limb girdle muscular dystrophies

Summary

Summary: A heterogenous group of inherited muscular dystrophy that can be autosomal dominant or autosomal recessive. There are many forms (called LGMDs) involving genes encoding muscle membrane proteins such as the sarcoglycan (SARCOGLYCANS) complex that interacts with DYSTROPHIN. The disease is characterized by progressing wasting and weakness of the proximal muscles of arms and legs around the HIPS and SHOULDERS (the pelvic and shoulder girdles).

Top Publications

  1. Khadilkar S, Singh R. Limb girdle muscular dystrophies in India. Neurol India. 2008;56:281-8 pubmed
    The recent years have seen remarkable progress in the field of limb girdle muscular dystrophies (LGMDs) with the advances in immunocytochemistry and genetics. Based on this, many subgroups have emerged...
  2. Chrobáková T, Hermanova M, Kroupová I, Vondracek P, Maríková T, Mazanec R, et al. Mutations in Czech LGMD2A patients revealed by analysis of calpain3 mRNA and their phenotypic outcome. Neuromuscul Disord. 2004;14:659-65 pubmed
    ..Further, we observed a reduction of dysferlin in muscle membrane in five of our seven LGMD2A patients by immunohistochemical analysis of muscle sections...
  3. Georgieva B, Todorova A, Tournev I, Mitev V, Kremensky I. C283Y gamma-sarcoglycan gene mutation in the Bulgarian Roma (Gypsy) population: prevalence study and carrier screening in a high-risk community. Clin Genet. 2004;66:467-72 pubmed
    ..Such regions should be with priority in the Bulgarian healthcare system for performing a carrier-screening program...
  4. Bushby K. Diagnosis and management of the limb girdle muscular dystrophies. Pract Neurol. 2009;9:314-23 pubmed publisher
    ..As more is understood about the clinical features of the different types of LGMD, targeted management is increasingly possible, especially focusing on those patients at high risk of cardiac and respiratory complications...
  5. Schoser B, Frosk P, Engel A, Klutzny U, Lochmuller H, Wrogemann K. Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H. Ann Neurol. 2005;57:591-5 pubmed
    ..The TRIM32 mutation found in the STM patients is identical to the causative mutation for LGMD2H (D487N), Haplotype analysis shows that the disease chromosomes share common ancestry...
  6. Klinge L, Harris J, Sewry C, Charlton R, Anderson L, Laval S, et al. Dysferlin associates with the developing T-tubule system in rodent and human skeletal muscle. Muscle Nerve. 2010;41:166-73 pubmed publisher
    ..These findings indicate that dysferlin is necessary for correct T-tubule formation, and dysferlin-deficient skeletal muscle is characterized by abnormally configured T-tubules...
  7. Kramerova I, Kudryashova E, Venkatraman G, Spencer M. Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin-proteasome pathway. Hum Mol Genet. 2005;14:2125-34 pubmed
    ..These studies suggest that accumulation of aged and damaged proteins can lead to cellular toxicity and a cell stress response in C3KO muscles, and that these characteristics are pathological features of LGMD2A...
  8. Nagaraju K, Rawat R, Veszelovszky E, Thapliyal R, Kesari A, Sparks S, et al. Dysferlin deficiency enhances monocyte phagocytosis: a model for the inflammatory onset of limb-girdle muscular dystrophy 2B. Am J Pathol. 2008;172:774-85 pubmed publisher
    ..Therefore, we hypothesize that mild myofiber damage in dysferlin-deficient muscle stimulates an inflammatory cascade that may initiate, exacerbate, and possibly perpetuate the underlying myofiber-specific dystrophic process...
  9. Daniele N, Richard I, Bartoli M. Ins and outs of therapy in limb girdle muscular dystrophies. Int J Biochem Cell Biol. 2007;39:1608-24 pubmed
    ..They comprise the well-known Duchenne Muscular Dystrophy (DMD) but also the group of Limb Girdle Muscular Dystrophies (LGMD) which account for a third to a fourth of DMD cases...

More Information

Publications62

  1. Moore S, Shilling C, Westra S, Wall C, Wicklund M, Stolle C, et al. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol. 2006;65:995-1003 pubmed
    ..The most common LGMDs in the United States are calpainopathies, dysferlinopathies, sarcoglycanopathies, and dystroglycanopathies...
  2. 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;29:240-7 pubmed
    ..In conclusion, the mutations here reported may cause muscular dystrophy by affecting the interaction properties of TRIM32...
