Will you find ways to support Power of Will?

An icon that marks all of our informational disease pages

Limb-Girdle Muscular Dystrophy (LGMD)

Limb-Girdle Muscular Dystrophy (LGMD)

What is limb-girdle muscular dystrophy?

Limb-girdle muscular dystrophy (LGMD) is a diverse group of disorders with many subtypes categorized by disease gene and inheritance. LGMD usually manifests in the proximal muscles around the hips and shoulders. (The proximal muscles are those closest to the center of the body; distal muscles are farther away from the center — for example, in the hands and feet).

The shoulder girdle is the bony structure that surrounds the shoulder area, and the pelvic girdle is the bony structure surrounding the hips. Collectively, these are called the limb girdles, and it is the observed weakness and atrophy (wasting) of the muscles connected to the limb girdles that has given this group of disorders its name.

Together, the group of disorders that constitute LGMD is the fourth most common genetic cause of muscle weakness with an estimated prevalence in about 2 in every 100,000 individuals.1,2,3

What are the symptoms of LGMD?

The unifying features of the LGMDs are the weakness and atrophy of the limb-girdle muscles. However, the age at which symptoms appear, and the speed and severity of disease progression, can vary.

Individuals may first notice a problem when they begin to walk with a “waddling” gait because of weakness of the hip and leg muscles. They may have trouble getting out of chairs, rising from a toilet seat, or climbing stairs. As this weakness progresses, the person may require the use of assistive mobility devices.3

Weakness in the shoulder area may make reaching over the head, holding the arms outstretched, or carrying heavy objects difficult. It may become increasingly hard to keep the arms above the head for such activities as combing one’s hair or arranging things on a high shelf. Some people find it harder to type on a computer or other keyboard and may even have trouble feeding themselves.

Some of the LGMD subtypes also are characterized by additional symptoms. For example, the heart can be affected in some types of LGMD, with weakness of the heart muscle (cardiomyopathy) and/or abnormal transmission of signals that regulate the heartbeat (conduction abnormalities or arrhythmias).3,4,5

Some disease subtypes also involve the muscles used for breathing, and for that reason, respiratory function, along with cardiac function, should be monitored regularly.2

Other symptoms may be present in some of the different subtypes of LGMD, including but not limited to joint stiffness, muscle cramps, enlargement of calf muscles, and involvement of distal muscles of the body such as those controlling the hands and feet.6,7

What causes LGMD?

Genes are the codes, or recipes, that cells use to manufacture the various proteins needed by the body. The genes associated with LGMD normally encode proteins that play vital roles in muscle function, regulation, and repair. When one of these genes contains a mutation (a flaw, such as missing or incorrect information), cells cannot produce the proteins needed for healthy muscles.

There are two major groups of LGMDs. Called LGMD1 and LGMD2, these two groups are classified by the respective inheritance patterns: autosomal dominant and autosomal recessive. If one copy of the abnormal gene is sufficient to cause the disease, it is said to be autosomal dominant; if two copies are needed, then the inheritance pattern is autosomal recessive. In some families, the inheritance pattern cannot be determined. For more details on the various inheritance patterns, see the NIH Genetics Home Reference.

Dozens of different genes, when mutated, have been shown to cause specific LGMD1 and LGMD2 subtypes. In these cases, the proteins associated with these genes are nonfunctional or deficient, and muscles are unable to function normally. Gradually, the muscles become weak enough that people experience the symptoms of LGMD.

In addition to the known LGMD1 and LGMD2 subtypes linked to specific genes, there are many cases of LGMD for which the causative gene is not yet known (and people with these cases are not identified as having a subtype-specific form of LGMD). Scientists are actively working to understand the causes of these unidentified subtypes of LGMD, because the more we understand about all the different causes of LGMD and the diverse ways that muscle can be compromised, the better chance we have of finding effective therapies to intervene in the pathological process.

What is the progression of LGMD?

At this time, progression in each type of LGMD cannot be predicted with certainty, although knowing the underlying genetic mutation can be helpful. Some forms of the disorder progress to loss of walking ability within a few years and cause serious disability, while others progress very slowly over many years and cause minimal disability.

LGMD can begin in childhood, adolescence, young adulthood, or even later. Both genders are affected equally.

When LGMD begins in childhood, some physicians say, the progression is usually faster and the disease more disabling. When the disorder begins in adolescence or adulthood, they say, it is generally not as severe and progresses more slowly. The course is usually one of slowly progressive, mostly symmetric weakness, with the exception of a few types with rapid progression or asymmetric weakness. 2

What is the status of research on LGMD?

