Rippling Muscle Disease Research Articles

Kardiale Manifestationen bei Muskeldystrophien

Muscular dystrophies (MD) are a clinically and genetically heterogeneous disease group. In the last few years, remarkable progress has been made in understanding the close und various relations between skeletal muscle disease and heart muscle disease. Cardiac involvement has been documented in a number of primary MDs and is even the dominant feature in some of them. The myocardium can be affected in the form of a dilated cardiomyopathy while the conduction system can be affected resulting in arrhythmias and conduction defects. Many patients with MD die because of cardiac complications like sudden cardiac death or congestive heart failure. Detailed clinical data about cardiac involvement are available for Duchenne/Becker MD, Emery-Dreifuss MD, myotonic dystrophy, and the different limb girdle MDs. Cardiac manifestations were also found in congenital MD, central core disease, proximal myotonic myopathy, and nemaline myopathy. No data about cardiac abnormalities are available in oculopharyngeal MD and rippling muscle disease. The heart of patients with primary MD should be carefully investigated because of the life-threatening events caused by cardiac complications. There is a strong need for a close collaboration between neurologists and cardiologists in order to provide optimal disease management for the affected patients.

Rippling muscle disease may be caused by “silent” action potentials in the tubular system of skeletal muscle fibers

Rippling muscle disease (RMD) is a generally benign, myotonic-like myopathy associated with rapid rolling contractions and percussion-induced contractions. These contractions are electrically silent in electromyographic recordings, which is taken as evidence that action potentials are not involved in the phenomena. The pathophysiological mechanisms underlying the symptoms have not been elucidated. Many cases of RMD are caused by mutations in caveolin-3, and aberrations in the tubular system are commonly observed. Here, recent data are discussed showing that action potentials can travel over substantial distances entirely within the transverse and longitudinal tubular systems of a muscle fiber and that stretch can induce such action potentials. Action potentials travelling in the tubular system in most circumstances probably cannot excite the sarcolemma and hence would not be detected. It is suggested that the distinctive contractions in RMD may be due to stretch-induced generation of action potentials within the tubular system.

Immune-mediated rippling muscle disease

The authors report a 44-year-old man with rippling muscle disease (RMD) who does not have a mutation in the caveolin-3 gene. Immunohistochemistry of the muscle biopsy revealed a marked reduction of caveolin-3 and a mosaic pattern of dysferlin immunostaining. Ultrastructural studies showed a loss of caveolae and alterations of the triad. Autoantibodies were directed against the sarcolemma, triad, and several unknown muscle proteins.

Autosomal recessive rippling muscle disease with homozygous CAV3 mutations

Annals of NeurologyVolume 57, Issue 2 p. 303-304 Letter Autosomal recessive rippling muscle disease with homozygous CAV3 mutations Christian Kubisch MD, Christian Kubisch MD Institute of Human Genetics, University Hospital Bonn, BonnSearch for more papers by this authorUwe-Peter Ketelsen MD, Uwe-Peter Ketelsen MD Department of Pediatrics and Adolescent Medicine, Division II: Pediatric Neurology and Muscle Diseases, University Hospital Freiburg, Freiburg, GermanySearch for more papers by this authorIngrid Goebel, Ingrid Goebel Institute of Human Genetics, University Hospital Bonn, BonnSearch for more papers by this authorHeymut Omran MD, Heymut Omran MD Department of Pediatrics and Adolescent Medicine, Division II: Pediatric Neurology and Muscle Diseases, University Hospital Freiburg, Freiburg, GermanySearch for more papers by this author Christian Kubisch MD, Christian Kubisch MD Institute of Human Genetics, University Hospital Bonn, BonnSearch for more papers by this authorUwe-Peter Ketelsen MD, Uwe-Peter Ketelsen MD Department of Pediatrics and Adolescent Medicine, Division II: Pediatric Neurology and Muscle Diseases, University Hospital Freiburg, Freiburg, GermanySearch for more papers by this authorIngrid Goebel, Ingrid Goebel Institute of Human Genetics, University Hospital Bonn, BonnSearch for more papers by this authorHeymut Omran MD, Heymut Omran MD Department of Pediatrics and Adolescent Medicine, Division II: Pediatric Neurology and Muscle Diseases, University Hospital Freiburg, Freiburg, GermanySearch for more papers by this author First published: 24 January 2005 https://doi.org/10.1002/ana.20350Citations: 18Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume57, Issue2February 2005Pages 303-304 RelatedInformation