  3. Sveen M, Schwartz M, Vissing J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol. 2006;59:808-15 pubmed
    ..The prevalence of limb girdle muscular dystrophy type 2I (LGMD2I) in northern Europe is unknown. We investigated this and the genotype-phenotype relation in LGMD2I...
  4. Kudryashova E, Kudryashov D, Kramerova I, Spencer M. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J Mol Biol. 2005;354:413-24 pubmed publisher
  5. Benayoun B, Baghdiguian S, Lajmanovich A, Bartoli M, Daniele N, Gicquel E, et al. NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A. FASEB J. 2008;22:1521-9 pubmed
    ..Deregulations in the NF-kappaB pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency...
  6. Huang Y, de Morrée A, van Remoortere A, Bushby K, Frants R, den Dunnen J, et al. Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle. Hum Mol Genet. 2008;17:1855-66 pubmed publisher
    ..Thus, our findings suggest interconnectivity between both diseases by revealing a novel physiological role for CAPN3 in regulating the dysferlin protein complex...
  7. Poppe M, Bourke J, Eagle M, Frosk P, Wrogemann K, Greenberg C, et al. Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I. Ann Neurol. 2004;56:738-41 pubmed
    ..These complications are a primary part of this specific type of limb-girdle muscular dystrophy, with important implications for management...
  8. Saenz A, Leturcq F, Cobo A, Poza J, Ferrer X, Otaegui D, et al. LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain. 2005;128:732-42 pubmed
    ..8%). However, if one of the analyses is lacking, the probability varies from 78.3 to 73.7% depending on the information available. When both tests are negative, the probability that the sample comes from a patient with LGMD2A was 12.2%...
  9. Frosk P, Greenberg C, Tennese A, Lamont R, Nylen E, Hirst C, et al. The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations. Hum Mutat. 2005;25:38-44 pubmed
    ..The occurrence of this mutation on a common core haplotype suggests that L276I is a founder mutation that is dispersed among populations of European origin...
  10. Gaul C, Deschauer M, Tempelmann C, Vielhaber S, Klein H, Heinze H, et al. Cardiac involvement in limb-girdle muscular dystrophy 2I : conventional cardiac diagnostic and cardiovascular magnetic resonance. J Neurol. 2006;253:1317-22 pubmed
  11. Albor A, El Hizawi S, Horn E, Laederich M, Frosk P, Wrogemann K, et al. The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkappaB. J Biol Chem. 2006;281:25850-66 pubmed
    ..Our results indicate that, by controlling Piasy stability, Trim32 regulates UVB-induced keratinocyte apoptosis through induction of NFkappaB and suggests loss of function of Trim32 in LGMD2H...
  12. Norwood F, de Visser M, Eymard B, Lochmuller H, Bushby K. EFNS guideline on diagnosis and management of limb girdle muscular dystrophies. Eur J Neurol. 2007;14:1305-12 pubmed
    The limb girdle muscular dystrophies (LGMD) are termed as such as they share the characteristic feature of muscle weakness predominantly affecting the shoulder and pelvic girdles; their classification has been completely revised in recent ..
  13. Duncan D, Kang P, Rabbat J, Briggs C, Lidov H, Darras B, et al. A novel mutation in two families with limb-girdle muscular dystrophy type 2C. Neurology. 2006;67:167-9 pubmed
    ..Patient 3 had del521T on her maternal allele and an exon 6 deletion on her paternal allele. Patients 1 and 2 are of Puerto Rican ancestry, suggesting the presence of a founder mutation in that population...
  14. Klinge L, Dekomien G, Aboumousa A, Charlton R, Epplen J, Barresi R, et al. Sarcoglycanopathies: can muscle immunoanalysis predict the genotype?. Neuromuscul Disord. 2008;18:934-41 pubmed publisher
    ..A concomitant reduction of dystrophin and beta-dystroglycan was observed more frequently than previously reported and illustrates the important differential diagnosis of DMD and BMD for sarcoglycan deficient LGMD...
  15. Guglieri M, Magri F, D Angelo M, 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;29:258-66 pubmed
    b>Limb girdle muscular dystrophies (LGMD) are characterized by genetic and clinical heterogeneity: seven autosomal dominant and 12 autosomal recessive loci have so far been identified...
  16. Kesari A, Fukuda M, Knoblach S, Bashir R, Nader G, Rao D, et al. Dysferlin deficiency shows compensatory induction of Rab27A/Slp2a that may contribute to inflammatory onset. Am J Pathol. 2008;173:1476-87 pubmed publisher
  17. Keira Y, Noguchi S, Kurokawa R, Fujita M, Minami N, Hayashi Y, et al. Characterization of lobulated fibers in limb girdle muscular dystrophy type 2A by gene expression profiling. Neurosci Res. 2007;57:513-21 pubmed
    ..From these results, we propose that abnormal increased expression of actin filament binding proteins may contribute to the changes of the intra-myofiber structures, observed in lobulated fibers in LGMD2A...
