Limb-Girdle Muscular Dystrophy Workup
- Author: Glenn Lopate, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE more...
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.[56, 57]
Next-generation sequencing supplemented with Sanger sequencing is currently the method advocated to diagnosis LGMD. Tageted panels for autosomal dominant or autosomal recessive LGMDs are avaialbe from several commercial laboratories. In addition, whole exome sequencing can find mutations not discovered with targed sequencing. In a large cohort of LGMD families 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.
Magnetic resonance imaging (MRI) can help differentiate forms of LGMD. Hyperintense signal change on T1 scans is seen in more severely affected muscles. An MRI study of 20 patients with LGMD showed the following:
Patients with LGMD2I had the most severe MRI changes in posterior and adductor thigh muscles, with less severe changes in gluteal and calf muscles.
Patients with LGMD2A have severe involvement of posterior and adductor thigh muscles with sparing of the sartorius. These patients also have severe and selective involvement of the medial gastrocnemius and soleus muscles.
Patients with LGMD2B can have a variable MRI picture with involvement of gastrocnemius in Miyoshi myopathy and involvement of glutei as well as anterior and posterior thigh muscle in patients with a LGMD phenotype. Tibialis anterior and axial abnormalities are described in patients with anterior tibial myopathy and axial myopathy, respectively. However, a study in 2010  showed similar MRI abnormalities, with predominant early involvement of the gastrocnemius and adductor magnus in patients with either a Miyoshi myopathy or LGMD presentation.
Patients with LGMD2D and with Becker muscular dystrophy had more severe MRI changes in the anterior thigh compartment than in the posterior thigh.
See the list below:
Needle electromyography (EMG) and nerve conduction studies (NCSs)
- Order EMG and NCSs in all patients with suspected LGMD to confirm the myopathic nature of the disease.
- NCS results are normal in LGMD.
- EMG shows early recruitment and the typical small-amplitude, narrow-duration, polyphasic motor-unit potentials that are seen in muscular diseases.
- Abnormal spontaneous activity in the form of fibrillations and positive sharp waves is not prominent but has been described in a few cases of LGMD. When present, it should raise the clinician's suspicion for an inflammatory myopathy, such as polymyositis.
- Cardiac involvement is common in the autosomal dominant syndromes of LGMD1A and 1B (50-65%). Cardiomyopathy and cardiac arrhythmias in LGMD1B may cause clinically significant morbidity. In patients with LGMD1E (dilated cardiomyopathy with conduction defect and muscular dystrophy), cardiomyopathy and arrhythmias are nearly always present.
- In the autosomal recessive LGMD syndromes, cardiomyopathy is uncommon except in LGMD2G and 2I, where as many as 30-50% of patients can have mild-to-moderate cardiomyopathy. In the sarcoglycanopathies (most often LGMD2E and 2F), cardiomyopathy is occasionally problematic.
- In myofibrillar myopathies, cardiac disease is common, occurring in more than 50% of cases. Presentation can be with cardiomyopathy or cardiac conduction disturbances.
- Annual screening with ECG (and possibly echocardiography if the patient is symptomatic) is important for quick diagnosis and follow-up in cases of LGMD and myofibrillar myopathy with cardiac disease.
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 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. 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. 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).
Examples of histologic findings are depicted in the images below.
Walton JN, Nattrass FJ. On the classification, natural history and treatment of the myopathies. Brain. 1954. 77(2):169-231. [Medline].
Thompson R, Straub V. Limb-girdle muscular dystrophies - international collaborations for translational research. Nat Rev Neurol. 2016 May. 12 (5):294-309. [Medline].
Moore SA, Shilling CJ, Westra S, Wall C, Wicklund MP, Stolle C, et al. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol. 2006 Oct. 65(10):995-1003. [Medline].
van der Kooi AJ, Frankhuizen WS, Barth PG, Howeler CJ, Padberg GW, Spaans F, et al. Limb-girdle muscular dystrophy in the Netherlands: gene defect identified in half the families. Neurology. 2007 Jun 12. 68(24):2125-8. [Medline].
Lo HP, Cooper ST, Evesson FJ, Seto JT, Chiotis M, Tay V, et al. Limb-girdle muscular dystrophy: diagnostic evaluation, frequency and clues to pathogenesis. Neuromuscul Disord. 2008 Jan. 18(1):34-44. [Medline].
Guglieri M, Magri F, D'Angelo MG, Prelle A, Morandi L, Rodolico C, et al. Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. Hum Mutat. 2008 Feb. 29(2):258-66. [Medline].
