Alternative titles; symbols
SNOMEDCT: 718850008; ICD10CM: G71.0342; ORPHA: 119; DO: 0110279;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q12 | Muscular dystrophy, limb-girdle, autosomal recessive 4 | 604286 | Autosomal recessive | 3 | SGCB | 600900 |
A number sign (#) is used with this entry because autosomal recessive limb-girdle muscular dystrophy-4 (LGMDR4) is caused by homozygous or compound heterozygous mutation in the gene encoding beta-sarcoglycan (SGCB; 600900) on chromosome 4q12.
Limb-girdle muscular dystrophies are characterized clinically by predominantly proximal muscle weakness of variable severity and dystrophic changes on muscle biopsy. LGMDR4 is in general a severe form of the disorder, with some patients developing symptoms before 8 years of age and losing the ability to ambulate in their second decade. Some patients have a milder course, with weakness evident in the teenage years and loss of walking ability in their fourth decade (summary by Lim et al., 1995 and Bonnemann et al., 1996).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2E was renamed LGMDR4.
Jackson and Strehler (1968) reported 5 nuclear Old Amish families from southern Indiana with autosomal recessive limb-girdle muscular dystrophy. The families showed links to an ancestral couple born in the late 1700s (Allamand et al., 1995). In 6 Amish families with LGMD from southern Indiana, Allamand et al. (1995) excluded linkage to the LGMD2A (LGMDR1; 253600) locus on chromosome 15q. Lim et al. (1995) reported the clinical features of 11 Amish patients from southern Indiana with autosomal recessive LGMD. All patients presented with proximal symmetric weakness and atrophy of the limb and trunk muscles. The average age at onset was 7.6 years (range 4 to 12), and loss of walking occurred between 12 and 38 years. Calf hypertrophy was also observed. There was marked intrafamilial variability.
Bonnemann et al. (1995) described a young girl with autosomal recessive LGMD. Immunostaining of her muscle biopsy showed specific loss of several components of the sarcoglycan complex: beta-sarcoglycan, alpha-sarcoglycan (SGCA; 600119), and 35-kD sarcoglycan (SGCD; 601411). Thus, secondary destabilization of the sarcoglycan complex is an important pathophysiologic event in autosomal recessive muscular dystrophy. Genetic analysis identified compound heterozygosity for 2 truncating mutations in the SGCB gene (600900.0002, 600900.0003).
Barresi et al. (2000) reported 2 unrelated males with LGMD2E who developed fatal dilated cardiomyopathy and died at ages 27 and 18 years, respectively. The affected first-cousin of 1 of the patients did not have cardiomyopathy. Both heart and skeletal muscle biopsies showed reductions in gamma- (SGCG; 608896) and alpha-sarcoglycan, confirming that mutations in 1 sarcoglycan gene can disrupt the whole dystrophin (DMD; 300377)-associated glycoprotein (DAG) complex. Barresi et al. (2000) concluded that cardiac function should be monitored in patients with LGMD and defective sarcoglycan expression. Molecular analysis identified compound heterozygous mutations in the SGCB gene in 1 patient (600900.0003; 600900.0009).
Prenatal Diagnosis
Pegoraro et al. (1999) reported the first prenatal diagnosis of LGMD2E by direct gene mutation detection.
Using pericentromeric markers and an intragenic polymorphic CA repeat on chromosome 4q12, Lim et al. (1995) demonstrated perfect cosegregation with autosomal recessive limb-girdle muscular dystrophy in Amish families from southern Indiana.
The transmission pattern of LGMDR4 in the families reported by Lim et al. (1995) was consistent with autosomal recessive inheritance.
In affected members of several Amish families with autosomal recessive LGMD, Lim et al. (1995) identified a homozygous mutation in the SGCB gene (600900.0001). Skeletal muscle biopsy showed a dramatic reduction in SGCB expression in the sarcolemma and a concomitant loss of adhalin (SGCA; 600119) and 35-DAG (SGCD; 601411), which was interpreted as representing a disruption of a functional subcomplex within the dystrophin-glycoprotein complex.
Bonnemann et al. (1996) identified novel mutations in the SGCB gene in 2 familial and 2 sporadic cases of severe childhood-onset LGMD. One patient carried a truncating mutation (600900.0004); the other 3 patients had missense mutations in exon 3.
Trabelsi et al. (2008) identified biallelic mutations in sarcoglycan genes in 46 (67%) of 69 patients with a clinical diagnosis of autosomal recessive LGMD. Twenty-six (56.5%) patients had SGCA mutations, 8 (17.3%) had SGCB mutations, and 12 (26%) had SGCG mutations. Seven of the 9 SGCB mutations were novel.