  18. Nguyen K, Bassez G, Krahn M, Bernard R, Laforet P, Labelle V, et al. Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes. Arch Neurol. 2007;64:1176-82 pubmed
    ..To describe the phenotypic spectrum of dysferlin (DYSF) gene mutations (which cause dysferlinopathies, autosomal recessive muscular dystrophies) in patients with a dysferlin protein deficiency...
  19. Schwartz M, Hertz J, Sveen M, Vissing J. LGMD2I presenting with a characteristic Duchenne or Becker muscular dystrophy phenotype. Neurology. 2005;64:1635-7 pubmed
    ..A point mutation, L276I has been found in all patients with LGMD2I studied so far. The authors screened for this mutation in 102 sporadic cases of Duchenne/Becker mutation-negative patients and found 13 patients with LGMD2I...
  20. Wenzel K, Geier C, Qadri F, Hubner N, Schulz H, Erdmann B, et al. Dysfunction of dysferlin-deficient hearts. J Mol Med (Berl). 2007;85:1203-14 pubmed
    ..Our data suggest that disturbances in dysferlin as well as Z-line proteins and transcription factors particularly under mechanical stress cause cardiomyopathy...
  21. Kramerova I, Kudryashova E, Tidball J, Spencer M. Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Hum Mol Genet. 2004;13:1373-88 pubmed
    ..These studies suggest a role for C3 in myofibrillogenesis and sarcomere remodeling...
  22. Nguyen K, Bassez G, Bernard R, Krahn M, Labelle V, Figarella Branger D, et al. Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies. Hum Mutat. 2005;26:165 pubmed
    ..In 23 patients, we identified two pathogenic mutations, while only one was identified in 11 patients. These mutations were widely spread in the coding sequence of the gene without any mutational "hotspot."..
  23. Klinge L, Dean A, Kress W, Dixon P, Charlton R, Müller J, et al. Late onset in dysferlinopathy widens the clinical spectrum. Neuromuscul Disord. 2008;18:288-90 pubmed publisher
    ..This case represents the eldest age of onset of dysferlinopathy reported so far and widens the clinical spectrum of this disease...
  24. Castro Gago M, Novo Rodríguez M, Pintos Martínez E, Gallano P, Eirís Puñal J. [Early onset adhalinopathy (LGMD2D) mimicking congenital muscular dystrophy]. Rev Neurol. 2001;32:631-5 pubmed
  25. Lin Y, Murakami T, Hayashi Y, Nishino I, Nonaka I, Yuo C, et al. A novel FKRP gene mutation in a Taiwanese patient with limb-girdle muscular dystrophy 2I. Brain Dev. 2007;29:234-8 pubmed
    ..Genetic analysis of fukutin-related protein (FKRP) gene revealed a novel compound heterozygous mutation of c.823C>T (p.R275C) and c.948delC, confirming the diagnosis of LGMD2I, the first reported case in East Asia...
  26. Munn M. Estimate of daily calorie needs for a neuromuscular disease patient receiving noninvasive ventilation. Am J Phys Med Rehabil. 2005;84:639-43 pubmed
    ..Because severe muscle wasting--which we define for the purposes of this article to be <30% of normal--is assumed, this analysis represents a near minimum daily energy need...
  27. Paradas C, Llauger J, Diaz Manera J, Rojas Garcia R, de Luna N, Iturriaga C, et al. Redefining dysferlinopathy phenotypes based on clinical findings and muscle imaging studies. Neurology. 2010;75:316-23 pubmed publisher
    ..Our objective was to find clinical or MRI markers to differentiate phenotypes of dysferlin myopathy regardless of initial symptoms...
  28. Baumeister S, Todorovic S, Milic Rasic V, Dekomien G, Lochmuller H, Walter M. Eosinophilic myositis as presenting symptom in gamma-sarcoglycanopathy. Neuromuscul Disord. 2009;19:167-71 pubmed publisher
    ..Eosinophilia has been reported previously in patients with Calpainopathy and Becker Muscular Dystrophy and might be an early, but transient feature of a wider range of muscular dystrophies...
  29. Pramono Z, Tan C, Seah I, See J, Kam S, Lai P, et al. Identification and characterisation of human dysferlin transcript variants: implications for dysferlin mutational screening and isoforms. Hum Genet. 2009;125:413-20 pubmed publisher
    ..The findings have potential implications for molecular diagnosis of dysferlinopathy and the identification of dysferlin isoforms...
