Evidence-based Guideline: Diagnosis and Treatment of Limb-Girdle Muscular Dystrophy

Evaluation and medical management of muscular dystrophies

In this section we address monitoring and medical management of complications.

Cardiac involvement. Clinical context. Our systematic review reveals that many, though not all, muscular dystrophy subtypes have associated cardiac involvement (EVID). Muscular dystrophy patients with cardiac involvement often do not have symptoms such as chest pain, pedal edema, or palpitations that precede cardiac morbidity or sudden cardiac death. Serious cardiac manifestations in patients with muscular dystrophy are often identified only with cardiology testing (PRIN). The detection and appropriate management of cardiac dysfunction are important to reduce morbidity and mortality (PRIN). Patients with muscular dystrophy often have improved quality of life following appropriate pharmacologic treatment, device placement, or surgical intervention for their cardiac involvement (RELA).^e506
Recommendations.

E1. Clinicians should refer newly diagnosed patients with

1. 
   LGMD1A, LGMD1B, LGMD1D, LGMD1E, LGMD2C–K, LGMD2M–P, BMD, EDMD, and MFM
   
2. 
   muscular dystrophy without a specific genetic diagnosis
   

for cardiology evaluation, including ECG and structural evaluation (echocardiography or cardiac MRI), even if they are asymptomatic from a cardiac standpoint, to guide appropriate management (Level B).
E1a. If ECG or structural cardiac evaluation (e.g., echocardiography) is abnormal, or if the patient has episodes of syncope, near-syncope, or palpitations, clinicians should order rhythm evaluation (e.g., Holter monitor or event monitor) to guide appropriate management (Level B).
E2. Clinicians should refer muscular dystrophy patients with palpitations or who are found to have symptomatic or asymptomatic tachycardia or arrhythmias for cardiology evaluation (Level B).
E3. Clinicians should refer muscular dystrophy patients with signs or symptoms of cardiac failure for cardiology evaluation (e.g., medical management, left ventricular assist device placement, or cardiac transplantation, as deemed necessary by the cardiologist) to prevent cardiac death (Level B).
Clinical context. Our systematic review found that muscular dystrophy patients with certain genetic subtypes (LGMD2A, LGMD2B, and LGMD2L) are at very low risk of concomitant cardiac involvement during the course of their disease (EVID). Asymptomatic patients with these muscular dystrophy subtypes would not benefit from cardiac testing. They would only be exposed to the added risk and costs associated with this testing. The quality of life in asymptomatic muscular dystrophy patients with genetic subtypes at very low risk of concomitant cardiac involvement is not improved by cardiology evaluation and testing (INFER).
Recommendation.

E4. It is not obligatory for clinicians to refer patients with LGMD2A, LGMD2B, and LGMD2L for cardiac evaluation unless they develop overt cardiac signs or symptoms (Level B).

Clinical context. Our systematic review has demonstrated an important risk of symptomatic involvement of both skeletal muscle and cardiac muscle in female carriers of dystrophinopathy and emerinopathy (EVID). About 15% of carriers of dystrophinopathy have cardiac involvement before 15 years of age. This increases to about 45% in patients above 15 years of age. Similarly, about 18% of female carriers of emerinopathy over the age of 60 years have typical ECG abnormalities (EVID). Carriers of these disorders may not have obvious symptoms of skeletal muscle or cardiac involvement (PRIN). The detection and appropriate management of skeletal muscle weakness and cardiac dysfunction is important in order to reduce morbidity and mortality (PRIN). Patients with muscle weakness and cardiac involvement from other disorders often have improved quality of life following appropriate management and treatment of cardiac dysfunction (RELA).^e507-e509
Recommendation.

E5. Clinicians should encourage female carriers of dystrophinopathy and emerinopathy to seek evaluation by a neuromuscular specialist and a cardiologist to assess for skeletal muscle and cardiac muscle involvement and to proactively treat cardiac involvement (Level B).