Kaindl et al. (2005) identified a homozygous 400-kb microdeletion of chromosome 4q11-q12 in 6 members of a consanguineous East Anatolian family with a severe form of LGMD2E with joint hyperlaxity and contractures. The deleted region included both the SGCB and SPATA18 (612814) genes. Other clinical features included onset between birth and 5 years, myopathic facies, and scoliosis. The proband had delayed motor development and lost the ability to walk by age 10 years. She had restrictive respiratory insufficiency, mild diastolic dysfunction of both ventricles, increased serum creatine kinase, type 2 diabetes mellitus, and polycystic ovary syndrome (PCOS; 184700). Three affected family members died of heart failure at ages 20, 30, and 35 years, respectively. Kaindl et al. (2005) commented that the phenotype was similar to that of Duchenne muscular dystrophy (DMD; 310200).
Passos-Bueno et al. (1999) studied 140 patients from 40 Brazilian families with one of 7 autosomal recessive limb-girdle muscular dystrophies (LGMDs). All LGMD2E and LGMD2F (LGMDR6; 601287) patients had a severe phenotype; considerable inter- and intrafamilial variability was observed in all other types of LGMD. Among the sarcoglycanopathies, serum CK levels were highest in the LGMD2D (LGMDR3; 608099) patients. Comparison between 40 LGMD2A (LGMDR1; 253600) patients and 52 LGMD2B (LGMDR2; 253601) patients showed that LGMD2A patients had a more severe course and higher frequency of calf hypertrophy (86% vs 13%), and that LGMD2B patients were more likely to be unable to walk on toes (70% vs 18%).
Alonso-Perez et al. (2020) reviewed genotype-phenotype correlations in 396 patients with a sarcoglycanopathy from 13 European countries, of whom 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 (253700), and 7 of LGMDR6 (601287). Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Onset of symptoms before 10 years of age and residual protein expression lower than 30% were identified as independent risk factors for losing ambulation before 18 years of age in LGMDR3, LGMDR4, and LGMDR5 patients. The most common mutation in LGMDR4 patients was c.341C-T.
Jackson and Carey (1961) reported autosomal recessive limb-girdle muscular dystrophy in 7 nuclear families among the Old Order Amish in northern Indiana. The maternal and paternal lines had common ancestors: 2 brothers married sisters in the early 1800s. These families were later shown to map to chromosome 15q and harbor a common pathogenic mutation in the CAPN3 gene (114240.0001), consistent with LGMD2A (Richard et al., 1995). Allamand et al. (1995) noted that the Amish families from northern and southern Indiana were interrelated by multiple consanguineous links and had a common ancestry that could be traced to the canton of Bern, Switzerland, where limb-girdle muscular dystrophy also has a high frequency (Young et al., 1992).
Araishi et al. (1999) developed a beta-sarcoglycan (BSG)-deficient transgenic mouse by incorporating a vector whose BSG insert lacked exon 2, which encodes the intracellular and transmembrane domains of the protein. The BSG -/- mice exhibited progressive muscular dystrophy, with extensive degeneration and regeneration of myofibers seen histologically. The BSG -/- mice also exhibited muscular hypertrophy characteristic of beta-sarcoglycanopathy in humans. Immunohistochemical and immunoblot analyses of BSG -/- mouse muscle demonstrated that deficiency of beta-sarcoglycan also caused loss of all other sarcoglycans as well as loss of sarcospan (601599) in the sarcolemma, similar to the findings of Bonnemann et al. (1995). On the other hand, laminin-alpha-2 (156225), alpha- and beta-dystroglycan (see 128239), and dystrophin were present in the sarcolemma. In addition, the dystrophin-dystroglycan complex in BSG -/- mice was either unstably assembled or easily dissociable compared to the complex in wildtype mice. The authors concluded that loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy, that beta-sarcoglycan is an important protein for formation of the sarcoglycan complex associated with sarcospan, and that the role of the sarcoglycan complex and sarcospan may be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton.
