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 ... 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).
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 ... 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. Vorgerd et al. (2001) reported a patient with sporadic RMD who carried a mutation in the CAV3 gene (601253.0007). Muscle biopsy of the patient showed reduced sarcolemmal caveolin-3 with punctated 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. 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 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) identified 4 mutations in the CAV3 gene (see, e.g., 601253.0001 and 601253.0005). They found that the ... In the families with rippling muscle disease described by Ricker et al. (1989) and Vorgerd et al. (1999), Betz et al. (2001) identified 4 mutations in the CAV3 gene (see, e.g., 601253.0001 and 601253.0005). They found that the same mutation in the CAV3 gene could cause multiple phenotypes. 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 and suggested that caveolinopathies, including RMD and limb-girdle muscular dystrophy type 1C, are part of a clinical continuum.