective, researchers still are not sure exactly how corticosteroids work (Strober 2006; NINDS 2011). Based on experience, corticosteroid therapy should be initiated in boys with DMD who are able to walk before they experience a plateau in their physical performance, and well before they lose their ability to walk (Bushby 2005).

Weakening and enlargement of the heart occurs in over 90% of DMD patients over 18 (Manzur 2009). A historical cohort study of DMD cases undergoing repeated cardiac evaluations from 1998–2002 revealed that, if started before evidence of heart failure, corticosteroids can delay the development of heart rhythm abnormalities (Markham 2008).

Adverse effects of corticosteroid treatment include short stature, acne, fluid retention, weight gain, growth retardation, asymptomatic cataracts, glucose intolerance, osteopenia (lower bone density), and fractures (NINDS 2011). These side effects sometimes limit the long-term use of corticosteroids (Walter 2007; Morrison 2011). Growth failure is of particular concern in boys with DMD receiving high-dose glucocorticoids. In 2012, the first study was performed that examined the effects of growth hormone in boys with DMD who had glucocorticoid-induced growth failure. The study found that after 1 year, growth hormone helped improve growth and did not cause adverse cardiopulmonary or neuromuscular effects (Rutter 2012).

• Angiotensin-converting enzyme (ACE) inhibitors are used to treat congestive heart failure and hypertension. In an animal model that develops symptoms similar to DMD, ACE inhibitors help to protect against deterioration of the heart muscle (Politano 2012). Furthermore, human clinical evidence revealed that a >60-month treatment with perindopril (Coversyl®), a long-acting ACE inhibitor, delayed the onset of left ventricular dysfunction in children with DMD, although some have questioned the methodological rigor of the study (Politano 2012; Domingo 2011).
• Tumor necrosis factor-alpha (TNF-α) inhibitors. Drugs that bind to and inhibit the inflammatory cytokine TNF-α, such as etanercept (Enbrel®), help reduce local muscle inflammation and delay the damage to muscle cells (Wang 2009).
• Drugs that block muscle spasms, such as dantrolene (Dantrium®) and mexiletine (Mexitil®), have also been used to prevent DM-associated muscle spasms and weakness (NINDS 2011).
• Antiepileptics. The frequency of epilepsy is higher in people with DMD than the general population (Pane 2013). In these cases, antiepileptic drugs such as carbamazepine (Tegretol®, Carbatrol®), phenytoin (Dilantin®), clonazepam (Klonopin®), and felbamate (Felbatol®), are used to control seizures (NINDS 2011).
• Antibiotics are important for treating respiratory infections (NINDS 2011).

Exon skipping

The most common type of mutation in the dystrophin gene occurs when one or more exons are deleted. This causes a near-to-complete loss of the dystrophin protein. When the deletion causes a shift in the “reading frame” (the grouping of nucleotides to form the blueprint for coding the protein) it is referred to as an out-of-frame intragenic deletion mutation and is associated with more severe disease. Deletions comprise 60‒65% of the mutations that occur in DMD. Duplication mutations (when extra exons are added) make up 5‒15% of DMD cases, while the remaining cases can be caused by several different types of mutations (Muntoni 2003).

A treatment that has shown at least some benefit for patients with muscular dystrophy is called exon skipping (Iftikhar 2020). This strategy bypasses the errors in the exons of the dystrophin gene so transcription can occur with high fidelity. As of late 2020, there are three exon skipping drugs FDA approved for the treatment of DMD patients. These drugs utilize short pieces of antisense oligonucleotides that mask the mutated region in the dystrophin pre-mRNA that is later used to instruct the assembly of the dystrophin protein. As a result, instead of there being a complete loss of dystrophin, there will be at least a truncated dystrophin produced, which is similar to a BMD type protein. This is not expected to completely reverse the symptoms of DMD but hopefully lead to a meaningful improvement (Iftikhar 2020).

