Alternative titles; symbols
SNOMEDCT: 709281006; ORPHA: 97238; DO: 0060255;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p25.3 | Rippling muscle disease 2 | 606072 | Autosomal dominant | 3 | CAV3 | 601253 |
A number sign (#) is used with this entry because of evidence that rippling muscle disease-2 (RMD2) is caused by heterozygous mutation in the gene encoding caveolin-3 (CAV3; 601253) on chromosome 3p25. Some patients have been reported with homozygous mutations.
Hereditary rippling muscle disease is an autosomal dominant disorder characterized by mechanically triggered contractions of skeletal muscle. In rippling muscle disease, mechanical stimulation leads to electrically silent muscle contractions that spread to neighboring fibers that cause visible ripples to move over the muscle. RMD is usually inherited as an autosomal dominant trait, but autosomal recessive inheritance has also been reported (Kubisch et al., 2005).
Genetic Heterogeneity of Rippling Muscle Disease
Another locus for RMD, designated RMD1 (600332), maps to chromosome 1q41.
Some cases of rippling muscle disease-2 were previously classified as a form of limb-girdle muscular dystrophy (type 1C; LGMD1C). Straub et al. (2018), on behalf of the LGMD workshop study group, reclassified LGMD1C as RMD2.
Torbergsen (1975) described myotonia with muscular hypertrophy and hyperirritability in 3 generations (with male-to-male transmission) and maintained that the disorder was distinct from Thomsen myotonia congenita (160800). In the most severely affected persons, unusual rolling muscle contractions were seen. It was not clear that Torbergsen (1975) had demonstrated a definite difference from Thomsen disease. However, Stephan et al. (1994) described a new 44-member pedigree segregating a similar disorder as an autosomal dominant trait. The patients experienced muscle cramps, pain, and stiffness, particularly with exercise. Balling of muscle occurred after percussion, and a characteristic lateral rolling movement of muscle occurred after contraction followed by stretching. Electromyography demonstrated that mechanical stimulation provoked electrically silent contractions.
Minetti et al. (1998) described 8 patients from 2 different families with what they classified as a form of autosomal dominant limb-girdle muscular dystrophy (LGMD1C) that was associated with a severe deficiency of caveolin-3 in muscle fibers (up to 95% reduction). In both families, initial motor milestones were normal and onset of disease was at about age 5 years. All had calf hypertrophy and mild to moderate proximal muscle weakness, and each adult patient showed a positive Gowers sign. Two patients in 1 family had multiple episodes of muscle cramps after physical effort. Serum creatine kinase levels were elevated 4- to 25-fold. Routine histologic and histochemical studies of muscle biopsies revealed only nonspecific myopathic changes of moderate severity.
Herrmann et al. (2000) reported a 4-year-old girl with lower limb myalgia and muscle cramps and an elevated serum creatine kinase. Skeletal muscle biopsy showed dystrophic changes and near complete loss of caveolin-3 expression.
Vorgerd et al. (2001) reported a patient with sporadic RMD who carried a mutation in the CAV3 gene (R26Q; 601253.0007). Muscle biopsy of the patient showed reduced sarcolemmal caveolin-3 with punctuated cytosolic staining, consistent with intracellular retention of an unstable protein. Neuronal nitric oxide synthase (nNOS) expression was normal. Vorgerd et al. (2001) suggested that increased inducibility of nNOS, caused by lack of inhibition by normal caveolin, may contribute to muscle hyperexcitability in RMD.
Figarella-Branger et al. (2003) reported a 71-year-old woman with the CAV3 R26Q mutation who had mild proximal muscle weakness, scapular winging, slight calf hypertrophy, and a positive Gowers sign. Muscle biopsy showed fibers of various sizes, centrally located nuclei, occasional necrotic and regenerative fibers, decreased dysferlin immunoreactivity, and near absence of caveolin-3. Although this was a late presentation, the authors could not rule out a very slow but myopathic evolution of a putative hyperCKemia in infancy. Figarella-Branger et al. (2003) suggested that this patient had a limb-girdle muscular dystrophy. They emphasized the heterogeneous clinical phenotypes that had been reported in association with this CAV3 mutation.
Kubisch et al. (2005) reported 2 German sibs who had childhood-onset of RMD by ages 7 and 13. Both patients reported nocturnal myalgia of the legs, showed percussion-induced rapid muscle contractions, and had elevated serum creatine kinase. Neither had cardiac involvement. Genetic analysis identified a homozygous mutation in the CAV3 gene (601253.0010), indicating autosomal recessive inheritance. The unaffected parents were both heterozygous for the mutation. Although the parents were not known to be consanguineous, they both originated from a small village in southern Germany.