Dysphagia and nutrition. Clinical context. Patients with muscular dystrophy may have difficulty receiving adequate oral intake due to dysphagia and/or inability to feed themselves due to excessive arm weakness (EVID). Maintaining adequate nutrition and body weight is important for optimizing strength, function, and quality of life (PRIN). When oral intake is inadequate, other means of maintaining intake, such as gastrostomy or jejunostomy feeding tubes, may be needed to maintain optimal nutrition (PRIN). There is evidence from related conditions (ALS) that maintenance of nutrition and body weight prolongs survival (RELA).^e501
Recommendation.

F1. Clinicians should refer muscular dystrophy patients with dysphagia, frequent aspiration, or weight loss for swallowing evaluation and/or gastroenterology evaluation to assess and manage swallowing function and aspiration risk, to teach patients techniques for safe and effective swallowing (e.g., “chin tuck” maneuver, altered food consistencies, etc.), and to consider placement of a gastrostomy/jejunostomy tube for nutritional support (Level B).

Pulmonary complications.

Clinical context. Our systematic review demonstrates that some forms of muscular dystrophy are associated with oropharyngeal or ventilator muscle weakness and that patients with these forms are at high risk for developing respiratory failure during the course of their disease. Patients with LGMD2B and LGMD2L rarely, if ever, have symptomatic respiratory involvement from their disease (EVID). Patients with respiratory failure from neuromuscular-related weakness often do not have symptoms, such as dyspnea, that precede the onset of respiratory failure. Impending respiratory failure in these patients is often identified only with pulmonary function tests (PRIN). Respiratory failure constitutes a major source of morbidity, interfering with daytime cognitive function and negatively affecting quality of life (PRIN). In addition, ventilatory and oropharyngeal weakness can threaten survival through the risk of upper airway obstruction and/or bellows failure (RELA).^e501 Patients with respiratory failure secondary to muscle weakness often have improved quality of life with noninvasive pulmonary ventilation (RELA).^e501
Recommendations.

G1. Clinicians should order pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright and, if normal, supine positions) or refer for pulmonary evaluation (to identify and treat respiratory insufficiency) in muscular dystrophy patients at the time of diagnosis, or if they develop pulmonary symptoms later in their course (Level B).

G1a. In patients with a known high risk of respiratory failure (e.g., those with LGMD2I or MFM), clinicians should obtain periodic pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright position and, if normal, in the supine position) or evaluation by a pulmonologist to identify and treat respiratory insufficiency (Level B).
G2. It is not obligatory for clinicians to refer patients with LGMD2B and LGMD2L for pulmonary evaluation or pulmonary function testing unless they are symptomatic (Level C).
G3. Clinicians should refer muscular dystrophy patients with excessive daytime somnolence, nonrestorative sleep (e.g., frequent nocturnal arousals, morning headaches, excessive daytime fatigue), or respiratory insufficiency based on pulmonary function tests for pulmonary or sleep medicine consultation for consideration of noninvasive ventilation to improve quality of life (Level B).
Cognitive dysfunction and learning disabilities. Clinical context. Although cognitive dysfunction, reduced IQ, and learning disabilities are not major factors in most patients with limb-girdle muscular dystrophy, they are noted in a few disorders, such as BMD and those disorders that cause a primary or secondary defect in α-dystroglycan (EVID). Identification and management of these disorders is important to delineate special needs and to provide the resources necessary for these patients to live as normal a life as possible (PRIN).
Recommendation.

H1. In muscular dystrophy patients with symptoms suggestive of cognitive dysfunction or learning disabilities, clinicians may order neuropsychological testing, MRI of the brain, and/or developmental pediatrics consultation to assess for and optimally manage CNS involvement (Level C).

Spinal deformities. Clinical context. Our systematic review has revealed the risk of evolving musculoskeletal spine deformities, such as scoliosis, kyphosis, or rigid spine syndrome, in various muscular dystrophies (EVID). These musculoskeletal deformities can result in discomfort and functional impairment, interfering with gait, activities of daily living, and pulmonary function (PRIN). The proper management of musculoskeletal spine deformities is important in order to reduce discomfort, preserve mobility or ability to sit in a wheelchair, and reduce pulmonary complications (RELA).^e506
Recommendations.