Two novel CAV3 gene mutations in Japanese families

Caveolin-3 deficiency is a rare, autosomal dominant, muscle disorder caused by caveolin-3 gene ( CAV3) mutations and consists of four clinical phenotypes: limb-girdle muscular dystrophy type 1C (LGMD-1C), rippling muscle disease, distal myopathy, and familial hyperCKemia. So far, only 13 mutations have been reported. We here report two novel heterozygous mutations, 96C>G (N32K) and 128T>A (V43E), in the CAV3 gene in two unrelated Japanese families with LGMD-1C. Both probands presented with elevated serum CK level with calf muscle hypertrophy in their childhood but without apparent muscle weakness. However, their mothers showed mild limb-girdle weakness in addition to high CK level. Caveolin-3 was deficient and caveolae were lacking in muscles from both patients. Our data confirm that caveolin-3 deficiency causes LGMD-1C and expand the variability in CAV3 gene mutations.

Phenotypic variability associated with Arg26Gln mutation in caveolin3.

Caveolin3 (CAV3) is a protein associated with dystrophin, dystrophin-associated glycoproteins, and dysferlin. Mutations in the CAV3 gene result in certain autosomal-dominant inherited diseases, namely, rippling muscle disease (RMD), limb-girdle muscular dystrophy type 1C (LGMD1C), distal myopathy, and hyperCKemia. In this report we show that a previously reported family with RMD has a mutation in the CAV3 gene. Affected individuals had either a characteristic RMD phenotype, a combination of RMD and LGMD1C phenotypes, or a LGMD1C phenotype, but one mutation carrier was asymptomatic at age 86 years. This phenotypic variability associated with mutations in CAV3 has been reported previously but only in a few families. It is important to remember the significant phenotypic variability associated with CAV3 mutations when counseling families with these mutations. These observations also suggest the presence of factors independent of the CAV3 gene locus that modify phenotype.

A CAV3 microdeletion differentially affects skeletal muscle and myocardium.

Caveolin-3 is the muscle-specific protein product of the caveolin gene family and an integral membrane component of caveolae. Mutations in the gene encoding caveolin-3 (CAV3) underlie four distinct disorders of skeletal muscle: the autosomal dominant form of limb-girdle muscular dystrophy type 1C (LGMD-1C), rippling muscle disease (RMD), sporadic and familial forms of hyperCKemia, and distal myopathy. To characterize a multigenerational Italian family affected by an autosomal dominant myopathic disorder and to assess the expression of caveolin-3, dystrophin, dystrophin-associated glycoproteins, and neuronal nitric oxide synthase in the myocardium of an affected patient. Clinical analysis involved 15 family members. Skeletal muscle expression of sarcolemmal proteins was evaluated by immunohistochemistry and western blot analysis in three affected individuals. Caveolar structures were analyzed through electron microscopy in muscle biopsies and in one heart biopsy. CAV3 genetic analysis showed a heterozygous 3-bp microdeletion (328-330del) in affected individuals, resulting in the loss of a phenylalanine (Phe97del) in the transmembrane domain. In the skeletal muscle, the mutation was associated with severe caveolin-3 deficiency and caveolar disorganization, whereas the expression of the other analyzed muscle proteins was unaltered. Remarkably, caveolin-3 was expressed in myocardium at a level corresponding to about 60% of that of control individuals and was correctly localized at the myocardial cell membranes, with preservation of cardiac myofiber caveolar structures. Clinical analysis revealed the concomitant presence in this family of the following phenotypes: RMD, LGMD, and hyperCKemia. Intrafamilial phenotypic heterogeneity is associated with caveolin-3 Phe97 microdeletion. The molecular network interacting with caveolin-3 in skeletal muscle and heart may differ.