Madrid et al. (2005) reported a father a son with RMD confirmed by genetic analysis (601253.0015). Unusual clinical features in both of these patients included congenital pes equinus deformity and early toe walking, which resolved after orthopedic surgical correction. In addition, the father had nonprogressive mild proximal muscle weakness, and the son demonstrated percussion-induced rapid contractions of the thenar muscles without overt rippling of other muscles. Muscle biopsy from the father showed sparse atrophic myofibers, some hypertrophied fibers, occasional split fibers, increased central myonuclei, and absence of caveolin-3 immunostaining. Electron microscopy showed sarcolemmal papillary projections covered with basal lamina and proliferation of T-tubules in split fibers. Madrid et al. (2005) postulated that hypertrophic myofibers may have split in response to stress.
In the families with rippling muscle disease described by Ricker et al. (1989) and Vorgerd et al. (1999), Betz et al. (2001) found linkage of the disorder to 3p25 at marker D3S1597 with a lod score of 4.68 (theta = 0.05). Betz et al. (2001) identified a maximum 2-point lod score of 6.95 at theta = 0.00 for D3S691.
The transmission pattern of RMD2 in most reported families (e.g., Betz et al., 2001) was consistent with autosomal dominant inheritance. The transmission pattern in some reported families (e.g., Kubisch et al., 2003) was consistent with autosomal recessive inheritance.
In affected members of 2 families with RMD2, who had been diagnosed with LGMD1C, Minetti et al. (1998) identified heterozygous mutations in the CAV3 gene (601253.0001 and 601253.0002).
In 2 of 82 patients with muscular dystrophy screened for mutations in the CAV3 gene, McNally et al. (1998) found mutations in the CAV3 gene. One patient was homozygous for a G56S substitution (601253.0003). This patient was the only affected member of her family and had developed proximal muscle weakness in the first decade. This variant was later reclassified as a variant of unknown significance. One patient was heterozygous for a C72W substitution (601253.0004). This patient had progressive proximal muscle weakness beginning in the first decade, but remained ambulatory in the mid-second decade. Her mother and 2 sibs had the identical missense change but did not have symptoms of muscular dystrophy, suggesting that a single abnormal allele is not sufficient to cause the phenotype and that the likely inheritance is autosomal recessive. The authors were unable to determine the nature of the second allele in the proband. McNally (1998) suspected that the phenotype was the result of either loss-of-function mutations or dominant-negative mutations; she doubted that haploinsufficiency leads to the disease. The family was lost to follow-up.
Among 61 Brazilian patients diagnosed with LGMD, de Paula et al. (2001) identified 2 patients with a heterozygous G56S mutation. Both patients had onset in adulthood, calf hypertrophy, elevated creatine kinase, and difficulty walking. Muscle protein analyses from both patients were normal. Screening of 200 normal Brazilian chromosomes revealed heterozygosity for the G56S change in 4 subjects and a C72W change in 1 subject. The authors concluded that the G56S and C72W changes are rare polymorphisms and do not cause the abnormal phenotype when present in just one allele. They noted the possibility that the variants might act as recessive mutations or interact with other genes involved in the dystrophic process.
In a Colombian patient and an Italian patient with severe rippling muscle disease, Kubisch et al. (2003) identified 2 different homozygous mutations in the CAV3 gene (601253.0009 and 601253.0010). One patient had muscle stiffness in his legs since the age of 3 and contractures of the Achilles tendon leading to gait disturbances, and the other patient had slowly progressive muscle weakness beginning in early adulthood. Both patients had elevated creatine kinase levels, hypertrophic skeletal muscles, and generalized rapid muscle contractions. Muscle biopsies showed almost complete loss of caveolin-3 expression and reduced dysferlin (603009). Neither patient had family members available for further study. Kubisch et al. (2003) noted that the patients were more severely clinically affected than those with heterozygous mutations.
In affected members of 5 families with RMD2, including the first-described RMD family reported by Torbergsen (1975) and the families reported by Ricker et al. (1989) and Vorgerd et al. (1999), Betz et al. (2001) identified heterozygous mutations in the CAV3 gene (see 601253.0001, 601253.0005-601253.0007).
Sunada et al. (2001) generated transgenic mice expressing the pro105-to-leu mutant caveolin-3 (P105L; 601253.0001). Mice showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, suggesting a dominant-negative effect of mutant caveolin-3.