I1. Clinicians should monitor patients with muscular dystrophy for the development of spinal deformities to prevent resultant complications and preserve function (Level B).

I2. Clinicians should refer muscular dystrophy patients with musculoskeletal spine deformities to an orthopedic spine surgeon for monitoring and surgical intervention if it is deemed necessary in order to maintain normal posture, assist mobility, maintain cardiopulmonary function, and optimize quality of life (Level B).
Osteoporosis. Clinical context. Our systematic review did not provide evidence regarding monitoring for osteoporosis with bone density testing (EVID). However, sedentary lifestyle is one risk factor for osteoporosis (PRIN). Therefore, patients with limb-girdle muscular dystrophy causing limited mobility may be prone to osteoporosis (INFER). They are also prone to falls and therefore may be at a high risk for injuries, including fractures (PRIN). The injuries may in turn further limit mobility (PRIN).
Recommendation.

J1. Clinicians may choose to evaluate patients with restricted mobility due to muscular dystrophy with bone density studies for osteoporosis in order to institute timely management and minimize fractures (Level C).

Infection prophylaxis. Clinical context. Our systematic review did not provide evidence regarding immunization with pneumococcal vaccination or annual influenza vaccination (EVID). Given the underlying respiratory muscle weakness or spinal deformities in some subtypes of muscular dystrophy, prevention of respiratory infections is important in order to avoid complications, such as respiratory failure, requiring ventilator support (RELA).^e510-e513 The Centers for Disease Control and Prevention (CDC) recommends pneumococcal polysaccharide vaccine (PPSV23) for “all adults aged 65 years and older; adults younger than age 65 years with chronic lung disease (including chronic obstructive pulmonary disease, emphysema, and asthma); chronic cardiovascular diseases; diabetes mellitus; chronic renal failure; nephrotic syndrome; chronic liver disease (including cirrhosis); alcoholism; cochlear implants; cerebrospinal fluid leaks; immunocompromising conditions; and functional or anatomic asplenia;…residents of nursing homes or long-term care facilities; and adults who smoke cigarettes” (PRIN).^e514 Patients with limb-girdle muscular dystrophy may be considered as having a chronic illness, may have cardiorespiratory involvement, and may be residents of long-term care facilities (INFER). Influenza vaccine is recommended annually for all persons over 6 months of age (PRIN).
Recommendation.

K1. Clinicians should recommend pneumococcal polysaccharide vaccine (PPSV23) as per the CDC schedule^e514 and annual influenza vaccine to patients with muscular dystrophy in order to prevent respiratory complications of pneumococcal pneumonia and influenza (Level B).

