Approach Considerations
In 2014, guidelines on the diagnosis and treatment of LGMD were issued by the American Academy of Neurology and the American Association of Neuromuscular and Electrodiagnostic Medicine. They included the following recommendations [2] :
-
Genetic diagnosis of patients with suspected muscular dystrophy should be guided by a clinical approach hinging on clinical phenotype, such as muscle involvement pattern, inheritance pattern, age at onset, and associated disease manifestations, including early contractures and cardiac or respiratory involvement (level B)
-
Patients newly diagnosed with an LGMD subtype who have a high cardiac complication risk should be referred for cardiologic evaluation even if they have no cardiac symptoms (level B)
-
Pulmonary function should be periodically tested in patients with LGMD with a high respiratory failure risk (level B)
-
Patients with muscular dystrophy should be referred to a clinic that has access to specialties—such as physical therapy, occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics—aimed at treating neuromuscular disorder patients (level B)
-
With the exception of research studies aimed at determining treatment safety and efficacy, patients with LGMD should not be offered LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone (level R)
Laboratory Studies
The single biochemical abnormality in limb-girdle muscular dystrophy (LGMD) syndrome is the elevation of the CK level. The CK elevation in the recessively inherited varieties is significantly higher than in the rest of the spectrum of LGMDs (eg, dominantly inherited, Erb dystrophy, pelvifemoral variety). However, the CK level is usually significantly lower than in patients with Duchenne or Becker dystrophy. Individuals with Duchenne or Becker dystrophy may have elevated creatine in the urine, but they do not have myoglobinuria. [49]
Other Tests
Electromyographic abnormalities are atypical in limb-girdle muscular dystrophy (LGMD), and EMG is more useful to exclude other disorders in the differential. Nerve conduction velocities do not show abnormalities in cases of LGMD. Repetitive stimulation produces good posttetanic potentiation and no myasthenic response. Rarely, EMG of a single fiber may reveal a mild decrease in fiber density and increased jitter, but the most consistent finding is normal fiber density.
Procedures
Muscle biopsy findings in limb-girdle muscular dystrophy are characterized by necrotic fibers with endomysial perivascular or perimysial mononuclear infiltration. (See image below.) A study by De Paepe et al indicated that in muscle biopsies performed in patients with limb-girdle muscular dystrophy, changes in the dystrophin complex are the most valuable aspect of the biopsy in differentiating the condition from myositis. [50]
Trichrome stain. Note variation in fiber size. Necrotic fiber giant fibers and cytoplasmic inclusions.
Histologic Findings
In limb-girdle muscular dystrophy (LGMD), hematoxylin and eosin stain and trichrome stain show a most striking predilection toward large fiber size (see image below).
Hematoxylin and eosin stain. Note the variation in fiber size. Necrotic fiber is shown with many nuclei (magnification 250X).
These large fibers show splitting (see image below) and can be 3-4 times the size of a normal fiber.
The splitting of fibers produces the false appearance of grouping and angulation without a large group of atrophic fibers. Frequently, ring fibers and cytoplasmic masses are also observed (see image below).
Some fibers are characterized by profuse internal nuclei (see image below).
Gomori trichrome stain. Note the variation in fiber size and subsarcolemmal vacuoles, central nuclei, and subsarcolemmal collection of trichrome-positive material.
The myoarchitecture shows evidence of necrosis and basophilia (see image below).
Increases in endomysial fibrous tissue are noted, without significant evidence of cellular response.
The histochemistry of the muscle biopsy specimens generally shows a predominance of type I fibers and a reduction of type IIB fibers. Because splitting is a common feature of this disease, the split fibers are shown to belong to the same fiber type and give an appearance of fiber-type grouping (see image below).
Electron micrograph showing abnormal mitochondria, a large lysosomal body, and a central nucleus.
Ultrastructure examination shows nonspecific changes consisting of Z-band spreading, mitochondrial abnormalities with inclusions as central nuclei, and disruption of the A and I bands (see image below).
Electron micrograph showing mitochondria with paracrystalline inclusions and lamellar bodies
In a morphometric analysis of muscle fibers in LGMD, Fanin and colleagues found not only differences in fiber size between the various forms of the disease but also variations in fiber atrophy between males and females. Evaluating 101 muscles from patients with LGMD, the investigators found significant fiber atrophy in LGMD types 2A and 2B but pronounced fiber hypertrophy in LGMD type 1C. They also found that in males with LGMD types 2A and 2B, muscle fiber atrophy was significantly greater than in male control subjects. In females with LGMD, however, fiber size was similar to that in female controls. Fanin et al stated that although it is possible that LGMD affects males more severely than females, the reasons behind this are unclear. [51]
-
Hematoxylin and eosin stain. Note the variation in fiber size. Necrotic fiber is shown with many nuclei (magnification 250X).
-
Marked endomysial fibrosis with atrophic and hypertrophic fibers.
-
Hematoxylin and eosin stain. Note the splitting of the fiber.
-
Gomori trichrome stain. Note the variation in fiber size and subsarcolemmal vacuoles, central nuclei, and subsarcolemmal collection of trichrome-positive material.
-
Light type I and dark type IIA fibers.
-
Electron micrograph showing abnormal mitochondria, a large lysosomal body, and a central nucleus.
-
Electron micrograph showing mitochondria with paracrystalline inclusions and lamellar bodies
-
Electron micrograph showing streaming of band Z and splitting of the muscle fiber. A central nucleus is surrounded by a collection of small mitochondria.
-
Trichrome stain. Note variation in fiber size. Necrotic fiber giant fibers and cytoplasmic inclusions.
-
Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, in dysferlin, and in caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan, can result in limb-girdle muscular dystrophy.
