Alternative titles; symbols
SNOMEDCT: 718180000; ICD10CM: G71.038; ORPHA: 34515; DO: 0110299;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.32 | Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 | 607155 | Autosomal recessive | 3 | FKRP | 606596 |
A number sign (#) is used with this entry because this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C5; MDDGC5), also designated LGMDR9 and LGMD2I, is caused by homozygous or compound heterozygous mutation in the gene encoding fukutin-related protein (FKRP; 606596) on chromosome 19q13.
Mutation in the FKRP gene can also cause a severe congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A5; MDDGA5; 613153) and a congenital muscular dystrophy-dystroglycanopathy with or without impaired intellectual development (type B5; MDDGB5; 606612).
MDGDC5 is an autosomal recessive muscular dystrophy characterized by variable age at onset, normal cognition, and no structural brain changes (Brockington et al., 2001). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2006).
For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
Bushby et al. (1998) described 7 patients, including 2 sib pairs, with late-onset limb-girdle muscular dystrophy. Apart from 1 patient, whose muscle problems began in childhood, the age at onset ranged from 17 to 40 years. The pattern of muscle involvement was similar from patient to patient, with hypertrophy of at least the calf muscles, absence of scapular winging, and predominant involvement of hip flexors and hamstrings more than quadriceps. Serum creatine kinase in all patients was at least 10 times normal, and muscle biopsies showed nonspecific dystrophic features. Six of the 7 patients were female. Linkage analysis excluded the merosin locus on chromosome 6q (156225). No abnormalities were detected on immunostaining for several proteins known to be involved in the limb-girdle muscular dystrophies, such as sarcoglycans alpha (SGCA; 600119), beta (SGCB; 600900), gamma (SGCG; 608896), and delta (SGCD; 601411), and calpain-3 (CAPN3; 114240).
Brockington et al. (2001) reported 17 families with FKRP-related limb-girdle muscular dystrophy, which they called LGMD2I. Age at onset ranged from 6 months to 40 years. The disorder presented as hypotonia, waddling gait, or difficulty in climbing stairs. There was weakness in the hip and shoulder girdle muscles, calf hypertrophy, and elevated serum creatine kinase. Histologic changes were characteristic of a muscular dystrophy in all patients. A variable reduction of alpha-dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin-2 (LAMA2; 156225) either by immunocytochemistry or Western blotting. Cognition was normal.
Mercuri et al. (2003) described in detail the clinical phenotypes of 18 patients with limb-girdle muscular dystrophy, some of whom had previously been described by Brockington et al. (2001). Eleven of the 18 patients showed early age at onset (less than 5 years), lost ambulation in their teens, and resembled boys with Duchenne muscular dystrophy (DMD; 310300). The other 7 patients had onset between 7 and 23 years, retained ambulation, and had a milder phenotype. In general, all patients with LGMD2I had proximal weakness, calf hypertrophy, tightness of the Achilles tendon, and elevated creatine kinase. Nine patients developed scoliosis, 6 required nocturnal ventilation, and 10 had signs of dilated cardiomyopathy on echocardiography. Muscle biopsy showed a slight reduction in laminin alpha-2 and variable expression of alpha-dystroglycan. Another detailed analysis of the LGMD2I phenotype was provided by Poppe et al. (2003).
Harel et al. (2004) reported a large consanguineous Bedouin family from northern Israel with LGMD2I. Nine of 11 affected patients were available for detailed study. Age at onset ranged from birth to 15 years; some patients had delayed motor milestones and minor symptoms during childhood, including difficulty in running or climbing stairs and frequent falls. The proximal lower limb muscles were the most severely affected, and 6 patients required wheelchairs by the second or third decades. All patients had hyperlordosis, kyphoscoliosis, or spinal fusion. One severely affected patient had involvement of the facial muscles. Some patients had restrictive lung disease, but none had primary cardiac involvement.
Poppe et al. (2004) reported 38 LGMD2I patients with the L276I mutation (606596.0004): 23 were homozygous, and 15 were compound heterozygous with another FKRP mutation. Twenty-one (55%) patients had cardiac involvement, defined as left ventricular wall motion abnormalities. Patients who were L276I heterozygotes had earlier onset of cardiomyopathy compared to homozygotes. Forty-four percent of patients had a decreased forced vital capacity less than 75%, and 39% of patients had diaphragmatic weakness. There was no absolute correlation between skeletal muscle weakness and cardiomyopathy or respiratory insufficiency; respiratory failure was observed in some patients who were still ambulatory.
Schwartz et al. (2005) found that 13 of 102 sporadic patients with a phenotype resembling Duchenne or Becker (300376) muscular dystrophy, but without mutations in the dystrophin gene (DMD; 300377), had mutations in the FKRP gene, consistent with a diagnosis of LGMD2I. Four of 7 patients showed reduced or irregular immunostaining for dystrophin on muscle biopsy. In 2 cases, a diagnosis of Becker muscular dystrophy had been made based on muscle biopsy and clinical findings, and prenatal diagnoses had been performed in their families based on that erroneous assumption.
