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

Appendix e-5: Classification of Evidence Schemes

Screening

Class I: A statistical, population-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations.

Class II: A statistical, non-referral-clinic-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients’ clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II or III criteria including consensus, expert opinion or a case report

Therapy

Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required:

1. 
   Concealed allocation
   
2. 
   primary outcome(s) clearly defined
   
3. 
   exclusion/inclusion criteria clearly defined
   
4. 
   adequate accounting for drop-outs and cross-overs with numbers sufficiently low to have minimal potential for bias
   
5. 
   relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.
   

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-e above OR a RCT in a representative population that lacks one criteria a-d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.

Appendix e-6: Clinical Contextual Profiles Determining Levels of Obligation for Recommendations
Diagnosis of Muscular Dystrophies

A00. Clinicians should refer patients with suspected muscular dystrophy to neuromuscular centers to optimize the diagnostic evaluation and subsequent management (Level B).

A0. For patients with suspected muscular dystrophy, clinicians should use a clinical approach to diagnosis based on the clinical phenotype, including the pattern of muscle involvement, inheritance pattern, age at onset, and associated manifestations (e.g., early contractures, cardiac or respiratory involvement) (Level B).

Limb-girdle pattern of weakness (figures 3 to 5).

A1. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal dominant inheritance, cardiomyopathy, respiratory involvement, EMG with myotonic or “pseudomyotonic” discharges (the latter characterized by runs of decrescendo positive sharp wave discharges without the typical waxing and waning in amplitude and frequency seen in myotonic discharges), ankle dorsiflexor weakness (foot drop), and muscle biopsy (if performed) showing features of myofibrillar myopathy, clinicians should perform genetic testing for mutations in the genes for desmin (LGMD1E), myotilin (LGMD1A), DNAJB6 (LGMD1D), ZASP, filamin C, αB-crystallin, and titin (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

A2. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal dominant inheritance, rippling muscles, and percussion-induced rapid contractions, clinicians should perform genetic testing for mutations in the caveolin-3 gene (LGMD1C) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

A3. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal dominant inheritance, early humeroperoneal weakness, contractures (neck, elbows, knee, ankle), and cardiomyopathy, clinicians should perform genetic testing for mutations in the lamin A/C gene (LGMD1B or AD-EDMD) (Level B).

A4. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal dominant inheritance, distal weakness, myotonic discharges on EMG, past or family history of Paget disease, frontotemporal dementia, or motor neuron disease, clinicians should perform genetic testing for mutations in VCP (hIBMPFD) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

A5. In patients with limb-girdle weakness and suspected muscular dystrophy who either do not have clinical features to suggest a specific form of dystrophy or in whom initial genetic testing is not informative, clinicians should perform muscle biopsy in order to delineate characteristic features that direct further genetic testing (such as immunohistochemistry/immunoblotting for various sarcolemmal proteins, calpain-3, or features of myofibrillar myopathy; see figures 4 and 5) or to exclude an alternative diagnosis (e.g., a metabolic myopathy, mitochondrial myopathy, congenital myopathy, or inflammatory myopathy) (Level B).

A6. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal recessive inheritance, scapular winging but no calf hypertrophy, and normal cardiorespiratory function, clinicians should perform initial genetic testing for mutations in calpain-3 (LGMD2A). Patients of English, French, Spanish, Italian, Portuguese, or Brazilian descent may have a higher pretest probability of this disorder (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

A7. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal recessive inheritance and calf atrophy and weakness (i.e., inability to stand on toes), clinicians should perform genetic testing for mutations in anoctamin-5 (LGMD2L) or dysferlin (LGMD2B). If the onset of symptoms is in the teens or early 20s or the patient is from Asia, clinicians should assess for dysferlin mutations first and, if negative, test for anoctamin-5 mutations. If the onset of symptoms is in the 30s or later or the patient is of English or northern European ancestry, clinicians should assess for anoctamin-5 mutations first and, if negative, test for dysferlin mutations (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

A8. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal recessive inheritance and muscle biopsy immunohistochemistry showing reduction in α-, β-, γ-, or δ-sarcoglycans, clinicians should perform genetic testing for mutations in the sarcoglycan genes (LGMD2C–2F) (Level B).

A9. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal recessive inheritance who are of Hutterite descent, clinicians should perform genetic testing for mutations in TRIM32 (LGMD2H) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.
A10. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal recessive inheritance, scapular winging, calf hypertrophy, and early cardiorespiratory involvement, clinicians should perform initial genetic testing for mutations in FKRP (LGMD2I). Patients of northern European descent may have a higher pretest probability of this disorder (Level B).

A11. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal recessive inheritance and mental retardation, clinicians should screen for mutations in genes that cause primary or secondary deficiency of α-dystroglycan (LGMD2K, LGMD2M, LGMD2N, LGMD2O, and LGMD2P) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

A12. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal recessive inheritance and epidermolysis bullosa or pyloric atresia, clinicians should perform genetic testing for mutations in plectin (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

A13. In male patients with limb-girdle weakness and suspected muscular dystrophy with probable X-linked inheritance, clinicians should perform genetic testing for mutations in the dystrophin gene (Duchenne or Becker muscular dystrophy) (Level B).