Fanin M, Nascimbeni AC, Aurino S, Tasca E, Pegoraro E, Nigro V, et al. Frequency of LGMD gene mutations in Italian patients with distinct clinical phenotypes. Neurology. 2009 Apr 21. 72(16):1432-5. [Medline].
Groen EJ, Charlton R, Barresi R, Anderson LV, Eagle M, Hudson J, et al. Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A. Brain. 2007 Dec. 130:3237-49. [Medline].
Nguyen K, Bassez G, Krahn M, Bernard R, Laforêt P, Labelle V, et al. Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes. Arch Neurol. 2007 Aug. 64(8):1176-82. [Medline].
Vilchez JJ, Gallano P, Gallardo E, Lasa A, Rojas-García R, Freixas A. Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population. Arch Neurol. 2005 Aug. 62(8):1256-9. [Medline].
Seror P, Krahn M, Laforet P, Leturcq F, Maisonobe T. Complete fatty degeneration of lumbar erector spinae muscles caused by a primary dysferlinopathy. Muscle Nerve. 2008 Mar. 37(3):410-4. [Medline].
Klinge L, Aboumousa A, Eagle M, Hudson J, Sarkozy A, Vita G. New aspects on patients affected by dysferlin deficient muscular dystrophy. J Neurol Neurosurg Psychiatry. 2010 Sep. 81(9):946-53. [Medline].
Ferreiro A, Mezmezian M, Olivé M, Herlicoviez D, Fardeau M, Richard P. Telethonin-deficiency initially presenting as a congenital muscular dystrophy. Neuromuscul Disord. 2011 Jun. 21(6):433-8. [Medline].
Olivé M, Shatunov A, Gonzalez L, Carmona O, Moreno D, Quereda LG, et al. Transcription-terminating mutation in telethonin causing autosomal recessive muscular dystrophy type 2G in a European patient. Neuromuscul Disord. 2008 Dec. 18(12):929-33. [Medline].
Saccone V, Palmieri M, Passamano L, Piluso G, Meroni G, Politano L, et al. Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H. Hum Mutat. 2008 Feb. 29(2):240-7. [Medline].
Palmieri A, Manara R, Bello L, Mento G, Lazzarini L, Borsato C. Cognitive profile and MRI findings in limb-girdle muscular dystrophy 2I. J Neurol. 2011 Jul. 258(7):1312-20. [Medline].
Sveen ML, Schwartz M, Vissing J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol. 2006 May. 59(5):808-15. [Medline].
Stensland E, Lindal S, Jonsrud C, Torbergsen T, Bindoff LA, Rasmussen M, et al. Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with Limb Girdle Muscular Dystrophy 2I. Neuromuscul Disord. 2011 Jan. 21(1):41-6. [Medline].
Mathews KD, Stephan CM, Laubenthal K, Winder TL, Michele DE, Moore SA, et al. Myoglobinuria and muscle pain are common in patients with limb-girdle muscular dystrophy 2I. Neurology. 2011 Jan 11. 76(2):194-5. [Medline]. [Full Text].
Hanisch F, Grimm D, Zierz S, Deschauer M. Frequency of the FKRP mutation c.826C>A in isolated hyperCKemia and in limb girdle muscular dystrophy type 2 in German patients. J Neurol. 2010 Feb. 257(2):300-1. [Medline].
Wahbi K, Meune C, Hamouda el H, Stojkovic T, Laforêt P, Bécane HM, et al. Cardiac assessment of limb-girdle muscular dystrophy 2I patients: an echography, Holter ECG and magnetic resonance imaging study. Neuromuscul Disord. 2008 Aug. 18(8):650-5. [Medline].
Pénisson-Besnier I, Hackman P, Suominen T, Sarparanta J, Huovinen S, Richard-Crémieux I, et al. Myopathies caused by homozygous titin mutations: limb-girdle muscular dystrophy 2J and variations of phenotype. J Neurol Neurosurg Psychiatry. 2010 Nov. 81(11):1200-2. [Medline].
Jarry J, Rioux MF, Bolduc V, Robitaille Y, Khoury V, Thiffault I, et al. A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to 11p13-p12. Brain. 2007 Feb. 130:368-80. [Medline].
Bolduc V, Marlow G, Boycott KM, Saleki K, Inoue H, Kroon J, et al. Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am J Hum Genet. 2010 Feb 12. 86(2):213-21. [Medline]. [Full Text].
Hicks D, Sarkozy A, Muelas N, Koehler K, Huebner A, Hudson G, et al. A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy. Brain. 2011 Jan. 134:171-82. [Medline].