Rehabilitative management and treatment of muscular dystrophies

Clinical rehabilitative management. Clinical context. Our evidence-based review of the literature on rehabilitative management of muscular dystrophies (LGMD, EDMD, and distal myopathy) consisted primarily of single Class III studies. Thus, the currently available data are not adequate to properly assess the effect of any rehabilitation modality (endurance and strength training, bracing, and assistive devices, including new computer-based technology) (EVID). Large well-designed clinical trials are therefore required to evaluate the role of rehabilitative treatments for these disorders (INFER). However, the principles of the long-term management of patients with these disorders must emphasize maintaining mobility and functional independence for as long as possible, with a focus on maximizing quality of life. The prevention and management of comorbidities, both expected and acquired, is a major part of such management. These comorbidities would include joint contractures, scoliosis, osteoporosis, dysphagia, and restrictive lung disease (expected), as well as obesity, metabolic syndrome, and stress fractures (acquired). Patient-centered, proactive, and collaborative decision making (including all relevant team members) is important, taking into account the patient’s wishes and family and social circumstances. An important aspect of ongoing management includes proactively preparing patients with muscular dystrophy and their families for the long-term consequences of muscular dystrophies and engaging in discussions regarding end-of-life care. This helps patients come to terms with their condition and prepare for the expected complications of their form of muscular dystrophy and avoids the need for hasty decisions made in the throes of a medical crisis (PRIN). There is evidence from studies in other neuromuscular diseases, including ALS, that a multidisciplinary approach is the most effective way to deliver care (RELA).^e515 This model is endorsed by the Muscular Dystrophy Association, which also sponsors these types of clinics. This level of care usually occurs at a tertiary or academic-based medical center, with clinics designed specifically to care for patients with muscular dystrophy and other neuromuscular disorders. The primary clinic team members usually include a neurologist and a physiatrist, along with physical and occupational therapists. Neurogeneticists, pulmonologists, cardiologists, gastroenterologists, orthopedic surgeons, and speech-language pathologists are part of the team. Rehabilitation psychologists, social workers, and vocational rehabilitation counselors can also be valuable members of the team. Once the diagnosis is confirmed, the rehabilitation team, under the direction of a physician (preferably a neuromuscular-trained specialist), can manage clinical problems long-term. Ideally, this would include complete functional assessments using reliable, standardized, reproducible measures in order to quantify a patient’s physical and psychosocial performance at any given point in the disease process. This not only helps monitor a patient’s overall level of health but also facilitates evaluation for possible enrollment in a clinical trial. With the loss of mobility will come the need for progressively more assistance with activities of daily living, as well as potential medical complications (PRIN). When writing therapy prescriptions, clinicians should be aware of the current allowances from payers for outpatient physical therapy. Patients with muscular dystrophy should see physical and occupational therapists who are experienced in treating these disorders. These therapists often practice in a tertiary care, medical center–based setting (PRIN).
Recommendations.

L1. Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties (e.g., physical therapy, occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics) designed specifically to care for patients with muscular dystrophy and other neuromuscular disorders in order to provide efficient and effective long-term care (Level B).

L2. Clinicians might discuss opportunities for participation in clinical trials, if available, with muscular dystrophy patients (Level C).
L3. Clinicians should recommend that patients with muscular dystrophy have periodic assessments by a physical and occupational therapist for symptomatic and preventive screening (Level B).
L4. While respecting and protecting patient autonomy, clinicians should proactively anticipate and facilitate patient and family decision making as the disease progresses, including decisions regarding loss of mobility, need for assistance with activities of daily living, medical complications, and end-of-life care (Level B).
L5. For patients with muscular dystrophy, clinicians should prescribe physical and occupational therapy, as well as bracing and assistive devices that are adapted specifically to the patient’s deficiencies and contractures, in order to preserve mobility and function and prevent contractures (Level B).
Strength training and aerobic exercise training. Clinical context. As mentioned earlier, our evidence-based review of the literature on rehabilitation management of muscular dystrophies (LGMD, EDMD, and distal myopathy) consisted primarily of single Class III studies. Thus, the currently available data are not adequate to properly assess the effect of any rehabilitation modality (endurance and strength training, bracing, and assistive devices, including new computer-based technology) (EVID). Despite inadequate research in this area, the available evidence suggests that this population would benefit from both strengthening and aerobic fitness training programs. Due to the muscle degeneration in muscular dystrophy, there may be some risk of exercise-induced muscle damage and subsequent overwork weakness following supramaximal, high-intensity exercise. Overwork weakness is defined as a prolonged decrease in absolute muscle strength and endurance following strenuous or excessive exercise. It is often accompanied by extreme delayed onset muscle soreness, peaking 1–5 days after exercise and possibly inducing myoglobinuria. Clinicians need to be prudent in their recommendations, encouraging alternating periods of physical activity and scheduled rest. Clinicians should also be aware that true overwork weakness has not been demonstrated in any trial of exercise done in this population to date. Future investigations should focus on the primary symptom of fatigue and quantify changes in the ability to work and participate in physical activities as outcome measures of an exercise program. All forms of physical exercise should therefore be prescribed cautiously, using a common sense approach (PRIN). There have been several randomized or quasi-randomized controlled trials comparing strength training programs, aerobic exercise programs, or both to non-training controls in patients with a variety of neuromuscular disorders (RELA).^e516-e518 On the basis of this literature, both strength training and aerobic exercise programs appear to be safe, without any notable deleterious effects. However, limitations in the design of these trials prevent any conclusions regarding possible benefit (EVID, RELA).
Recommendations.