A14. In patients with limb-girdle weakness and suspected muscular dystrophy with probable autosomal recessive inheritance and no other specific clinical features or in whom muscle biopsy does not inform genetic testing, clinicians should perform dried blood spot test for α-glucosidase (acid maltase) deficiency or Pompe disease (Level B).

A15. In female patients with limb-girdle weakness and suspected muscular dystrophy with probable X-linked inheritance, clinicians should perform genetic testing for dystrophin mutations or perform a muscle biopsy and immunostain for dystrophin to assess for a mosaic pattern of staining. If abnormal immunostaining is present, clinicians should confirm the diagnosis of manifesting carrier of dystrophinopathy with genetic testing for mutations in the dystrophin gene (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

Humeroperoneal weakness (figure e-1).

B1. In patients with humeroperoneal weakness and suspected muscular dystrophy with probable autosomal dominant inheritance, early cardiac involvement, and no joint laxity, clinicians should perform genetic testing for mutations in the lamin A/C gene (AD-EDMD, LGMD1B). If the inheritance pattern is probably X-linked, clinicians should perform genetic testing for mutations in the emerin gene (XR-EDMD) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

B2. In patients with humeroperoneal weakness and suspected muscular dystrophy with early cardiac involvement and no joint laxity who do not possess mutations in the lamin A/C or emerin gene, clinicians should perform muscle biopsy to delineate characteristic abnormalities that direct further genetic testing (see figure e-1 for muscle biopsy features that direct genetic testing) (Level B).

B3. In patients with humeroperoneal weakness and suspected muscular dystrophy with probable autosomal dominant inheritance, joint laxity, protuberant calcaneus, and no cardiac involvement, clinicians should perform genetic testing for mutations in the collagen VI gene (Bethlem myopathy). If the inheritance pattern is probably autosomal recessive with congenital onset, clinicians should perform genetic testing for mutations in the collagen VI gene (Ullrich myopathy) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

Distal muscular dystrophy.

C1. In patients with late adult onset of index finger and wrist extensor weakness followed by atrophy and weakness of hand muscles and muscle biopsy showing rimmed vacuoles, clinicians should make a diagnosis of Welander distal myopathy. Patients of Swedish or Finnish descent may have a higher pretest probability of this disorder. Clinicians should confirm the diagnosis with genetic testing for Welander myopathy when testing becomes commercially available (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

C2. In patients with suspected distal muscular dystrophy and probable autosomal recessive inheritance with early onset of calf weakness, clinicians should perform genetic testing for mutations in the anoctamin-5 and dysferlin genes. If the patient is of northern European descent, clinicians should perform initial genetic testing for mutations in the anoctamin-5 gene (LGMD2L) and, if negative, perform genetic testing for mutations in the dysferlin gene (LGMD2B). If the patient is from eastern Asia (Japan, China, Korea), clinicians should perform initial genetic testing for mutations in the dysferlin gene (LGMD2B, Miyoshi myopathy) and, if negative, perform genetic testing for mutations in the anoctamin-5 gene (LGMD2L) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

C3. In patients with suspected distal muscular dystrophy and probable autosomal recessive inheritance with early onset (<30 years of age) of progressive foot drop who are of Japanese or Middle Eastern Jewish descent, clinicians should perform initial genetic testing for GNE mutations (AR-hIBM) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

C4. In patients with suspected distal muscular dystrophy without the clinical features in C2 or C3 above, clinicians should perform a muscle biopsy to direct further genetic testing (see figure e-2 for biopsy and clinical features that direct genetic testing) (Level B).



Other diagnostic considerations.

D1. In patients with muscular dystrophy who have proximal as well as distal weakness, clinicians should use specific clinical features (e.g., rippling muscles, cardiomyopathy, atrophy of specific muscle groups, irritability on EMG) and biopsy features (MFM, reduction of emerin immunostaining, presence of rimmed vacuoles) to guide genetic testing, which may include mutations in the genes causing the various forms of MFM (see section on MFM), LGMD2B (dysferlin), LGMD2L (anoctamin-5), LGMD2J (titin), LGMD1C (caveolin-3), and EDMD (emerin and lamin A/C) (Level B).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

D2. In patients with suspected muscular dystrophy in whom initial genetic testing, muscle biopsy, and dried blood spot test for Pompe disease do not provide a diagnosis, clinicians may obtain genetic consultation or perform parallel sequencing of targeted exomes, whole-exome sequencing, whole-genome screening, or next-generation sequencing to identify the genetic abnormality (Level C).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level C using informal consensus.

Evaluation and Medical Management of Muscular Dystrophies

Cardiac involvement in muscular dystrophies.

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).

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).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level B using informal consensus.

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.

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.

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.

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).

There was substantial consensus after round 2. Based on the modifiers (availability, financial burden, variations), the panel selected Level C using informal consensus.