In a retrospective analysis of 26 patients with LGMD2I, Mathews et al. (2011) found that 7 (27%) had at least 1 episode of myoglobinuria following physical exertion. In 3 cases, myoglobinuria was the presenting symptom of the disorder. Another common reported feature in this group was myalgia with pain or cramps, occurring in 16 (61%) of 26 patients.
Sveen et al. (2007) found that moderate-intensity endurance training was a safe and effective method to increase exercise performance and daily function in patients with FKRP-related limb-girdle muscular dystrophy. Nine patients, all ambulatory and homozygous for an FKRP L276I mutation (606596.0004), completed a 12-week cycling program consisting of 30-minute sessions at 65% maximal oxygen uptake. Creatine kinase levels did not increase significantly, and muscle morphology was unaffected. Sveen et al. (2007) noted that patients with the L276I mutation tend to have a mild phenotype.
In a large consanguineous Tunisian family with an autosomal recessive form of limb-girdle muscular dystrophy, Driss et al. (2000) found linkage of the disorder to a locus on chromosome 19q13.3.
The transmission pattern of LGMD2I in the families reported by Brockington et al. (2001) was consistent with autosomal recessive inheritance.
In 17 families with LGMD2I, Brockington et al. (2001) identified several mutations in the FKRP gene. Affected individuals from 15 of the 17 families had an identical L276I (606596.0004) mutation; individuals in 5 families were homozygous for this recurrent mutation. Patients with the L276I change had a clinically less severe LGMD2I phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDC1C (MDDGB5; 606612). Four of the families had previously been described by Bushby et al. (1998).
In the consanguineous Tunisian family originally reported by Driss et al. (2000) in which 13 members had LGMD2I, Driss et al. (2003) identified a homozygous mutation in the FKRP gene (606596.0006). The patients had symmetric proximal muscle weakness and wasting in all 4 limbs. No heart involvement was found. Immunohistochemical and immunoblot analysis showed abnormal expression of alpha-dystroglycan and alpha-2 laminin, supporting the hypothesis that FKRP has a role in the interaction between components of the extracellular matrix.
In 16 patients with LGMD2I from 13 Brazilian families, de Paula et al. (2003) identified 10 distinct mutations, including 9 novel mutations, in the FKRP gene (see, e.g., 606596.0012-606596.0015). The most common mutation, L276I (606596.0004), was identified in 9 of 26 alleles.
In 8 affected members of a large consanguineous Bedouin family with LGMD2I, Harel et al. (2004) identified a homozygous mutation in the FKRP gene (R45W; 606596.0011).
In affected members of 5 Hutterite families with LGMD, Frosk et al. (2005) identified homozygosity for the L276I mutation in the FKRP gene (606596.0004). The same mutation occurs in non-Hutterite patients with LGMD from Europe, Canada, and Brazil, and appears to be a founder mutation dispersed among populations of European origin. LGMD2H (LGMDR8; 254110), due to mutation in the TRIM32 gene (D487N; 602290.0001), is a more common form of LGMD among Hutterites and may be limited to the Hutterite population. Frosk et al. (2005) found that Hutterite LGMD2I patients with the FKRP mutation had an earlier age at diagnosis, a more severe course, and higher serum creatine kinase than LGMD2H patients with the TRIM32 mutation. In addition, some of the LGMD2I patients showed calf hypertrophy, cardiac symptoms, and severe reactions to general anesthesia; none of these features were present among LGMD2H patients.
Frosk et al. (2005) reported a Hutterite family in which 2 boys, aged 7 and 10 years, were homozygous for both the LGMD2H-related TRIM32 mutation, D487N, and the LGMD2I-related FKRP mutation, L276I. Although they presented at an early age with exercise intolerance and increased serum creatine kinase, the clinical phenotype was not significantly more severe than that of patients with isolated LGMD2H or LGMD2I. Both parents and 3 other sibs were homozygous for the D487N mutation, with highly variable phenotypic expression.
Sveen et al. (2006) identified FKRP mutations in 38 of 99 Danish individuals with a clinical diagnosis of LGMD2, making LGMD2I the most common LGMD subtype in this country. Of the 38 individuals, 27 were homozygous for L276I, and 11 were compound heterozygous for L276I and another pathogenic FKRP mutation. The homozygous patients had later onset, milder clinical progression, and less muscle weakness compared to compound heterozygous patients, all of whom were wheelchair-bound by their mid-twenties. Cardiac and respiratory involvement was found in both groups. Nine L276I homozygous, but no compound heterozygous, patients had initial symptoms of exertional myoglobinuria. The L276I mutation was identified in 1 of 200 control alleles.
