What is the role of muscle biopsy in the workup of limb-girdle muscular dystrophy (LGMD)?

Updated: Aug 15, 2019
  • Author: Monica Saini, MD, MBBS, MRCP(UK); Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Muscle biopsy is the most important diagnostic evaluation of patients in whom LGMD is suspected.

In most cases of LGMD, routine histochemical studies show typical dystrophic features, including various degrees of muscle-fiber degeneration and regeneration, variation in fiber size with small round fibers, and endomysial fibrosis.

Details of routine muscle histochemistry include the following:

  • In LGMD1A the muscle biopsy may show rimmed vacuoles.

  • In LGMD1C the muscle biopsy may show only mild myopathic features.

  • In LGMD2B the biopsy may show perimysial and perivascular T-cell infiltrates and upregulation of major histocompatibility complex (MHC-1), and may be mistaken for polymyositis.

  • In LGMD2G there may be rimmed vacuoles.

  • In LGMD2H the biopsy may show features of sarcotubular myopathy (see Congenital myopathy).

  • In LGMD2J the muscle biopsy may be myopathic with rimmed vacuoles.

Immunohistochemical findings are as follows:

  • Dystrophin testing is usually the first step in dystrophic biopsy performed by using antibodies against the N-terminus, rod, and C-terminus. A minor reduction in dystrophin staining can be seen in sarcoglycanopathies. Conversely, a minor reduction in sarcoglycan staining may occur in dystrophinopathies.

  • All sarcoglycan antibodies should be tested next. While the pattern of sarcoglycan deficiency can be quite variable in sarcoglycanopathies, some generalizations can be made. [73] If α-sarcoglycan and γ-sarcoglycan are both absent, there is frequently a mutation in α-sarcoglycan (LGMD2D). Patients with a γ-sarcoglycan mutation (LGMD2C) have complete absence of γ-sarcoglycan. Patients with reduced levels of γ-sarcoglycan usually have a mutation in α-sarcoglycan (LGMD2D) or less commonly of β-sarcoglycan (LGMD2E).

  • Antibodies to dysferlin and calpain-3 are also important in evaluating LGMDs. Patients with LGMD2A have reduced staining for calpain-3 by Western blot. Reduction or loss of staining for the 60kD band is more sensitive and specific than loss of staining for the 30kD band. Loss of staining for both bands occurs in about 25% of cases and is highly specific for a calpain-3 mutation. About 25% of patients with a mutation may have a normal Western blot. Patients with LGMD2A may have reduction in immunohistochemical staining for dysferlin. Staining for dystrophin and the sarcoglycans is normal. Calpain-3 staining may be reduced in other disorders including LGMD1C, LGMD2B, LGMD2I, LGMDJ, and dystrophinopathies.

  • Patients with LGMD2B have reduced or absent immunohistochemical staining for dysferlin as well as absent or reduced Western blot staining. Absence of staining is highly specific for a mutation in the dysferlin gene, but there is no correlation between the level of staining and the severity of disease. However, a mutation in dysferlin was always found in patients with reduction in Western blot staining to less than 20% of normal. [74] Calpain-3 staining may also be reduced. Dystrophin and sarcoglycan staining is normal.

  • Patients with LGMDI, LGMD2K and LGMD2M all have reduced staining for glycosylated α-dystroglycan. There may also be a reduction in staining for laminin-α2.

  • Patients with LGMD1A often have increased staining for myotilin, desmin, and for other proteins typically found in myofibrillar myopathies (see below).

  • Patients with LGMD1C have reduced staining for caveolin-3 by immunohistochemistry and Western blot. There may also be reduced staining for dysferlin on immunohistochemistry.

  • Myofibrillar myopathies

    • General features include myopathic changes as well as the presence of hyaline/cytoplasmic bodies.

    • Immunohistochemistry shows aggregates containing desmin as well as numerous other proteins (myotilin, laminin-B, ubiquitin, αβ-crystallin, β-amyloid, dystrophin).

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