  30. Nakao K, Yazawa S, Hayashi Y, Nishino I, Shiomi K, Nakazato M. [Late-onset sarcoglycanopathy: a cause of repeated muscle cramps after exertion]. Rinsho Shinkeigaku. 2009;49:167-71 pubmed
    ..Late-onset sarcoglycanopathy has rarely been described. In the present patient, his mild clinical condition, subclinical cardiomyopathy and possible involvement of polyneuropathy are unique features...
  31. Manzur A, Muntoni F. Diagnosis and new treatments in muscular dystrophies. J Neurol Neurosurg Psychiatry. 2009;80:706-14 pubmed publisher
    Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and limb girdle muscular dystrophies (LGMD) represent a significant proportion of paediatric and adult neuromuscular neurology practice...
  32. Charlton R, Henderson M, Richards J, Hudson J, Straub V, Bushby K, et al. Immunohistochemical analysis of calpain 3: advantages and limitations in diagnosing LGMD2A. Neuromuscul Disord. 2009;19:449-57 pubmed publisher
    ..However immunoblot is still needed when CAPN3 is present on sections to show secondary CAPN3 reduction and to identify LGMD2A with variable reduction of CAPN3 bands...
  33. Woodman S, Sotgia F, Galbiati F, Minetti C, Lisanti M. Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases. Neurology. 2004;62:538-43 pubmed
    ..This review examines in detail the reported cases of patients with caveolin-3 mutations and their corresponding muscle disease phenotypes...
  34. Groen E, Charlton R, Barresi R, Anderson L, Eagle M, Hudson J, et al. Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A. Brain. 2007;130:3237-49 pubmed
    ..Our analysis confirms that our strategy is still valid to prioritize genetic testing in this complex group of patients, provided patients with normal protein but a suggestive clinical phenotype are not excluded from genetic testing...
  35. Balci B, Wilichowski E, Haliloglu G, Talim B, Aurino S, Kremer E, et al. Beta-sarcoglycan gene mutations in Turkey. Acta Myol. 2004;23:154-8 pubmed
  36. Kararizou E, Manta P, Kalfakis N, Gkiatas K, Vassilopoulos D. Morphologic and morphometrical study of the muscle spindle in muscular dystrophy. Anal Quant Cytol Histol. 2007;29:148-52 pubmed
    ..To determine the morphologic and the morphometrical features of spindles in biopsies of patients with different types of muscular dystrophy and investigate the possible involvement of the spindle in the pathologic process of these diseases...
  37. Izzedine H, Brocheriou I, Eymard B, Le Charpentier M, Romero N, Lenaour G, et al. Loss of podocyte dysferlin expression is associated with minimal change nephropathy. Am J Kidney Dis. 2006;48:143-50 pubmed
    ..We therefore suggest that dysferlin is present in glomeruli and may be associated with glomerular permeability...
  38. Kramerova I, Beckmann J, Spencer M. Molecular and cellular basis of calpainopathy (limb girdle muscular dystrophy type 2A). Biochim Biophys Acta. 2007;1772:128-44 pubmed
    ..In this review, we summarize the known biochemical and physiological features of calpain 3 and hypothesize why mutations result in disease...
  39. Hermans M, Pinto Y, Merkies I, de Die Smulders C, Crijns H, Faber C. Hereditary muscular dystrophies and the heart. Neuromuscul Disord. 2010;20:479-92 pubmed publisher
    ..In this review, we present a comprehensive overview of hereditary muscular dystrophies associated with cardiac disease to provide an efficient strategy for the expertise and management of these diseases...
  40. Bertipaglia I, Bourg N, Richard I, Pahlman A, Andersson L, James P, et al. A proteomic study of calpain-3 and its involvement in limb girdle muscular dystrophy type 2a. Cell Calcium. 2009;46:356-63 pubmed publisher
    ..In vitro experiments have then revealed that only PDLIM1 is cleaved directly by the protease, and that a fragment of about 8 kDa is released from the C-terminal portion of the protein...
  41. Fendri K, Kefi M, Hentati F, Amouri R. Genetic heterogeneity within a consanguineous family involving the LGMD 2D and the LGMD 2C genes. Neuromuscul Disord. 2006;16:316-20 pubmed
    The sarcoglycanopathies are a group of autosomal recessive limb girdle muscular dystrophies (AR-LGMD 2) characterised by mutations in gene encoding one of the sarcoglycan subunits...
