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Limb Girdle Muscular Dystrophy
Abstract & Commentary
By Michael Rubin, MD, FRCP(C), Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin is on the speaker's bureau for Athena Diagnostics, and does research for Pfizer and Merck.
Synopsis: Proteomic and molecular genetic testing is a critical part of the diagnostic algorithm for limb girdle muscular dystrophy (LGMD).
Source: Norwood F, de Visser M, Eymard B, et al. EFNS guideline on diagnosis and management of limb girdle muscular dystrophies. Eur J Neurol 2007;14:1305-1312.
Molecular biology has evoked a peaceful revolution in neurology, particularly in the delineation and classification of the various forms of limb girdle muscular dystrophy (LGMD). It's time for an update. First described by Walton and Nattrass,1 21 forms are currently classified based on linkage studies and are divided between those that are autosomal dominant (n = 5), designated LGMD1A-E, or autosomal recessive (n = 14), designated LGMD2A-N. Two of the dominant forms may, in rare instances, be recessive. Such molecular diagnosis has more than only nosological value, as certain forms carry cardiac or respiratory complications that may warrant early intervention. Based on a MEDLINE, Cochrane database, and EMBASE search, among others, the following consensus recommendations for the management of LGMD were devised by the European Federation of Neurological Societies (EFNS).
Although all LGMDs demonstrate pelvic and shoulder girdle involvement, thorough clinical assessment remains the backbone of evaluation and should guide further investigation. Some clinical pearls of note will be listed here. Neonatal hypotonia, commonly seen in congenital muscular dystrophy and myopathy, is seen only in LGMD1B, involving the lamin A/C gene mutation. Neonatal contractures are not seen in LGMD, but may occur later in childhood, along with spinal rigidity, most commonly in LGMD1B and more mildly in LGMD2A (calpain 3 gene mutation). Purely distal muscle involvement may be seen in early LGMD2B (Miyoshi type dysferlin deficiency), LGMD1B, or LGMD1C (caveolin 3 gene mutation). Scapular winging most frequently is seen in LGMD2A and 2C-F (sarcoglycan gene mutations), while hip abductors are relatively preserved in LGMD2A. Muscle hypertrophy may be seen, usually involving the gastrocnemius, but it may involve other muscles as well. This may include the tongue in LGMD1C, LGMD2C-F (where scoliosis is most often seen among the LGMD), and LGMD2I (fukutin-related protein gene mutation, FKRP, one of the most common forms of LGMD). LGMD2I muscle hypertrophy, associated with cardiac and respiratory compromise, may be misdiagnosed as Becker's muscular dystrophy. Geographically, only Brazilians are reported with LGMD2G (telethonin gene mutation) and only Canadians with LGMD2H (TRIM32 gene mutation). Finland had the first LGMD2J (titin gene mutation) cases. Cardiomyopathy or dysrhythmias are common in LGMD1B, LGMD2C-F, and LGMD2I. Respiratory muscle weakness is common in LGMD2C-F and LGMD2I.
Patient workup should include serum creatine kinase (CK) measurement. CK is normal or mildly elevated in LGMD1A and 1B; moderately elevated in LGMD1C, 2A, 2C-F, and 2I; or more than ten-fold elevated in LGMD2B. Electrodiagnostic studies add little but will exclude neuropathy. Muscle imaging does not yet warrant the expense or trouble, but can preempt selecting an end-stage muscle for biopsy. Muscle tissue is best obtained by open biopsy, and standard histological techniques as well as immunohistochemistry and immunoblotting should be performed. DNA analysis remains the gold standard for diagnosis and allows for carrier identification and presymptomatic diagnosis.
Consultation with pulmonologists for LGMD2C-F and 2I, and cardiologists for LGMD1B, 2C-F, and 2I, is critical, as these forms are associated with hypoventilation, respiratory failure, conduction defects, or cardiomyopathy. Physical therapy is probably beneficial but no papers specifically address this issue. Genetic counseling is appropriate. No drug is of profound benefit for LGMD but creatine produced a 3% benefit in 6 patients with sarcoglycanopathy. Co-enzyme Q10 (ubiquinone) has not been studied. Prednisone has been empirically used with some benefit in LGMD2C-F because of its reported benefit in Duchenne dystrophy. More recently, prednisolone (0.35 mg/kg/d) was reportedly beneficial in two LGMD2I patients.2 Although both developed dilated cardiomyopathy during treatment, this was felt to be a consequence of the disease rather than the treatment.
Any online literature search quickly reveals that the LGMD medical literature is overwhelming, making it barely possible to keep abreast given the sheer number of papers published. Novel mutations are reported weekly, as are variant phenotypes, but most are irrelevant to the average busy practitioner. Yet a recent literature review yielded this clinically relevant question: Should testing for the protein deficiency be performed before or after DNA analysis? The answer is: Before. Nevertheless, it appears that although molecular diagnosis has greater success when a protein alteration already has been detected, efficiency varies between LGMD forms.3 Doubling of the LGMD2A mutation detection rate was achieved when the calpain 3 protein test was previously performed, whereas sarcoglycanopathy diagnosis was 20-fold greater when molecular testing followed muscle biopsy immuno-fluorescence. Let the clinician beware.
1. Walton JN, Nattrass FJ. Brain 1954;77:169-231.
2. Canki-Klain N, Zagar M, Alfirevic-Ungarov T, et al. Eur J Pediatr Neurol 2007;11:353-357.
3. Darin N, Kroksmark AK, Ahlander AC, et al. Neuromuscul Disord 2007;17:810-811.