Godfrey C, Escolar D, Brockington M, Clement EM, Mein R, Jimenez-Mallebrera C, et al. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy. Ann Neurol. 2006 Nov. 60(5):603-10. [Medline].
Puckett RL, Moore SA, Winder TL, Willer T, Romansky SG, Covault KK, et al. Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation. Neuromuscul Disord. 2009 May. 19(5):352-6. [Medline]. [Full Text].
Vuillaumier-Barrot S, Quijano-Roy S, Bouchet-Seraphin C, Maugenre S, Peudenier S, Van den Bergh P. Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype. Neuromuscul Disord. 2009 Mar. 19(3):182-8. [Medline].
Murakami T, Hayashi YK, Ogawa M, Noguchi S, Campbell KP, Togawa M, et al. A novel POMT2 mutation causes mild congenital muscular dystrophy with normal brain MRI. Brain Dev. 2009 Jun. 31(6):465-8. [Medline]. [Full Text].
Biancheri R, Falace A, Tessa A, Pedemonte M, Scapolan S, Cassandrini D, et al. POMT2 gene mutation in limb-girdle muscular dystrophy with inflammatory changes. Biochem Biophys Res Commun. 2007 Nov 30. 363(4):1033-7. [Medline].
Hara Y, Balci-Hayta B, Yoshida-Moriguchi T, Kanagawa M, Beltrán-Valero de Bernabé D, Gündesli H. A dystroglycan mutation associated with limb-girdle muscular dystrophy. N Engl J Med. 2011 Mar 10. 364(10):939-46. [Medline].
Gundesli H, Talim B, Korkusuz P, Balci-Hayta B, Cirak S, Akarsu NA. Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy. Am J Hum Genet. 2010 Dec 10. 87(6):834-41. [Medline].
Cetin N, Balci-Hayta B, Gundesli H, Korkusuz P, Purali N, Talim B. A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies. J Med Genet. 2013 Jul. 50(7):437-43. [Medline].
Bögershausen N, Shahrzad N, Chong JX, von Kleist-Retzow JC, Stanga D, Li Y. Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. Am J Hum Genet. 2013 Jul 11. 93(1):181-90. [Medline].
Carss KJ, Stevens E, Foley AR, et al. Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan. Am J Hum Genet. 2013 Jul 11. 93 (1):29-41. [Medline].
Cabrera-Serrano M, Ghaoui R, Ravenscroft G, Johnsen RD, Davis MR, Corbett A, et al. Expanding the phenotype of GMPPB mutations. Brain. 2015 Apr. 138 (Pt 4):836-44. [Medline].
Cirak S, Foley AR, Herrmann R, et al. ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain. 2013 Jan. 136 (Pt 1):269-81. [Medline].
Tasca G, Moro F, Aiello C, Cassandrini D, Fiorillo C, Bertini E, et al. Limb-girdle muscular dystrophy with α-dystroglycan deficiency and mutations in the ISPD gene. Neurology. 2013 Mar 5. 80 (10):963-5. [Medline].
Chardon JW, Smith AC, Woulfe J, Pena E, Rakhra K, Dennie C, et al. LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues. Clin Genet. 2015 Dec. 88 (6):558-64. [Medline].
Schindler RF, Scotton C, Zhang J, et al. POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. J Clin Invest. 2016 Jan. 126 (1):239-53. [Medline].
Aboumousa A, Hoogendijk J, Charlton R, Barresi R, Herrmann R, Voit T, et al. Caveolinopathy--new mutations and additional symptoms. Neuromuscul Disord. 2008 Jul. 18(7):572-8. [Medline].
Greenberg SA, Salajegheh M, Judge DP, Feldman MW, Kuncl RW, Waldon Z. Etiology of limb girdle muscular dystrophy 1D/1E determined by laser capture microdissection proteomics. Ann Neurol. 2012 Jan. 71(1):141-5. [Medline].
Sarparanta J, Jonson PH, Golzio C, Sandell S, Luque H, Screen M. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet. 2012 Apr. 44(4):450-5, S1-2. [Medline].
Harms MB, Sommerville RB, Allred P, Bell S, Ma D, Cooper P. Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Ann Neurol. 2012 Mar. 71(3):407-16. [Medline].
Palenzuela L, Andreu AL, Gamez J, et al. A novel autosomal dominant limb-girdle muscular dystrophy (LGMD 1F) maps to 7q32.1-32.2. Neurology. 2003 Aug 12. 61(3):404-6. [Medline].