M1. Clinicians may advise patients with muscular dystrophy that aerobic exercise combined with a supervised submaximal strength training program is probably safe (Level C).

M2. Clinicians may advise patients with muscular dystrophy that gentle, low-impact aerobic exercise (swimming, stationary bicycling) improves cardiovascular performance, increases muscle efficiency, and lessens fatigue (Level C).
M3. Clinicians may counsel patients with muscular dystrophy to hydrate adequately, not to exercise to exhaustion, and to avoid supramaximal, high-intensity exercise (Level C).
M4. Clinicians should educate patients with muscular dystrophy who are participating in an exercise program about the warning signs of overwork weakness and myoglobinuria, which include feeling weaker rather than stronger within 30 minutes after exercise, excessive muscle soreness 24–48 hours following exercise, severe muscle cramping, heaviness in the extremities, and prolonged shortness of breath (Level B).
Medical treatments. Clinical context. Our systematic review of treatments available for LGMD revealed that adeno-associated virus gene transfer increased the expression of the γ-sarcoglycan and α-sarcoglycan genes in the injected muscle for 1 and 6 months, respectively^{e494,e498,e500} (EVID). These are small proof-of-concept studies. Despite evidence of increased expression of the target protein at the site of injection, effects on the clinical course of the disorder and the long-term side effects of this treatment are yet to be determined (INFER).

Our systematic review found that neutralizing antibody to myostatin (MYO-029) is probably safe and tolerable in patients with BMD and LGMD2A–E and 2I at doses of 1 and 3 mg/kg, although a few serious side effects were noted which require further research. Cutaneous hypersensitivity is noted at 10 and 30 mg/kg doses. There are no data regarding long-term safety. There is probably a trend toward increase in lean body muscle mass, but the study was not powered to assess efficacy^e493 (EVID).

Our systematic review found only one study evaluating the effect of myoblast transplantation^e496 and one study evaluating the effects of subcutaneous growth hormone injections in BMD,^e497 both with inconclusive results.
Recommendations.

N1. Clinicians should not offer patients with LGMD gene therapy outside of a research study designed to determine the efficacy and safety of the treatment (Level R).

N2. Clinicians should not offer patients with LGMD neutralizing antibody to myostatin outside of a research study designed to determine the efficacy and safety of the treatment (Level R).
N3. Clinicians should not offer patients with BMD myoblast transplantation or subcutaneous growth hormone injections outside of a research study designed to determine the efficacy and safety of the treatment (Level R).
RECOMMENDATIONS FOR FUTURE RESEARCH

As the category of LGMDs expands rapidly with advances in molecular diagnostics and new disorders due to specific gene defects are identified, there is need for research in the following areas.

1. 
   Larger prospective, long-term, population-based studies are required to establish the prevalence of these rare disorders, identify the ethnic populations among which they are most prevalent, and evaluate their long-term course, including the incidence of cardiorespiratory complications.
   
2. 
   Ongoing studies of genotype/phenotype correlation are needed to help establish phenotypic patterns based on genotype and to describe the various phenotypes that are caused by one genotype.
   
3. 
   The optimal management of cardiorespiratory complications (e.g., frequency and types of screening, effective treatments) should be evaluated.
   
4. 
   Well-designed studies of the effectiveness of exercise programs, physical therapy, and endurance training are needed.
   
5. 
   Studies of other treatments should be conducted, including symptomatic treatments such as the effect of orthotics for contractures (nonsurgical/surgical) on mobility and quality of life, as well as specific disease-modifying treatments such as gene therapy and stem cell therapy.
   
6. 
   Preliminary data suggest that corticosteroids may be effective in α-dystroglycanopathies. This finding needs to be replicated in larger, controlled studies.