The Limb-Girdle Muscular Dystrophies and the Dystrophinopathies (Muscle Disease 2016)

Educational Objectives

The goal of this lecture is to improve diagnosis and treatment of muscle disease. After hearing and assimilating this lecture, the clinician will be better able to:

1. Interpret genetic testing for patients with suspected limb-girdle muscular dystrophies.
2. Compare and contrast Becker muscular dystrophy and Duchenne muscular dystrophy.

Summary

Limb-girdle muscular dystrophies (LGMDs): Complex group of genetic and dystrophic disorders of muscle characterized by proximal weakness in shoulders and hips; inheritance either autosomal dominant (LGMD type 1) or autosomal recessive (LGMD type 2); despite their similarities, dystrophinopathies not considered subcategory of LGMDs; LGMDs found in 1 to 6 per 100,000 persons.

Diagnosis of LGMD: Approach to diagnosis changing; traditional approach — evaluation based on clinical phenotype; clinician characterized distribution and pattern of weakness, then sought associated features such as cardiac involvement, prominent contractures, scapular winging, or weakness of finger flexors or knee extensors; EMG assesses pattern of severe muscular involvement; muscle biopsy usually performed, which may demonstrate prominent necrosis, proliferation of connective tissue, inflammation, or vacuoles; biopsy and electrodiagnostic findings combined with clinical picture and degree of elevation of CK to diagnose type of LGMD; advent of molecular genetic testing has allowed clinicians to use all of this information to test for gene most likely to be involved; for example, in patient with autosomal dominant disorder, prominent contractures, and cardiac involvement, testing for mutation in gene for lamin A/C indicated.

Genetic testing: In last 3 to 5 years, diagnostic methods have evolved toward “inverted paradigm” approach; patients with pattern of weakness suggesting LGMD now often assessed initially with genetic panels in lieu of biopsy; panel may test for 40 to 60 genetic disorders of muscle; some companies offer limb-girdle panels; such testing may identify multiple variations in genes, many of which not associated with patient’s disease; for example, titin gene large, and 95% of individuals have nonpathogenic variations in this gene; report may identify several variations of questionable relevance (may not truly be associated with disease); in such cases, clinician may need to order biopsy, electrodiagnostic studies, and cardiac testing to try to identify other abnormalities and determine whether genetic findings pathogenic; merits of each approach (traditional versus inverted paradigm) debated.

Misdiagnosis: Every form of LGMD presents with proximal weakness, elevated CK, and myopathic EMG; patients frequently misdiagnosed with polymyositis; although patients with LGMD often believe disorder had recent onset, careful exploration of history may reveal that weakness began years earlier; most patients with LGMD display restricted pattern of weakness on physical examination; for example, extensors of knee may be weak while ankle dorsiflexors and flexors of knee normal; in contrast, inflammatory muscle diseases associated with more diffuse pattern of weakness; discrepancy in strength of neighboring muscles should prompt consideration of LGMD; contractures and cardiac manifestations also suggest LGMD; recessive diseases more common than dominant diseases.

Management of LGMDs: No treatment available for most patients with LGMD; however, as with some dystrophinopathies (eg, Duchenne muscular dystrophy), specific LGMD disorders respond to prednisone or other immunosuppressants; examples include LGMD2B (dysferlin deficiency) and LGMD2I (fukutin-related protein [FKRP] deficiency); clinician should consider trial of prednisone while monitoring side effects closely; otherwise, treatment mainly supportive; type of LGMD should be identified and cardiac or pulmonary status should be monitored; many patients require bilevel positive airway pressure (BPAP) at night; insidious respiratory involvement often missed; bracing, wheelchairs, and other supportive care provided as needed.

Dystrophinopathies: Although dystrophinopathies X-linked LGMDs, these diseases historically categorized separately from LGMD; with typical X-linked inheritance, women carry gene but only sons manifest disease; however, “manifesting carriers” of dystrophinopathies may develop elevated CK, proximal weakness, and cardiac involvement, especially as they age (leading to erroneous impression of dominant disorder); laboratory testing — 65% to 70% of Duchenne and Becker dystrophies caused by deletions or duplications in dystrophin gene; 25% to 30% caused by point mutations or intronic mutations not detected on initial screening for deletions or duplications; some panels test for point mutations but not for deletions or duplications; therefore, choice of laboratory important; Duchenne and Becker dystrophies more common than most types of LGMD; dystrophin gene testing often performed first in young boys, especially if CK high.

Clinical features of dystrophinopathies: Becker dystrophy milder than Duchenne dystrophy; most patients with Duchenne dystrophy have out-of-frame mutation that disrupts reading frame of mRNA; such patients have no detectable dystrophin; those with Becker dystrophy usually have in-frame deletions so that reading frame preserved; these patients may have reduced amount of dystrophin, or dystrophin may be reduced in size or partially nonfunctional; patients with Duchenne dystrophy present with proximal weakness, often with enlarged calves; falling observed at 3 to 5 years of age; disease usually rapidly progressive, and child needs wheelchair by 9 to 12 years of age; Becker dystrophy milder, can present in adulthood, and involves heart; pulmonary involvement usually severe in Duchenne dystrophy and correlates well with degree of peripheral weakness; in Becker dystrophy, pulmonary involvement may be mild or severe; children with Duchenne dystrophy require frequent cardiac echocardiography and pulmonary function testing; most patients need BPAP, and many children with Duchenne dystrophy need tracheostomy and full ventilatory support.

Diagnosis of dystrophinopathies: Onset of Duchenne dystrophy typically at 2 to 5 years of age; children begin to trip and fall and develop classic Gower sign (inability to rise from floor without pushing with hands, and using hands to “walk up” legs); CK usually markedly elevated (>10,000 U/L); when these findings present, genetic testing indicated and muscle biopsy unnecessary.

Management of dystrophinopathies: Similar to that of LGMD but corticosteroids (including prednisone and deflazacort) beneficial; steroids prolong ambulation by 3 to 5 years and benefit cardiac and pulmonary function, activities of daily living, and quality of life; steroids should be introduced when child starts to fall frequently; dose of prednisone 0.75 mg/kg/d; deflazacort has fewer side effects but not yet available in United States; dosing similar to that for prednisone; alternative dosing regimens have been tried, including 5 mg/kg/d on weekends only, or alternating 10 days on and 10 days off steroids; no formal studies conducted on use of steroids for Becker dystrophy, but this treatment reasonable to consider.

Readings

Iyadurai SJP, Kissel JT. The limb-girdle muscular dystrophies and the dystrophinopathies. Continuum (Minneap Minn) 2016;22(6 Muscle and Neuromuscular Junction Disorders).

Disclosures

For this program, the following was disclosed: Dr. Kissel has received personal compensation for serving on a consulting board of AveXis, Inc, as journal editor of Muscle & Nerve, and as a consultant for Novartis AG. Dr. Kissel has received research/grant funding as principal investigator of a study from the National Institutes of Health and has received funding for clinical trials from AveXis, Inc; AxelaCare Health Solutions, LLC; BioMarin; CSL Behring; Cytokinetics, Inc; Ionis Pharmaceuticals; and Quintiles, Inc; and receives publishing royalties from Oxford University Press. Unlabeled Use of Products/Investigational Use Disclosure: Dr. Kissel discusses the unlabeled/investigational use of corticosteroids to treat Duchenne muscular dystrophy. To view disclosures of planning committee members with relevant financial relationships, visit: audiodigest.org/continuumaudio/committee. All other members of the planning committee report nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

CA052203

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.