Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine

Abstract

Objective: To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs).

Methods: Systematic review and practice recommendation development using the American Academy of Neurology guideline development process.

Results: Most LGMDs are rare, with estimated prevalences ranging from 0.07 per 100,000 to 0.43 per 100,000. The frequency of some muscular dystrophies varies based on the ethnic background of the population studied. Some LGMD subtypes have distinguishing features, including pattern of muscle involvement, cardiac abnormalities, extramuscular involvement, and muscle biopsy findings. The few published therapeutic trials were not designed to establish clinical efficacy of any treatment.

Principal recommendations: For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on clinical phenotype, inheritance pattern, and associated manifestations (Level B). Clinicians should refer newly diagnosed patients with an LGMD subtype and high risk of cardiac complications for cardiology evaluation even if they are asymptomatic from a cardiac standpoint (Level B). In patients with LGMD with a known high risk of respiratory failure, clinicians should obtain periodic pulmonary function testing (Level B). Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties designed specifically to care for patients with neuromuscular disorders (Level B). Clinicians should not offer patients with LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment (Level R). Detailed results and recommendations are available on the Neurology® Web site at Neurology.org.

Figure 1. Conceptual approach to a patient with a suspected limb-girdle muscular dystrophy

Figure 2. General classification of myopathies

The differential diagnosis of myopathy includes several diverse conditions, both inherited and acquired. The neuromuscular examination, ancillary laboratory tests, and EMG assist in the differential diagnosis of these disorders. The term other muscular dystrophies is used here to indicate hereditary disorders of muscle that have 3 major phenotypes of weakness: limb-girdle, humeroperoneal, and distal. MD = muscular dystrophy. *Other muscular dystrophy phenotypes. Limb-girdle pattern of weakness: symmetric weakness predominantly affecting the proximal legs and arms. Distal muscles may be involved but to a much lesser extent. Neck flexors and extensors may be involved. Humeroperoneal: humeral muscles (biceps and triceps) and the anterior compartment of the distal leg muscles. May be asymmetric. Distal: weakness involving the anterior or posterior compartments of the distal legs or the distal arm/forearm muscles. Other patterns, such as distal arm/proximal leg (inclusion body myositis), ptosis/ophthalmoplegia (myasthenia gravis, myotonic dystrophy, some congenital myopathies, oculopharyngeal muscular dystrophy, mitochondrial myopathy), and neck extensor weakness (dropped head syndrome) (amyotrophic lateral sclerosis, myasthenia gravis, inflammatory myopathies, isolated neck extensor myopathy), may be noted and suggest specific diagnoses other than limb-girdle muscular dystrophy and variants, as noted in parentheses. **Autosomal dominant, autosomal recessive, or X-linked inheritance may be responsible in sporadic cases. Figures 3–5, e-1, and e-2 discuss the clinical approach to diagnosis using the inheritance pattern and the pattern of weakness (as outlined in figure 2) as a starting point.

Figure 3. Diagnostic approach to patients with a limb-girdle pattern of weakness and suspected muscular dystrophy with an autosomal dominant inheritance pattern

*Autosomal dominant, autosomal recessive, or X-linked inheritance may be responsible in sporadic cases. EDMD = Emery-Dreifuss muscular dystrophy; hIBMPFD = hereditary inclusion body myopathy with Paget disease and frontotemporal dementia; LGMD = limb-girdle muscular dystrophy; VCP = valosin-containing protein.

Figure 4. Diagnostic approach to patients with a limb-girdle pattern of weakness and suspected muscular dystrophy with an autosomal recessive inheritance pattern

*Autosomal dominant, autosomal recessive, or X-linked inheritance may be responsible in sporadic cases. LGMD = limb-girdle muscular dystrophy.

Figure 5. Diagnostic approach to patients with a limb-girdle pattern of weakness and suspected muscular dystrophy with an X-linked recessive inheritance pattern

In females, a manifest X-linked disorder may be considered if there is a familial presentation with males more affected than females. *Autosomal dominant, autosomal recessive, or X-linked inheritance may be responsible in sporadic cases. MD = muscular dystrophy.