Vieira NM, Naslavsky MS, Licinio L, Kok F, Schlesinger D, Vainzof M, et al. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum Mol Genet. 2014 Aug 1. 23 (15):4103-10. [Medline].
Fischer D, Kley RA, Strach K, Meyer C, Sommer T, Eger K, et al. Distinct muscle imaging patterns in myofibrillar myopathies. Neurology. 2008 Sep 2. 71(10):758-65. [Medline].
Selcen D, Muntoni F, Burton BK, Pegoraro E, Sewry C, Bite AV, et al. Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol. 2009 Jan. 65(1):83-9. [Medline]. [Full Text].
Odgerel Z, Sarkozy A, Lee HS, McKenna C, Rankin J, Straub V. Inheritance patterns and phenotypic features of myofibrillar myopathy associated with a BAG3 mutation. Neuromuscul Disord. 2010 Jul. 20(7):438-42. [Medline].
Beckmann JS, Spencer M. Calpain 3, the "gatekeeper" of proper sarcomere assembly, turnover and maintenance. Neuromuscul Disord. 2008 Dec. 18(12):913-21. [Medline].
Cacciottolo M, Numitone G, Aurino S, Caserta IR, Fanin M, Politano L, et al. Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations. Eur J Hum Genet. 2011 Sep. 19(9):974-80. [Medline]. [Full Text].
Markert CD, Ning J, Staley JT, Heinzke L, Childers CK, Ferreira JA, et al. TCAP knockdown by RNA interference inhibits myoblast differentiation in cultured skeletal muscle cells. Neuromuscul Disord. 2008 May. 18(5):413-22. [Medline].
Lommel M, Cirak S, Willer T, Hermann R, Uyanik G, van Bokhoven H. Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies. Neurology. 2010 Jan 12. 74(2):157-64. [Medline].
Torella A, Fanin M, Mutarelli M, Peterle E, Del Vecchio Blanco F, Rispoli R. Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F. PLoS One. 2013. 8(5):e63536. [Medline].
Ferrer I, Olivé M. Molecular pathology of myofibrillar myopathies. Expert Rev Mol Med. 2008 Sep 3. 10:e25. [Medline].
Hughes S. Guideline to Aid Muscular Dystrophy Diagnosis, Management. Medscape Medical News. Available at http://www.medscape.com/viewarticle/833400. Accessed: October 19, 2014.
Naravanaswami P., et al. . 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. Neurology. 2014 Oct. 14;83(16):1453-63. [Full Text].
Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, et al. Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned. JAMA Neurol. 2015 Dec. 72 (12):1424-32. [Medline].
Paradas C, Llauger J, Diaz-Manera J, Rojas-García R, De Luna N, Iturriaga C. Redefining dysferlinopathy phenotypes based on clinical findings and muscle imaging studies. Neurology. 2010 Jul 27. 75(4):316-23. [Medline].
Trabelsi M, Kavian N, Daoud F, Commere V, Deburgrave N, Beugnet C, et al. Revised spectrum of mutations in sarcoglycanopathies. Eur J Hum Genet. 2008 Jul. 16(7):793-803. [Medline].
Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, et al. Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol. 2010 Nov. 68(5):629-38. [Medline]. [Full Text].
Wagner KR, Fleckenstein JL, Amato AA, et al. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008 May. 63 (5):561-71. [Medline].
Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, et al. 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. Neurology. 2014 Oct 14. 83 (16):1453-63. [Medline].
Balci B, Uyanik G, Dincer P, et al. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscul Disord. 2005 Apr. 15(4):271-5. [Medline].
Bar H. Mucke N. Ringler P. Muller SA. Kreplak L. Katus HA. Aebi U. Herrmann H. Impact of disease mutations on the desmin filament assembly process. J Molec Biol. Jul 2006. 360:1031-42. [Medline].
Boito CA, Melacini P, Vianello A, et al. Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I. Arch Neurol. 2005. 62:1894-9. [Medline].
Bönnemann CG, Bushby K. The limb-girdle muscular dystrophies. Engel AG, Franzini-Armstrong C. Myology. 3rd ed. New York, NY: McGraw Hill; 2004. 1077-1121.
Clement EM, Godfrey C, Tan J, Brockington M, Torelli S, Feng L. Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant. Arch Neurol. 2008 Jan. 65(1):137-41. [Medline].
D'Amico A, Tessa A, Bruno C. Expanding the clinical spectrum of POMT1 phenotype. Neurology. 2006. 66:1564-7. [Medline].