Betz, R. C., Schoser, B. G. H., Kasper, D., Ricker, K., Ramirez, A., Stein, V., Torbergsen, T., Lee, Y.-A., Nothen, M. M., Wienker, T. F., Malin, J.-P., Propping, P., Reis, A., Mortier, W., Jentsch, T. J., Vorgerd, M., Kubisch, C. Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. Nature Genet. 28: 218-219, 2001. [PubMed: 11431690] [Full Text: https://doi.org/10.1038/90050]
de Paula, F., Vainzof, M., Bernardino, A. L. F., McNally, E., Kunkel, L. M., Zatz, M. Mutations in the caveolin-3 gene: when are they pathogenic? Am. J. Med. Genet. 99: 303-307, 2001. [PubMed: 11251997] [Full Text: https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1168>3.0.co;2-o]
Figarella-Branger, D., Pouget, J., Bernard, R., Krahn, M., Fernandez, C., Levy, N., Pellissier, J. F. Limb-girdle muscular dystrophy in a 71-year-old woman with an R27Q mutation in the CAV3 gene. Neurology 61: 562-564, 2003. [PubMed: 12939441] [Full Text: https://doi.org/10.1212/01.wnl.0000076486.57572.5c]
Herrmann, R., Straub, V., Blank, M., Kutzick, C., Franke, N., Jacob, E. N., Lenard, H.-G., Kroger, S., Voit, T. Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. Hum. Molec. Genet. 9: 2335-2340, 2000. [PubMed: 11001938] [Full Text: https://doi.org/10.1093/oxfordjournals.hmg.a018926]
Kubisch, C., Ketelsen, U.-P., Goebel, I., Omran, H. Autosomal recessive rippling muscle disease with homozygous CAV3 mutations. (Letter) Ann. Neurol. 57: 303-304, 2005. [PubMed: 15668980] [Full Text: https://doi.org/10.1002/ana.20350]
Kubisch, C., Schoser, B. G. H., v. During, M., Betz, R. C., Goebel, H.-H., Zahn, S., Ehrbrecht, A., Aasly, J., Schroers, A., Popovic, N., Lochmuller, H., Schroder, J. M., Bruning, T., Malin, J.-P., Fricke, B., Meinck, H.-M., Torbergsen, T., Engels, H., Voss, B., Vorgerd, M. Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease. Ann. Neurol. 53: 512-520, 2003. [PubMed: 12666119] [Full Text: https://doi.org/10.1002/ana.10501]
Madrid, R. E., Kubisch, C., Hays, A. P. Early-onset toe walking in rippling muscle disease due to a new caveolin-3 gene mutation. Neurology 65: 1301-1303, 2005. [PubMed: 16247063] [Full Text: https://doi.org/10.1212/01.wnl.0000180963.85963.73]
McNally, E. M., de Sa Moreira, E., Duggan, D. J., Bonnemann, C. G., Lisanti, M. P., Lidov, H. G. W., Vainzof, M., Passos-Bueno, M. R., Hoffman, E. P., Zatz, M., Kunkel, L. M. Caveolin-3 in muscular dystrophy. Hum. Molec. Genet. 7: 871-877, 1998. [PubMed: 9536092] [Full Text: https://doi.org/10.1093/hmg/7.5.871]
McNally, E. M. Personal Communication. Chicago, Ill. 6/8/1998.
Minetti, C., Sotgia, F., Bruno, C., Scartezzini, P., Broda, P., Bado, M., Masetti, E., Mazzocco, M., Egeo, A., Donati, M. A., Volonte, D., Galbiati, F., Cordone, G., Bricarelli, F. D., Lisanti, M. P., Zara, F. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nature Genet. 18: 365-368, 1998. [PubMed: 9537420] [Full Text: https://doi.org/10.1038/ng0498-365]
Ricker, K., Moxley, R. T., Rohkamm, R. Rippling muscle disease. Arch. Neurol. 46: 405-408, 1989. [PubMed: 2705900] [Full Text: https://doi.org/10.1001/archneur.1989.00520400065020]
Stephan, D. A., Buist, N. R. M., Chittenden, A. B., Ricker, K., Zhou, J., Hoffman, E. P. A rippling muscle disease gene is localized to 1q41: evidence for multiple genes. Neurology 44: 1915-1920, 1994. [PubMed: 7936247] [Full Text: https://doi.org/10.1212/wnl.44.10.1915]
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]
Sunada, Y., Ohi, H., Hase, A., Ohi, H., Hosono, T., Arata, S., Higuchi, S., Matsumura, K., Shimizu, T. Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity. Hum. Molec. Genet. 10: 173-178, 2001. [PubMed: 11159934] [Full Text: https://doi.org/10.1093/hmg/10.3.173]
Torbergsen, T. A family with dominant hereditary myotonia, muscular hypertrophy, and increased muscular irritability, distinct from myotonia congenita Thomsen. Acta Neurol. Scand. 51: 225-232, 1975. [PubMed: 1146501] [Full Text: https://doi.org/10.1111/j.1600-0404.1975.tb07603.x]
Vorgerd, M., Bolz, H., Patzold, T., Kubisch, C., Malin, J.-P., Mortier, W. Phenotypic variability in rippling muscle disease. Neurology 52: 1453-1459, 1999. [PubMed: 10227634] [Full Text: https://doi.org/10.1212/wnl.52.7.1453]
Vorgerd, M., Ricker, K., Ziemssen, F., Kress, W., Goebel, H. H., Nix, W. A., Kubisch, C., Schoser, B. G. H., Mortier, W. A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation. Neurology 57: 2273-2277, 2001. [PubMed: 11756609] [Full Text: https://doi.org/10.1212/wnl.57.12.2273]