Phosphofructokinase Muscle-Specific Isoform Requires Caveolin-3 Expression for Plasma Membrane Recruitment and Caveolar Targeting: Implications for the Pathogenesis of Caveolin-Related Muscle Diseases

Previous co-immunoprecipitation studies have shown that endogenous PFK-M (phosphofructokinase, muscle-specific isoform) associates with caveolin (Cav)-3 under certain metabolic conditions. However, it remains unknown whether Cav-3 expression is required for the plasma membrane recruitment and caveolar targeting of PFK-M. Here, we demonstrate that recombinant expression of Cav-3 dramatically affects the subcellular localization of PFK-M, by targeting PFK-M to the plasma membrane, and by trans-locating PFK-M to caveolae-enriched membrane domains. In addition, we show that the membrane recruitment and caveolar targeting of PFK-M appears to be strictly dependent on the concentration of extracellular glucose. Interestingly, recombinant expression of PFK-M with three Cav-3 mutants [DeltaTFT (63 to 65), P104L, and R26Q], which harbor the same mutations as seen in the human patients with Cav-3-related muscle diseases, causes a substantial reduction in PFK-M expression levels, and impedes the membrane recruitment of PFK-M. Analysis of skeletal muscle tissue samples from Cav-3(-/-) mice directly demonstrates that Cav-3 expression regulates the phenotypic behavior of PFK-M. More specifically, in Cav-3-null mice, PFK-M is no longer targeted to the plasma membrane, and is excluded from caveolar membrane domains. As such, our current results may be important in understanding the pathogenesis of Cav-3-related muscle diseases, such as limb-girdle muscular dystrophy-1C, distal myopathy, and rippling muscle disease, that are caused by mutations within the human Cav-3 gene.

The biology of caveolae: lessons from caveolin knockout mice and implications for human disease.

Caveolae, plasma membrane invaginations that serve as membrane organizing centers, are found in most cell types, but are enriched in adipocytes, endothelial cells, and myocytes. Three members of the caveolin family (Cav-1, -2, and -3) are essential for the formation of caveolae. Specialized motifs in the caveolin proteins function to recruit lipids and proteins to caveolae for participation in intracellular trafficking of cellular components and operation in signal transduction. Mutations in the gene encoding CAV-1 are associated with the development and progression of breast cancers, whereas mutations in the CAV-3 gene result in Rippling Muscle Disease and a form of Limb-Girdle Muscular Dystrophy. The generation of caveolin-null mice has confirmed the essential role of these proteins in caveolae biogenesis and in the pathophysiology of diverse tissues. Caveolin-null mice provide new animal models for studying the pathogenesis of a number of human diseases, including cancer, diabetes, atherosclerosis, restrictive lung disease and pulmonary fibrosis, cardiomyopathy, muscular dystrophy, and bladder dysfunction.

Acquired rippling muscle disease with myasthenia gravis

Rippling muscle disease (RMD) is a rare disorder that occurs in both familial and sporadic forms. Seven patients have previously been reported with myasthenia gravis and sporadic RMD. There have been conflicting reports of the electrophysiological characteristics of rippling muscles in this acquired form. Another such patient is reported, and the clinical, electrophysiological, and laboratory features of this disorder are described. In addition, this patient had alopecia areata and recurrent metastatic thymoma, years after resection of a benign thymoma. This report emphasizes the clinical manifestations of RMD in association with myasthenia gravis (RMD-MG), and its distinctive features, in this and previously reported patients.

Caveolin-3 Mutations in Rippling Muscle Disease

Two unrelated patients with novel homozygous missense mutations (L86P and A92T) in caveolin-3 gene (CAV3), presenting with a severe form of rippling muscle disease (RMD), are reported from the University of Bonn, and other centers in Germany.

Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.

Heterozygous missense mutations in the caveolin-3 gene (CAV3) cause different muscle disorders. Most patients with CAV3 alterations present with rippling muscle disease (RMD) characterized by signs of increased muscle irritability without muscle weakness. In some patients, CAV3 mutations underlie the progressive limb-girdle muscular dystrophy type 1C (LGMD1C). Here, we report two unrelated patients with novel homozygous mutations (L86P and A92T) in CAV3. Both presented with a more severe clinical phenotype than usually seen in RMD. Immunohistochemical and immunoblot analyses of muscle biopsies showed a strong reduction of caveolin-3 in both homozygous RMD patients similar to the findings in heterozygous RMD. Electron microscopy studies showed a nearly complete absence of caveolae in the sarcolemma in all RMD patients analyzed. Additional plasma membrane irregularities (small plasmalemmal discontinuities, subsarcolemmal vacuoles, abnormal papillary projections) were more pronounced in homozygous than in heterozygous RMD patients. A stronger activation of nitric oxide synthase was observed in both homozygous patients compared with heterozygous RMD. Like in LGMD1C, dysferlin immunoreactivity is reduced in RMD but more pronounced in homozygous as compared with heterozygous RMD. Thus, we further extend the phenotypic variability of muscle caveolinopathies by identification of a severe form of RMD associated with homozygous CAV3 mutations.

Consequences of a novel caveolin-3 mutation in a large German family.

Mutations in the human caveolin-3 gene (cav-3) on chromosome 3p25 have been described in limb girdle muscular dystrophy, rippling muscle disease, hyperCKemia, and distal myopathy. Here, we describe the genetic, myopathological, and clinical findings in a large German family harboring a novel heterozygous mutation (GAC-->GAA) in codon 27 of the cav-3 gene. This missense mutation causes an amino acid change from asparagine to glutamate (Asp27Glu) in the N-terminal region of the Cav-3 protein, which leads to a drastic decrease of Cav-3 protein expression in skeletal muscle tissue. In keeping with an autosomal dominant mode of inheritance, this novel cav-3 mutation was found to cosegregate with neuromuscular involvement in the reported family. Ultrastructural analysis of Cav-3-deficient muscle showed an abnormal folding of the plasma membrane as well as multiple vesicular structures in the subsarcolemmal region. Neurological examination of all nine subjects from three generations harboring the novel cav-3 mutation showed clear evidence of rippling muscle disease. However, only two of these nine patients showed isolated signs of rippling muscle disease without muscle weakness or atrophy, whereas five had additional signs of a distal myopathy and two fulfilled the diagnostic criteria of a coexisting limb girdle muscular dystrophy. These findings indicate that mutations in the human cav-3 gene can lead to different and overlapping clinical phenotypes even within the same family. Different clinical phenotypes in caveolinopathies may be attributed to so far unidentified modifying factors/genes in the individual genetic background of affected patients.

Inhibition of Lipid Raft-dependent Signaling by a Dystrophy-associated Mutant of Caveolin-3

Specific point mutations in caveolin-3, a predominantly muscle-specific member of the caveolin family, have been implicated in limb-girdle muscular dystrophy and in rippling muscle disease. We examined the effect of these mutations on caveolin-3 localization and function. Using two independent assay systems, Raf activation in fibroblasts and neurite extension in PC12 cells, we show that one of the caveolin-3 point mutants, caveolin-3-C71W, specifically inhibits signaling by activated H-Ras but not by K-Ras. To gain insights into the effect of the mutant protein on H-Ras signaling, we examined the localization of the mutant proteins in fibroblastic cells and in differentiating myotubes. Unlike the previously characterized caveolin-3-DGV mutant, the inhibitory caveolin-3-C71W mutant reached the plasma membrane and colocalized with wild type caveolins. In BHK cells, caveolin-3-C71W associated with caveolae and in differentiating muscle cells with the developing T-tubule system. In contrast, the caveolin-3-P104L mutant accumulated in the Golgi complex and had no effect on H-Ras-mediated Raf activation. Inhibition by caveolin-3-C71W was rescued by cholesterol addition, suggesting that the mutant protein perturbs cholesterol-rich raft domains. Thus, we have demonstrated that a naturally occurring caveolin-3 mutation can inhibit signaling involving cholesterol-sensitive raft domains.