MDA-supported scientists are pursuing several exciting strategies in muscular dystrophy research that have implications for LGMD. These strategies include gene therapy, exon skipping, stop codon read through, and myostatin blocking.

To learn more, read The Changing Landscape of LGMD Research.

Subtypes of LGMD

Below is a list of LGMD subtypes. Type 1 LGMDs are dominantly inherited, requiring only one mutation for symptoms to result. Type 2 LGMDs are recessively inherited, requiring two mutations, one from each parent for symptoms to appear. Sometimes, LGMDs are referred to by their names, not their numbers, and some types have not been assigned numbers. The discovery of genetically distinct subtypes has redefined the classification of LGMD and has led to nomenclature designating the autosomal dominant forms as LGMD1A, 1B, 1C, etc., and the autosomal recessive forms as LGMD2A, 2B, 2C, etc.

Dominant LGMD subtype numbers:

LGMD Subtype Gene Comment

LGMD1A

MYOT 8

 

LGMD1B

LMNA9, 10

Most common autosomal dominant type, accounts for 5-10% of all cases

LGMD1C

CAV37, 11

 

LGMD1D

DNAJB612, 13

 

LGMD1E

DES14

 

LGMD1F

TNP0315

 

LGMD1G

HNRNPDL16, 17

 

LGMD1H

Unknown18

 

Recessive LGMD subtype numbers:

LGMD Subtype Gene Comment

LGMD2A

CAPN319

Most common type world-wide, accounts for 15-40% of all LGMD cases

LGMD2B

DYSF 20

The second most common type, accounts for 5-35% of LGMD cases21

LGMD2C

SGCG22

LGMD2D

SGCA22

LGMD2E

SGCB22

LGMD2F

SGCD22

LGMD2G

TCAP23, 24

LGMD2H

TRIM3225

LGMD2I

FKRP15

LGMD2J

TTN26, 27

LGMD2K

POMT128

LGMD2L

ANO529

LGMD2M

FKTN30

LGMD2N

POMT231, 32

LGMD2O

POMGnT133

LGMD2P

DAG134

LGMD2Q

PLEC135

LGMD2R

DES36

LGMD2S

TRAPPC1137

LGMD2T

GMPPB38

LGMD2U

ISPD39

LGMD2V

GAA40

LGMD2W

LIMS241

LGMD2X

BVES

LGMD2Y

TOR1A1P1

References

  1. Understanding Neuromuscular Disease Care. IQVIA Institute. Parsippany, NJ. (2018).
  2. Narayanaswami, P. et al. Evidence-based guideline summary?: Diagnosis and treatment of limb-girdle and distal dystrophies. Neurology (2014).
  3. Wicklund, M. P. Limb-Girdle Muscular Dystrophies. in Encyclopedia of the Neurological Sciences (2014). doi:10.1016/B978-0-12-385157-4.00623-0
  4. Menezes, M. P. et al. Importance and challenge of making an early diagnosis in LMNA-related muscular dystrophy. Neurology (2012). doi:10.1212/WNL.0b013e318250d839
  5. Cagliani, R. et al. A CAV3 microdeletion differentially affects skeletal muscle and myocardium. Neurology (2003). doi:10.1212/01.WNL.0000097320.35982.03
  6. Kirschner, J. & Bönnemann, C. G. The Congenital and Limb-Girdle Muscular Dystrophies: Sharpening the Focus, Blurring the Boundaries. Archives of Neurology (2004). doi:10.1001/archneur.61.2.189
  7. Minetti, C. et al. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat. Genet. (1998). doi:10.1038/ng0498-365
  8. Hauser, M. A. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum. Mol. Genet. (2002). doi:10.1093/hmg/9.14.2141
  9. Carboni, N., Mateddu, A., Marrosu, G., Cocco, E. & Marrosu, M. G. Genetic and clinical characteristics of skeletal and cardiac muscle in patients with lamin A/C gene mutations. Muscle and Nerve (2013). doi:10.1002/mus.23827
  10. Maggi, L. et al. LMNA-associated myopathies: The Italian experience in a large cohort of patients. Neurology (2014). doi:10.1212/WNL.0000000000000934
  11. Carbone, I. et al. Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia. Neurology (2000). doi:10.1212/WNL.54.6.1373
  12. Harms, M. B. et al. Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Ann. Neurol. (2012). doi:10.1002/ana.22683
  13. Sarparanta, J. et al. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat. Genet. (2012). doi:10.1038/ng.1103
  14. Messina, D. N., Speer, M. C., Pericak-Vance, M. A. & McNally, E. M. Linkage of Familial Dilated Cardiomyopathy with Conduction Defect and Muscular Dystrophy to Chromosome 6q23. Am. J. Hum. Genet. (2007). doi:10.1086/514896
  15. Melià, M. J. et al. Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene. Brain (2013). doi:10.1093/brain/awt074
  16. Starling, A., Kok, F., Passos-Bueno, M. R., Vainzof, M. & Zatz, M. 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). doi:10.1038/sj.ejhg.5201289
  17. Vieira, N. M. et al. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum. Mol. Genet. (2014). doi:10.1093/hmg/ddu127
  18. Bisceglia, L. et al. A new locus on 3p23-p25 for an autosomal-dominant limb-girdle muscular dystrophy, LGMD1H. Eur. J. Hum. Genet. (2010). doi:10.1038/ejhg.2009.235
  19. Huang, Y. et al. Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle. Hum. Mol. Genet. (2008). doi:10.1093/hmg/ddn081
  20. Nguyen, K. et al. Phenotypic study in 40 patients with dysferlin gene mutations: High frequency of atypical phenotypes. Arch. Neurol. (2007). doi:10.1001/archneur.64.8.1176
  21. Liu, J. et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat. Genet. (1998). doi:10.1038/1682
  22. Kirschner, J. & Lochmüller, H. Sarcoglycanopathies. Handbook of Clinical Neurology (2011). doi:10.1016/B978-0-08-045031-5.00003-7
  23. Moreira, E. S. et al. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat. Genet. (2000). doi:10.1038/72822
  24. Moreira, E. S. et al. The Seventh Form of Autosomal Recessive Limb-Girdle Muscular Dystrophy Is Mapped to 17q11-12. Am. J. Hum. Genet. (2007). doi:10.1086/513889
  25. Kudryashova, E., Kudryashov, D., Kramerova, I. & Spencer, M. J. 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). doi:10.1016/j.jmb.2005.09.068
  26. Udd, B., Kääriänen, H. & Somer, H. Muscular dystrophy with separate clinical phenotypes in a large family. Muscle Nerve (1991). doi:10.1002/mus.880141103
  27. Hackman, P. et al. Tibial Muscular Dystrophy Is a Titinopathy Caused by Mutations in TTN, the Gene Encoding the Giant Skeletal-Muscle Protein Titin. Am. J. Hum. Genet. (2002). doi:10.1086/342380
  28. Dinçer, P. et al. A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of a-dystroglycan. Neuromuscul. Disord. (2003). doi:10.1016/S0960-8966(03)00161-5
  29. Bolduc, V. 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). doi:10.1016/j.ajhg.2009.12.013
  30. Godfrey, C. et al. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy. Ann. Neurol. (2006). doi:10.1002/ana.21006
  31. Biancheri, R. et al. POMT2 gene mutation in limb-girdle muscular dystrophy with inflammatory changes. Biochem. Biophys. Res. Commun. (2007). doi:10.1016/j.bbrc.2007.09.066
  32. Godfrey, C. et al. Refining genotype-phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain (2007). doi:10.1093/brain/awm212
  33. Clement, E. M. et al. Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant. Arch. Neurol. (2008). doi:10.1001/archneurol.2007.2
  34. Hara, Y. et al. A Dystroglycan Mutation Associated with Limb-Girdle Muscular Dystrophy. N. Engl. J. Med. (2011). doi:10.1056/nejmoa1006939
  35. Zhong, J. et al. Novel compound heterozygous PLEC mutations lead to early-onset limb-girdle muscular dystrophy 2Q. Mol. Med. Rep. (2017). doi:10.3892/mmr.2017.6309
  36. Cetin, N. et al. A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: Distinct histopathological outcomes compared with desminopathies. J. Med. Genet. (2013). doi:10.1136/jmedgenet-2012-101487
  37. Bögershausen, N. et al. 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). doi:10.1016/j.ajhg.2013.05.028
  38. Oestergaard, S. T. et al. Muscle involvement in limb-girdle muscular dystrophy with GMPPB deficiency (LGMD2T). Neurol. Genet. (2016). doi:10.1212/NXG.0000000000000112
  39. Cirak, S. et al. ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain (2013). doi:10.1093/brain/aws312
  40. Preisler, N. et al. Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies. Mol. Genet. Metab. (2013). doi:10.1016/j.ymgme.2013.08.005
  41. Chardon, J. W. et al. LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues. Clin. Genet. (2015). doi:10.1111/cge.12561

Looking for more information, support or ways to get involved?