Allamand, V., Broux, O., Bourg, N., Richard, I., Tischfield, J. A., Hodes, M. E., Conneally, P. M., Fardeau, M., Jackson, C. E., Beckmann, J. S. Genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy in a genetic isolate (Amish) and evidence for a new locus. Hum. Molec. Genet. 4: 459-463, 1995. [PubMed: 7795603] [Full Text: https://doi.org/10.1093/hmg/4.3.459]
Alonso-Perez, J., Gonzalez-Quereda, L., Bello, L., Guglieri, M., Straub, V., Gallano, P., Semplicini, C., Pegoraro, E., Zangaro, V., Nascimento, A., Ortez, C., Comi, G. P., and 48 others. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy. Brain 143: 2696-2708, 2020. Note: Erratum: Brain 146: e9, 2023. [PubMed: 32875335] [Full Text: https://doi.org/10.1093/brain/awaa228]
Araishi, K., Sasaoka, T., Imamura, M., Noguchi, S., Hama, H., Wakabayashi, E., Yoshida, M., Hori, T., Ozawa, E. Loss of the sarcoglycan complex and sarcospan leads to muscular dystrophy in beta-sarcoglycan-deficient mice. Hum. Molec. Genet. 8: 1589-1598, 1999. [PubMed: 10441321] [Full Text: https://doi.org/10.1093/hmg/8.9.1589]
Barresi, R., Di Blasi, C., Negri, T., Brugnoni, R., Vitali, A., Felisari, G., Salandi, A., Daniel, S., Cornelio, F., Morandi, L., Mora, M. Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations. J. Med. Genet. 37: 102-107, 2000. [PubMed: 10662809] [Full Text: https://doi.org/10.1136/jmg.37.2.102]
Bonnemann, C. G., Modi, R., Noguchi, S., Mizuno, Y., Yoshida, M., Gussoni, E., McNally, E. M., Duggan, D. J., Angelini, C., Hoffman, E. P., Ozawa, E., Kunkel, L. M. Beta-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Nature Genet. 11: 266-273, 1995. Note: Erratum: Nature Genet. 12: 110 only, 1996. [PubMed: 7581449] [Full Text: https://doi.org/10.1038/ng1195-266]
Bonnemann, C. G., Passos-Bueno, M. R., McNally, E. M., Vainzof, M., Moreira, E. S., Marie, S. K., Pavanello, R. C. M., Noguchi, S., Ozawa, E., Zatz, M., Kunkel, L. M. Genomic screening for beta-sarcoglycan gene mutations: missense mutations may cause severe limb-girdle muscular dystrophy type 2E (LGMD 2E). Hum. Molec. Genet. 5: 1953-1961, 1996. [PubMed: 8968749] [Full Text: https://doi.org/10.1093/hmg/5.12.1953]
Jackson, C. E., Carey, J. H. Progressive muscular dystrophy: autosomal recessive type. Pediatrics 28: 77-84, 1961. [PubMed: 13718465]
Jackson, C. E., Strehler, D. A. Limb-girdle muscular dystrophy: clinical manifestations and detection of preclinical disease. Pediatrics 41: 495-502, 1968. [PubMed: 5637795]
Kaindl, A. M., Jakubiczka, S., Lucke, T., Bartsch, O., Weis, J., Stoltenburg-Didinger, G., Aksu, F., Oexle, K., Koehler, K., Huebner, A. Homozygous microdeletion of chromosome 4q11-q12 causes severe limb-girdle muscular dystrophy type 2E with joint hyperlaxity and contractures. (Abstract) Hum. Mutat. 26: 279-280, 2005. Note: Full article online.
Lim, L. E., Duclos, F., Broux, O., Bourg, N., Sunada, Y., Allamand, V., Meyer, J., Richard, I., Moomaw, C., Slaughter, C., Tome, F. M. S., Fardeau, M., Jackson, C. E., Beckmann, J. S., Campbell, K. P. Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nature Genet. 11: 257-265, 1995. [PubMed: 7581448] [Full Text: https://doi.org/10.1038/ng1195-257]
Passos-Bueno, M. R., Vainzof, M., Moreira, E. S., Zatz, M. Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G. Am. J. Med. Genet. 82: 392-398, 1999. [PubMed: 10069710] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990219)82:5<392::aid-ajmg7>3.0.co;2-0]
Pegoraro, E., Fanin, M., Angelini, C., Hoffman, E. P. Prenatal diagnosis in a family affected with beta-sarcoglycan muscular dystrophy. Neuromusc. Disord. 9: 323-325, 1999. [PubMed: 10407854] [Full Text: https://doi.org/10.1016/s0960-8966(99)00020-6]
Richard, I., Broux, O., Allamand, V., Fougerousse, F., Chiannilkulchai, N., Bourg, N., Brenguier, L., Devaud, C., Pasturaud, P., Roudaut, C., Hillaire, D., Passos-Bueno, M.-R., Zatz, M., Tischfield, J. A., Fardeau, M., Jackson, C. E., Cohen, D., Beckmann, J. S. Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 81: 27-40, 1995. [PubMed: 7720071] [Full Text: https://doi.org/10.1016/0092-8674(95)90368-2]
Straub, V., Murphy, A., Udd, B. 229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromusc. Disord. 28: 702-710, 2018. [PubMed: 30055862] [Full Text: https://doi.org/10.1016/j.nmd.2018.05.007]
Trabelsi, M., Kavian, N., Daoud, F., Commere, V., Deburgrave, N., Beugnet, C., Llense, S., Barbot, J. C., Vasson, A., Kaplan, J. C., Leturcq, F., Chelly, J. Revised spectrum of mutations in sarcoglycanopathies. Europ. J. Hum. Genet. 16: 793-803, 2008. [PubMed: 18285821] [Full Text: https://doi.org/10.1038/ejhg.2008.9]
Young, K., Foroud, T., Williams, P., Jackson, C. E., Beckmann, J. S., Cohen, D., Conneally, P. M., Tischfield, J., Hodes, M. E. Confirmation of linkage of limb-girdle muscular dystrophy, type 2, to chromosome 15. Genomics 13: 1370-1371, 1992. [PubMed: 1505977] [Full Text: https://doi.org/10.1016/0888-7543(92)90074-3]