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Brockington, M., Yuva, Y., Prandini, P., Brown, S. C., Torelli, S., Benson, M. A., Herrmann, R., Anderson, L. V. B., Bashir, R., Burgunder, J.-M., Fallet, S., Romero, N., and 10 others. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum. Molec. Genet. 10: 2851-2859, 2001. [PubMed: 11741828] [Full Text: https://doi.org/10.1093/hmg/10.25.2851]
Bushby, K., Anderson, L. V., Pollitt, C., Naom, I., Muntoni, F., Bindoff, L. Abnormal merosin in adults: a new form of late onset muscular dystrophy not linked to chromosome 6q2. Brain 121: 581-588, 1998. [PubMed: 9577386] [Full Text: https://doi.org/10.1093/brain/121.4.581]
De Paula, F., Vieira, N., Starling, A., Yamamoto, L. U., Lima, B., de Cassia Pavanello, R., Vainzof, M., Nigro, V., Zatz, M. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Europ. J. Hum. Genet. 11: 923-930, 2003. [PubMed: 14647208] [Full Text: https://doi.org/10.1038/sj.ejhg.5201066]
Driss, A., Amouri, C., Hamida, C. B., Souilem, N., Gouider-Khouja, N., Hamida, M. B., Hentati, F. A new locus for autosomal recessive limb girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3. Neuromusc. Disord. 10: 240-246, 2000. [PubMed: 10838249] [Full Text: https://doi.org/10.1016/s0960-8966(00)00099-7]
Driss, A., Noguchi, S., Amouri, R., Kefi, M., Sasaki, T., Sugie, K., Souilem, S., Hayashi, Y. K., Shimizu, N., Minoshima, S., Kudoh, J., Hentati, F., Nishino, I. Fukutin-related protein gene mutated in the original kindred limb-girdle MD 2I. Neurology 60: 1341-1344, 2003. [PubMed: 12707439] [Full Text: https://doi.org/10.1212/01.wnl.0000065886.82930.c5]
Frosk, P., Del Bigio, M. R., Wrogemann, K., Greenberg, C. R. Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I. Europ. J. Hum. Genet. 13: 978-982, 2005. [PubMed: 15886712] [Full Text: https://doi.org/10.1038/sj.ejhg.5201436]
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Harel, T., Goldberg, Y., Shalev, S. A., Chervinski, I., Ofir, R., Birk, O. S. Limb-girdle muscular dystrophy 2I: phenotypic variability within a large consanguineous Bedouin family associated with a novel FKRP mutation. Europ. J. Hum. Genet. 12: 38-43, 2004. [PubMed: 14523375] [Full Text: https://doi.org/10.1038/sj.ejhg.5201087]
Mathews, K. D., Stephan, C. M., Laubenthal, K., Winder, T. L., Michele, D. E., Moore, S. A., Campbell, K. P. Myoglobinuria and muscle pain are common in patients with limb-girdle muscular dystrophy 2I. Neurology 76: 194-195, 2011. [PubMed: 21220724] [Full Text: https://doi.org/10.1212/WNL.0b013e3182061ad4]
Mercuri, E., Brockington, M., Straub, V., Quijano-Roy, S., Yuva, Y., Herrmann, R., Brown, S. C., Torelli, S., Dubowitz, V., Blake, D. J., Romero, N. B., Estournet, B., Sewry, C. A., Guicheney, P., Voit, T., Muntoni, F. Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann. Neurol. 53: 537-542, 2003. [PubMed: 12666124] [Full Text: https://doi.org/10.1002/ana.10559]
Mercuri, E., Topaloglu, H., Brockington, M., Berardinelli, A., Pichiecchio, A., Santorelli, F., Rutherford, M., Talim, B., Ricci, E., Voit, T., Muntoni, F. Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations. Arch. Neurol. 63: 251-257, 2006. [PubMed: 16476814] [Full Text: https://doi.org/10.1001/archneur.63.2.251]
Poppe, M., Bourke, J., Eagle, M., Frosk, P., Wrogemann, K., Greenberg, C., Muntoni, F., Voit, T., Straub, V., Hilton-Jones, D., Shirodaria, C., Bushby, K. Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I. Ann. Neurol. 56: 738-741, 2004. [PubMed: 15505776] [Full Text: https://doi.org/10.1002/ana.20283]
Poppe, M., Cree, L., Bourke, J., Eagle, M., Anderson, L. V. B., Birchall, D., Brockington, M., Buddles, M., Busby, M., Muntoni, F., Wills, A., Bushby, K. The phenotype of limb-girdle muscular dystrophy type 2I. Neurology 60: 1246-1251, 2003. Note: Erratum: Neurology 61: 150 only, 2003. [PubMed: 12707425] [Full Text: https://doi.org/10.1212/01.wnl.0000058902.88181.3d]
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Sveen, M.-L., Schwartz, M., Vissing, J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann. Neurol. 59: 808-815, 2006. [PubMed: 16634037] [Full Text: https://doi.org/10.1002/ana.20824]