Each of these three approved drugs have been shown in clinical trials to cause a statistically significant increase in dystrophin levels; however, this has so far failed to translate into meaningfully improved clinical status. Clinical research is very limited, and post-marketing pharmacovigilance is necessary to assess long-term safety and efficacy. If ongoing studies do not generate significant benefit, the FDA may withdraw their approval (Darras 2020).

In 2016, eteplirsen (Exondys 51) became the first of the three drugs to receive approval (Iftikhar 2020; DHHS 2016). It is approved for patients amenable to exon 51 skipping, which is applicable to approximately 13% of those with DMD (Darras 2020). This approval was controversial, as the clinical data was not robust. In a randomized controlled clinical study, patients were randomized to receive either weekly intravenous infusions of eteplirsen or placebo for 25 weeks; the placebo group was then switched to receive active drug in an open-label manner until 48 weeks (Mendell 2013). Participants who received the drug for the full duration of the study walked a significantly greater distance during a 6-minute walk test compared with the placebo/delayed drug group at 48 weeks. Some data suggest eteplirsen may do more to delay DMD disease progression than improve late-stage symptoms; it is currently being prescribed pediatrically (Dzierlega 2020; Darras 2020).

In 2019, golodirsen (Vyondys 53) received approval for patients amenable to exon 53 skipping, which is applicable to approximately 8% of those with DMD (Dzierlega 2020; FDA 2019). A preliminary trial in children found that dystrophin levels increased with golodirsen treatment and is currently investigating if it will yield a clinical benefit at week 144; results are expected to come soon (Frank 2020). In addition, a current phase III clinical study (ESSENCE) is recruiting patients to determine the efficacy of golodirsen in addition to a new investigational antisense oligonucleotide drug for patients amenable to exon 45 skipping (Sarepta Therapeutics, Inc. 2020).

In 2020, viltolarsen (Viltepso) became the latest drug approved for DMD; it is also approved for patients amenable to exon 53 skipping (FDA 2020). In functional tests from clinical research, viltolarsen-treated patients had some improvement over historical controls in their performance on a 6-minute walk test and time to run/walk 10 meters (Clemens 2020). Mild-to-moderate adverse events were observed. A follow-up study is currently evaluating the long-term effects of this drug (Clemens 2019).

Ataluren (Translarna, PTC124), an exon-skipping drug approved in the European Union and United Kingdom, but not currently approved in the United States, targets nonsense mutations in the dystrophin gene (Darras 2020). Nonsense mutations form premature stop codons which terminate protein translation early, resulting in a truncated and dysfunctional dystrophin protein. This is the etiology in approximately 10‒15% of those with DMD (Muntoni 2003; McDonald 2017). Ataluren is a different type of compound compared to the antisense oligonucleotide type drugs, and it acts directly on the ribosome instead of the pre-mRNA in order to selectively skip its target exons (McDonald 2017). In a phase II study, only minimal benefits were observed in muscle strength and time functions (Darras 2020). In a phase III randomized trial, patients treated with ataluren did not improve their scores on the 6-minute walk test; however, there was improvement in a specified subgroup of participants (McDonald 2017).

Supportive Care

Supportive care has to be tailored to every patient’s particular circumstance and condition. Examples of this type of therapy include:

• Assisted ventilation is often needed in the later stages of muscular dystrophy to compensate for weakness in respiratory muscles (NINDS 2011). Daytime assisted ventilation is usually required in boys with DMD when their vital capacity, which is the maximum amount of air that can be exhaled after a forced breath, drops to 60% or below.
• Orthopedic devices, such as ankle-foot orthoses (orthopedic appliances that support deformed joints and/or bones), help prevent contractures and are often worn for life (NINDS 2011). Standing devices, such as knee-ankle-foot orthoses, have to be considered on an individual basis. They are usually offered to boys at the point when they can take only a few steps without help, and were shown to prolong walking for an average of 1.5–2 years (Kinali 2007; Guglieri 2011).
• Cardiac pacemaker implantation may be advised for some muscular dystrophy patients, as heart rhythm abnormalities may occur in some types of muscular dystrophy (Boriani 2003).
• Vaccination is important to prevent death from infectious diseases (eg, influenza) in patients with many types of dystrophy, who are especially prone to infection after respiratory failure (Amato 2011; Bushby 2010B; Guglieri 2011).
• Assistance with eating. Patients with DMD often have difficulty chewing and swallowing. Continued episodes of choking may lead to fear of eating and can prolong the length of mealtimes. Feeding difficulties were reported in 30% of DMD patients under age 25 (Aloysius 2008). A clinical assessment of swallowing is indicated when there is a 10% unintentional weight loss or a decline in the expected weight gain based on age (Bushby 2010B). Due to their swallowing difficulties, patients with oculopharyngeal muscular dystrophy could become socially withdrawn, and they should be advised about the possibility to eat before or after social gatherings, if they deem it necessary (Brais 2011).
• Pain management is a complex task in muscular dystrophies. Depending on the cause, pain management can range from physical therapy to drugs and, more rarely, orthopedic interventions (Bushby 2010B).
• Psychosocial management is an important intervention, particularly for more severe forms of muscular dystrophy. Treatment should be guided by prevention and early intervention. The increased rate of depression among DMD patients underscores the need to offer supportive interventions to patients and their families (Bushby 2010A).

Surgery

Scoliosis represents a major problem in patients with muscular dystrophy, particularly when children lose the ability to walk (Strober 2006). In addition, when left untreated, scoliosis can further affect respiratory function (Finsterer 2006). Patients with DMD who are not treated with glucocorticoids have a 90% chance of developing significant scoliosis. Scoliosis is generally progressive and can cause vertebral compression fractures (a collapse of the vertebrae after being weakened by osteoporosis) and affect respiratory function. However, while daily glucocorticoid administration reduces the risk of scoliosis and/or delays its onset, it also increases the risk of vertebral fractures (Bushby 2010B).

Alternatively, surgery can be used to correct scoliosis. The best timing for surgery is generally when the patient’s lung function is still satisfactory and before symptomatic heart problems start (Finsterer 2006). For lower limb contractures, no unanimous recommendations exist with regard to the timing of surgery. The type of intervention depends on individual circumstances and whether they are performed during the patient’s ambulatory (mobile) or non-ambulatory period (Bushby 2010B). Spinal stabilization through surgery is usually recommended before the curve of the spine reaches 30 degrees, because at more advanced stages, cardiopulmonary weakness makes surgery more risky (Strober 2006). Spinal fusion prevents further deformation of the spine, straightens the spine, eliminates pain, and slows respiratory decline (Bushby 2010B). Surgery can also be used to correct eyelid ptosis (drooping eyelid) and can be performed in patients with OPMD. Finally, in patients with a moderate to severe impairment of swallowing, surgery can be used to improve swallowing (Brais 2011).

While dietary changes are not enough to directly impact muscle degeneration, proper nutrition is essential because many patients with muscular dystrophy have limited mobility or are inactive due to muscle weakness. These limitations predispose them to obesity, dehydration, and constipation (NINDS 2011).

Nutritional requirements in patients with DMD have received relatively little attention, as revealed by a survey of 1491 articles conducted in 2009. This survey found only 6 articles that directly investigated nutritional requirements in boys with DMD, and only 3 of them were focused on younger children (Davidson 2009; Davoodi 2012). Nevertheless, this is an important aspect of management because steroid use, which is often started in early childhood, can exacerbate weight gain in many patients. Weight gain and obesity (attributed to mobility limitations) are more frequent in the early stages of muscular dystrophy, while malnutrition and weight loss are more common in later stages of the disease when patients have difficulty swallowing, breathing, or walking independently (Davidson 2009; NINDS 2011). In addition, obesity can further worsen the neuromuscular problems, as well as cardiovascular and respiratory function (Guglieri 2011; Morrison 2011).

A high-fiber, high-protein, low-calorie diet with proper fluid intake has been recommended for most patients with muscular dystrophy (NINDS 2011). For patients with OPMD, a high-protein diet is especially recommended, but can sometimes be challenging as swallowing difficulties become more accentuated, particularly for hard-to-chew foods, such as meat (Brais 2011).