  42. Fanin M, Tasca E, Nascimbeni A, Angelini C. Sarcolemmal neuronal nitric oxide synthase defect in limb-girdle muscular dystrophy: an adverse modulating factor in the disease course?. J Neuropathol Exp Neurol. 2009;68:383-90 pubmed publisher
    ..These results emphasize the value of nNOS immunohistochemical analysis in limb-girdle muscular dystrophy and provide additional insights for future therapeutic interventions in these disorders...
  43. Bushby K, Norwood F, Straub V. The limb-girdle muscular dystrophies--diagnostic strategies. Biochim Biophys Acta. 2007;1772:238-42 pubmed
    ..This brings advantages for the patients of today in recognising the specific risks of their disorders, and in the future will be the starting point for specific gene and protein based therapies...
  44. Parsons S, Millay D, Sargent M, Naya F, McNally E, Sweeney H, et al. Genetic disruption of calcineurin improves skeletal muscle pathology and cardiac disease in a mouse model of limb-girdle muscular dystrophy. J Biol Chem. 2007;282:10068-78 pubmed
    ..Our results suggest that inhibition of Cn may benefit select types of muscular dystrophy...
  45. Beckmann J, Spencer M. Calpain 3, the "gatekeeper" of proper sarcomere assembly, turnover and maintenance. Neuromuscul Disord. 2008;18:913-21 pubmed publisher
    ..Loss of these CAPN3-mediated activities can explain the "progressive" development of muscular dystrophy...
  46. Chrestian N, Valdmanis P, Echahidi N, Brunet D, Bouchard J, Gould P, et al. A novel mutation in a large French-Canadian family with LGMD1B. Can J Neurol Sci. 2008;35:331-4 pubmed
  47. Pradhan S. Clinical and magnetic resonance imaging features of 'diamond on quadriceps' sign in dysferlinopathy. Neurol India. 2009;57:172-5 pubmed publisher
  48. Stehlikova K, Zapletalová E, Sedlackova J, Hermanova M, Vondracek P, Maríková T, et al. Quantitative analysis of CAPN3 transcripts in LGMD2A patients: involvement of nonsense-mediated mRNA decay. Neuromuscul Disord. 2007;17:143-7 pubmed
    ..Our results illustrate the importance of DNA analysis for reliable establishment of mutation status, and provide a new insight into the process of mRNA decay in cells of LGMD2A patients...
  49. Pizzanelli C, Mancuso M, Galli R, Choub A, Fanin M, Nascimbeni A, et al. Epilepsy and limb girdle muscular dystrophy type 2A: double trouble, serendipitous finding or new phenotype?. Neurol Sci. 2006;27:134-6 pubmed
    Autosomal recessive limb girdle muscular dystrophies (LGMD) type 2A are a group of disorders characterised by progressive involvement of proximal limb girdle muscles and caused by changes in the CAPN3 gene...
  50. Meulemans A, De Paepe B, De Bleecker J, Smet J, Lissens W, Van Coster R, et al. Two novel mitochondrial DNA mutations in muscle tissue of a patient with limb-girdle myopathy. Arch Neurol. 2007;64:1339-43 pubmed
    ..Defects in the oxidative phosphorylation system can cause a broad spectrum of clinical symptoms ranging from an isolated myopathy to a multisystemic disorder...
  51. Kiyomoto B, Tengan C, Costa C, Oliveira A, Schmidt B, Gabbai A. Frequency of dystrophic muscle abnormalities in chronic progressive external ophthalmoplegia: analysis of 86 patients. J Neurol Neurosurg Psychiatry. 2006;77:541-3 pubmed
    ..A recent study suggested that dystrophic features are frequent in patients with chronic progressive external ophthalmoplegia (CPEO) with a high mutation load, but the actual frequency of these abnormalities in CPEO remains undetermined...
  52. Angelini C, Nardetto L, Borsato C, Padoan R, Fanin M, Nascimbeni A, et al. The clinical course of calpainopathy (LGMD2A) and dysferlinopathy (LGMD2B). Neurol Res. 2010;32:41-6 pubmed publisher
    Autosomal recessive limb girdle muscular dystrophies (LGMD type 2) are a clinically and genetically heterogeneous group of disorders, characterized by progressive involvement and wasting of limb girdle muscles...
  53. Bartoli M, Gicquel E, Barrault L, Soheili T, Malissen M, Malissen B, et al. Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation. Hum Mol Genet. 2008;17:1214-21 pubmed publisher
    ..This suggests a therapeutic approach for LGMD2D patients carrying mutations that impair alpha-sarcoglycan trafficking...