D'Amico A. Benedetti S. Petrini S. Sambuughin N. Boldrini R. Menditto I. Ferrari M. Verardo M. Goldfarb L. Bertini E. Major myofibrillar changes in early onset myopathy due to de novo heterozygous missense mutation in lamin A/C gene. Neuromuscular Disorders. Dec 2005. 15:847-50. [Medline].
Fanin M, Nascimbeni AC, Angelini C. Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations. J Med Genet. 2007. 44:38-43. [Medline].
Fischer D, Walter MC, Kesper K. Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs. J Neurol. 2005. 252:538-47. [Medline].
Foroud T, Pankratz N, Batchman AP, et al. A mutation in myotilin causes spheroid body myopathy. Neurology. 2005 Dec 27. 65(12):1936-40. [Medline].
Fulizio L, Nascimbeni AC, Fanin M, et al. Molecular and muscle pathology in a series of caveolinopathy patients. Hum Mutat. 2005 Jan. 25(1):82-9. [Medline].
Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007 Oct. 130(Pt 10):2725-35. [Medline].
Goudeau B. Rodrigues-Lima F. Fischer D. Casteras-Simon M. Sambuughin N. de Visser M. Laforet P. Ferrer X. Chapon F. Sjoberg G. Kostareva A. Sejersen T. Dalakas MC. Goldfarb LG. Vicart P. Variable pathogenic potentials of mutations located in the desmin alpha-helical domain. Human Mutation. Sep 2006. 27:906-13. [Medline].
Guglieri M, Magri F, Comi GP. Molecular etiopathogenesis of limb girdle muscular and congenital muscular dystrophies: boundaries and contiguities. Clinica Chimica Acta. 2005. 361:54-79. [Medline].
Kramerova I, Beckmann JS, Spencer MJ. Molecular and cellular basis of calpainopathy (limb girdle muscular dystrophy type 2A). Biochim Biophys Acta. 2007 Feb. 1772(2):128-44. [Medline].
Neuromuscular Disease Center. Dilated cardiomyopathy. St Louis, Mo: Washington University. Available at www.neuro.wustl.edu/neuromuscular/msys/cardiac2.htm#dilated. Accessed: January 12, 2006.
Neuromuscular Disease Center. Large or prominent muscles. Familial partial lipodystrophy (Kobberling-Dunnigan syndrome). St Louis, Mo: Washington University. Available at www.neuro.wustl.edu/neuromuscular/mother/mlarge.html#kds. Accessed: September 19, 2005.
Olive M, Goldfarb LG, Shatunov A, et al. Myotilinopathy: refining the clinical and myopathological phenotype. Brain. 2005 Oct. 128(Pt 10):2315-26. [Medline].
Ozawa E, Mizuno Y, Hagiwara Y. Molecular and cell biology of the sarcoglycan complex. Muscle Nerve. 2005. 32:563-76. [Medline].
Penisson-Besnier I. Talvinen K. Dumez C. Vihola A. Dubas F. Fardeau M. Hackman P. Carpen O. Udd B. Myotilinopathy in a family with late onset myopathy. Neuromuscular Disorders. July 2006. 16:427-31. [Medline].
Pestronk A. Neuromuscular Disease Center. St Louis, Mo: Washington University. Available at http://www.neuro.wustl.edu/neuromuscular.
Raju R. Dalakas MC. Absence of upregulated genes associated with protein accumulations in desmin myopathy. Muscle Nerve. Mar 2007. 35:386-8. [Medline].
Saenz A, Leturcq F, Cobo AM, et al. LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain. 2005 Apr. 128(Pt 4):732-42. [Medline].
Schoser BG, Frosk P, Engel AG. Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H. Ann Neurol. 2005. 57:591-595. [Medline].
Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopathy. Neurology. 2004 Apr 27. 62(8):1363-71. [Medline].
Selcen D, Engel AG. Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol. 2005 Feb. 57(2):269-76. [Medline].
Selcen D, Engel AG. Myofibrillar myopathies. Engel AG, Franzini-Armstrong C, eds. Myology. 3rd ed. New York, NY: McGraw Hill; 2004. 1187-202.
Starling A, Kok F, Passos-Bueno MR, et al. A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. Eur J Hum Genet. 2004 Dec. 12(12):1033-40. [Medline].
Vorgerd M. van der Ven PF. Bruchertseifer V. Lowe T. Kley RA. Schroder R. Lochmuller H. Himmel M. Koehler K. Furst DO. Huebner A. A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy. Am J Hum Genet. Aug 2005. 77:297-304. [Medline].