Coenzyme Q10. Coenzyme Q10 (CoQ10) is a strong antioxidant and plays a central role in cellular energy production. Evidence from human and animal studies implicates CoQ10 deficiency in the development of some forms of muscular dystrophy (Folkers 1995; Siciliano 2001; Tedeschi 2000). 

A study that examined CoQ10 and a combination of CoQ10 and resveratrol in an animal model revealed that high-dose CoQ10 and the CoQ10/resveratrol combination therapy decreased muscle damage and increased muscle integrity (Potgieter 2011). In a pilot study conducted on 12 children with DMD undergoing treatment with corticosteroids, addition of CoQ10 supplementation sufficient to achieve a serum CoQ10 level of 2.5 mg/mL led to an 8.5% increase in muscle strength (Spurney 2011). Furthermore, a 12-month clinical trial that administered idebenone, a synthetic analogue of CoQ10, to 13 children with DMD found improved cardiac and respiratory markers compared to placebo (Buyse 2011).

Two additional clinical trials, cumulatively comprising 27 patients with various forms of muscular dystrophy including DMD, DM, BMD and LGMD, revealed that 100 mg of CoQ10 daily for 3 months improved heart parameters and subjective measures of physical performance compared to placebo. In the first trial, functional improvements corresponded with increasing blood levels of CoQ10 from 0.5 – 0.85 µg/mL prior to treatment to 1.1 – 2.9 µg/mL after treatment. Additional benefits may have been seen with higher dosing since some patients’ blood levels of CoQ10 did not increase significantly. The authors conclude, “Patients suffering from these muscle dystrophies and the like, should be treated with vitamin Q10 indefinitely” (Folkers 1995). Life Extension® suggests an optimal CoQ10 level of at least 3 µg/mL.

Resveratrol. Resveratrol is a phytochemical found in grape skins, Japanese knotweed, and red wine. Its administration for 32 weeks in an animal model of muscular dystrophy led to significantly less muscle loss compared to a control group. Oxidative damage in muscle tissue also decreased significantly with resveratrol supplementation (Hori 2011). Another study conducted on experimental mice that do not express dystrophin revealed that resveratrol supplementation decreased inflammation and increased the genetic coding of a protein called utrophin, which can functionally replace dystrophin (Gordon 2012; ParentProjectMD 2012). Additional evidence suggesting resveratrol may represent an important intervention in muscular dystrophy derives from a 2013 animal model wherein oral administration of resveratrol to genetically dystrophin-deficient mice protected the animals’ hearts against enlargement and fibrosis and restored cardiac function (Kuno 2013).

Creatine. Long used as a supplement by athletes to enhance strength, endurance, and muscle recovery after exercise, creatine may also benefit people with muscular dystrophy. Creatine is a naturally occurring amino acid-like compound that helps provide energy for muscle cells. Evidence suggests it has musculoskeletal and neuroprotective effects (Pearlman 2006; Radley 2007; Tarnopolsky 2011). When creatine is metabolized by the body, it enters muscle cells and promotes protein synthesis and reduces protein breakdown (Hespel 2001; Persky 2001). In addition, it functions as an antioxidant and activates stem cells in muscles that have the ability to self-renew and contribute to regeneration after injury and damage (Tarnopolsky 2011; Relaix 2012). Studies in an animal model of DMD revealed that creatine supplementation improves mitochondrial function (mitochondria are the “powerhouses” of cells), increases muscle health, and decreases muscle cell death (Passaquin 2002).

