What is the role of lab tests 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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Creatine kinase testing aids diagnosis.

  • Autosomal recessive limb-girdle muscular dystrophies (LGMDs) often cause extremely high CK levels. The sarcoglycanopathies (LGMD2C-2F) and LGMD2B markedly elevate CK levels by 10-150 times normal. The other autosomal recessive LGMDs usually cause CK elevations that are 3-80 times normal.

  • Autosomal dominant LGMD1C can result in high CK elevations of 5-25 times normal. All other autosomal dominant LGMDs result in CK levels between normal and 15 times normal.

  • Myofibrillar myopathies have CK levels ranging from normal to 7 times normal.

  • Consider other myopathies that markedly elevate CK levels: dystrophinopathies, dermatomyositis and/or polymyositis, hypothyroid myopathy, rhabdomyolysis, and acid maltase deficiency.

A guideline for the diagnosis and management of patients with limb-girdle or distal muscular dystrophies, issued by the American Academy of Neurology and the American Association of Neuromuscular & Electrodiagnostic Medicine, calls for referral of patients suspected of having MD to a specialist center for evaluation and genetic testing. The guideline provides algorithms for diagnosis based on the clinical phenotype, including pattern of muscle involvement, inheritance pattern, age of onset, and associated manifestations (e.g. contractures, cardiomyopathy, respiratory failure).  If initial targeted genetic testing (either single gene or a panel of LGMDs) is negative, a muslce biopsy showld be obtained to look at the immunohistochemical staining patterns using antibodies directed at known disease associated proteins (e.g. dystrophin, sarcoglycans, merosin, α-dystroglycan, dysferlin, cveloin-3, etc) and to look for distinguishing features (e.g. rimmed vacuoles, myofibrillar myopathy).  If subsequent targeted genetic testing remains negative then whole exome sequncing should be performed. [64, 65]

Next‐generation sequencing (NGS)‐based gene‐panel testing, using targeted NGS panel, is now available for the diagnosis of LGMD. Whole genome sequencing has additional benefits of identifying novel pathogenic mutations and putative phenotype-influencing variants, as well as identifying potential digenic or multigenic contribution to LGMD especially in patients with atypical presentations and /or progression. [66, 67]

In a large cohort of LGMD families [68] 35% were diagnosed based on protein-based testing (muslce biopsy) followed by targeted candidate gene testing.  Of the remaining patients, 60 families underwent whole exome sequencing, pathogenic mutations in known myopathy genes were identified in 45% of the families.  Interestingly, about half of the identified genes were not LGMD genes, highlighting the clinical overlap between LGMD and other myopathies.  Common causes of phenotypic overlap included genes causing collagen myopathy, metabolic myopathies and congenital myopathies.

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