Rippling muscle disease: a review.

Rippling muscle disease (RMD) is a benign myopathy with symptoms and signs of muscular hyperexcitability. The typical finding is electrically silent muscle contractions provoked by mechanical stimuli and stretch. After the first description in 1975, there have been several publications on this disorder. Although RMD most often is reported with autosomal dominant inheritance, some sporadic cases are found, and an association with other diseases such as myasthenia gravis has also been reported. The pathophysiological mechanism is still not clarified. Abnormalities in calcium homeostasis in the sarcoplasmic reticulum have been proposed as the most probable causes. However, recent genetic studies make a primary channelopathy unlikely. In this article, a review of this curious disease is presented.

A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation.

To determine the cause of sporadic rippling muscle disease (RMD) in a 24-year-old patient. RMD is a rare myopathy characterized by percussion-induced rapid muscle contractions (PIRC), muscle mounding, and rippling waves. We have recently found that autosomal dominant RMD is caused by mutations in the caveolin-3 gene (CAV3) on chromosome 3p25. Possibly, increased activity of neuronal nitric oxide synthase (nNOS) contributes to the clinical characteristics of increased mechanical muscle hyperexcitability. Clinical examination, mutational analysis, and immunohistochemistry of muscle tissue were performed in a patient with sporadic RMD. The authors observed a de novo CAV3 missense mutation Arg26Gln. Immunohistochemistry showed reduced caveolin-3 surface expression in a muscle biopsy. In addition, the authors found normal sarcolemmal nNOS expression and a reduced expression of alpha-dystroglycan in muscle fibers. These data confirm that RMD is caused by CAV3 mutations. Moreover, there is evidence that CAV3 mutations may also be found in patients without a positive family history of RMD.

Severe autosomal recessive rippling muscle disease

Rippling muscle disease (RMD) has previously been reported as a skeletal myopathy that was attributed to a defect in the sarcomere. Here we report a new form of RMD that is more severe, characterized by fatal arrhythmic cardiomyopathy and delayed bone age. Mortality has previously not been associated with RMD. With this report we hope to raise awareness that a subset of patients with this clinical entity are predisposed to severe cardiac disease.

Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.

Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.

Rippling muscle disease: Evidence for phenotypic and genetic heterogeneity

We describe the clinical features of a family with rippling muscle disease. Muscle stiffness and myalgia were the most prominent symptoms. Muscle rippling, although distinctive, was present in only 6 of the 11 affected family members, whereas persistent muscle contraction to muscle percussion was present in all affected adults. Although this persistent contraction resembled percussion myotonia, it was electrically silent and is therefore more aptly called “percussion contracture.” We also observed two clinical features not emphasized in previously reported kindreds: mild but asymptomatic weakness of face or proximal muscles was present in 5 of 11 affected members, and 5 individuals also complained of toe walking after a prolonged period of inactivity, reflecting the disproportionate involvement of the calf muscles. The pedigree suggested autosomal dominant inheritance. Our linkage analysis excluded the region on chromosome 1q identified in a previous linkage study. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 340–344, 2001

Phenotypic variability in rippling muscle disease

To the Editor: Vorgerd et al. are to be commended for their description of phenotypic variability in two previously unreported kindreds with autosomal dominant rippling muscle disease (RMD).1 Accurate description of the clinical manifestations of rippling muscle disorders is important because of the potential basic science ramifications. Because these disorders are typified by stretch or percussion-induced contractions that are “electrically silent” (i.e., without myotonia), we have suggested that these disorders represent the first clinical evidence for the existence of stretch-activated or mechanosensitive channels in humans. …