A clinical trial in which creatine monohydrate (0.1 g/kg/day) was administered to boys with DMD for 4 months found an increase in their fat-free mass and hand grip strength, which occurred independently of steroid usage (Radley 2007). Another study looking at patients with DMD and BMD reported that supplementation with 3 g/day of creatine for 3 months almost doubled the length of time it took for subjects to fatigue (Pearlman 2006). Supplementation was well tolerated in both children and adults, and the benefits also extended to patients undergoing treatment with corticosteroids (Tarnopolsky 2011). In another clinical trial, children and adults with muscular dystrophy were given creatine at doses of 5 and 10 g/day, respectively, for 8 weeks. The treatment was well tolerated and the researchers reported a modest improvement in muscle strength and day-to-day activities.  Benefits were evident in all types of muscular dystrophy studied, which included DMD, BMD, FHMD, and LGMD (Walter 2000). A study that employed technologically advanced methods to monitor muscle physiology in children with DMD found that daily supplementation with 5 g of creatine for 8 weeks led to enhanced cellular energy metabolism; the effect was more pronounced in subjects under 7 years of age (Banerjee 2010).

Omega-3 fatty acids. Omega-3 fatty acids are essential components of cellular membranes. In an animal model of muscular dystrophy, degeneration of skeletal muscle was prevented in animals fed a diet enriched in omega-3 fatty acids from birth until death. The animals fed omega-3 fatty acids had larger muscle cells and were able to more efficiently repair injured muscle. In fact, the preservation of skeletal and heart muscle structure was so pronounced that it improved the animals’ longevity. This study only found benefits when omega-3 supplementation was initiated at weaning, before muscle damage started; it did not appear to be useful when supplementation was initiated in adulthood. This finding, which reveals that results can be obtained solely by dietary intervention, supports the idea that affecting the essential components of cell membranes may also provide a strategy to ameliorate muscular dystrophy in humans (Fiaccavento 2010).

Vitamin D. Vitamin D and calcium are essential for muscle and bone growth and function. Vitamin D supplementation is especially important for patients with severe forms of muscular dystrophy, such as DMD, because: 1) The patients’ bone density is often decreased as a result of decreased mobility, 2) osteoporosis is more frequent in these patients as a result of the adverse effects of corticosteroid treatment, and 3) a decreased exposure to sunlight decreases vitamin D levels (Beytía 2012). A prospective study that included 33 boys with DMD showed that two years of treatment with calcidiol (25-hydroxy vitamin D), combined with an adjusted dietary calcium intake equal to the internationally recommended daily allowance, corrected the vitamin D deficiency and increased bone mass in about two-thirds of the participants (Bianchi 2011).

Taurine. The organic compound taurine is distributed throughout the body and is especially abundant in skeletal muscle, where it functions as an antioxidant and is essential for cellular growth and function (Silva 2011). In fact, mice genetically prone to taurine deficiency display incomplete and abnormal muscular development and decreased capacity for exercise (Miyazaki 2013). Moreover, evidence from an animal experiment shows that taurine supplementation improves muscle performance and protects against damage during electrical stimulation (Goodman 2009).

A few animal studies suggest taurine may confer benefits in muscular dystrophy. In one animal model, mice with muscular dystrophy were given a glucocorticoid (prednisolone) or taurine alone or in combination for 4 – 8 weeks. While both treatments improved functional measures of muscle health, combined treatment with both compounds acted synergistically to augment the functional improvement beyond what was achieved with either alone (Cozzoli 2011). Another mouse model of muscular dystrophy found that taurine supplementation countered the negative effects of excessive exercise over 4 – 8 weeks (De Luca 2003).

In a small human trial on nine patients with myotonic dystrophy, taurine administration led to a significant improvement in myotonia and improved function of muscle cell membranes. The researchers observed no significant side effects of taurine treatment (Durelli 1983).

Glutamine. In an animal model of muscular dystrophy, supplementation with L-glutamine was found to decrease the ratio of oxidized to total skeletal muscle glutathione, indicating that glutamine may be protective against oxidative stress (Mok 2008). In a study on boys with DMD, 13 boys receiving 0.5 g/kg/day glutamine orally for 10 days were compared to a control group of 13 boys who received a nonspecific amino acid mix. Overall, glutamine supplementation was associated with an inhibition of protein degradation (Mok 2006). Another group of researchers analyzed the rate of glutamine synthesis in six children with DMD in comparison with healthy controls. They found that glutamine synthesis was significantly reduced in children with DMD and concluded glutamine “might therefore be a 'conditionally essential' amino-acid in DMD” (Hankard 1999).

L-Carnitine.  L-carnitine is an amino-acid-like compound important for fat metabolism. It is evolving as a promising new potential therapy, based on laboratoryexperiments with DMD patient muscle cells, where it seems to restore muscle cell membrane fluidity (Le Borgne 2012). This is important because a deficiency of dystrophin is known to cause alterations in membrane fluidity and permeability that lead to an increase in reactive oxygen species and muscle damage (Malik 2012).

Melatonin. Melatonin is a hormone most frequently associated with the sleep-wake cycle. It is also a powerful antioxidant that protects cells from the damage caused by free oxygen radicals. In an animal model of muscular dystrophy, melatonin administration increased the total amount of glutathione (a powerful endogenous antioxidant), lowered the ratio of oxidized to reduced glutathione, and lowered the activity of plasma creatine kinase, all actions that work to protect cells from damage (Hibaoui 2011). Melatonin also reduced plasma creatine kinase levels in boys with DMD, and decreased their markers of inflammation (Chahbouni 2010). Furthermore, levels of oxidative stress in red blood cells, which are normally increased in DMD, were lowered after 3 months of melatonin treatment (Chahbouni 2011).

Green tea. Green tea contains powerful phytochemicals that benefit health in several ways; one of its major active constituents is the polyphenol epigallocatechin gallate (EGCG). In an animal model of muscular dystrophy, 1 week of supplementation with green tea extract reduced muscle deterioration by approximately 35% (in a leg muscle). The same researchers later found that green tea extract greatly improved muscle force and resistance to fatigue with 1 week of supplementation. However, these effects were not seen after 5 weeks of supplementation, suggesting that green tea may prevent, but not counteract, muscle degeneration (Dorchies 2006). A study that subcutaneously administered EGCG to mice (4 times a week for 8 weeks) found a delay in the onset of muscle damage, without adverse effects. The benefits included a decrease in serum creatine kinase activity levels back to normal, an increase in the area occupied by muscle fibers relative to damaged tissue in the diaphragm and certain leg muscles, and a positive effect on muscle contraction (Nakae 2008). Another animal model of muscular dystrophy showed that 21-day-old male mice that had their diet supplemented with green tea extract had a 128% increase in their total running distance over 3 weeks (Call 2008).

Vitamin E and Selenium. Vitamin E and selenium are antioxidants that protect cells against damage. In several animal species, selenium deficiency causes disorders that resemble muscular dystrophy; supplementation prevents these disorders. In boys with DMD who received selenium and vitamin E for one year, followed by a one-year observation period without treatment, a slightly more rapid deterioration of muscle strength was reported in the second year when they did not receive any treatment. This finding may suggest that treatment with selenium and vitamin E provided a slight delay in deterioration (Gamstorp 1986). Another study identified a new selenoprotein, a type of protein that contains a special amino acid residue called selenocysteine, which was involved in a congenital type of muscular dystrophy (Moghadaszadeh 2001). This finding supports the idea that the variable effectiveness observed from supplementation may actually be explained by different underlying disease causes (Moghadaszadeh 2001; Rederstorff 2006).

N-acetylcysteine. N-acetylcysteine (NAC) is an antioxidant and has been shown to decrease muscle damage and increase muscle force in an animal model of muscular dystrophy. NAC added to the drinking water of animals was found to reverse the dysregulation of dystrophin-associated proteins caused by oxidative stress and reduce the expression NF-κB, a factor involved in inflammation and muscle damage. The authors conclude, “Our data show that NAC can provide considerable protection against the ongoing muscle degeneration in intact mdx mice [an animal model of DMD] and against damage resulting from stretched contractions. The logical extension of these findings is to combine NAC, or other antioxidants, with blockers of parallel damage pathways … in order to provide a more effective therapeutic approach for DMD.” Although encouraging, clinical trials are needed to test its potential utility in humans (Malik 2012; Whitehead 2008).