CAV3 – Rippling Muscle Disease 2

Rippling Muscle Disease 2 (RMD2) is an autosomal recessive myopathy characterized by exercise‐induced muscle stiffness and visible rippling waves on muscle contraction. The muscle‐specific caveolin-3 protein, encoded by CAV3, is essential for caveolae formation in skeletal muscle. Mutations in CAV3 disrupt sarcolemmal caveolae integrity, leading to increased membrane excitability and myofiber hyperirritability. RMD2 is distinguished from dominant caveolinopathies by its recessive inheritance and more severe membrane pathology. Clinically, patients exhibit pronounced muscle rippling without early contractile weakness or elevated creatine kinase levels. Distinguishing RMD2 from other genetic or inflammatory myopathies requires integration of genetic and histopathological data.

Genetic evidence for CAV3 association with RMD2 is based on two unrelated patients harboring homozygous CAV3 variants. One patient carried c.277G>A (p.Ala93Thr) and the other a p.Leu86Pro change, each in the homozygous state, with no family history of muscle disease (PMID:12666119). These variants are absent from population databases and predicted to abrogate caveolin-3 function. No additional affected relatives were reported, consistent with an autosomal recessive pattern. The observation of identical histopathology in both individuals strengthens the genotype–phenotype link. Overall, the genetic data provide moderate evidence under ClinGen criteria.

Functional assays corroborate the pathogenicity of homozygous CAV3 mutations in RMD2. Immunohistochemical and immunoblot analyses of patient muscle biopsies demonstrated a marked reduction of caveolin-3 protein at the sarcolemma, more profound than in heterozygous cases (PMID:12666119). Electron microscopy revealed a near‐complete absence of caveolae and additional plasma membrane irregularities, including subsarcolemmal vacuoles and papillary projections. Both homozygous patients showed elevated neuronal nitric oxide synthase activation in muscle fibers, suggesting secondary dysregulation of signaling pathways. These findings confirm a loss‐of‐function mechanism leading to membrane instability and hyperexcitability. Concordance across molecular, biochemical, and ultrastructural studies provides moderate functional support.

No conflicting reports challenge the association between CAV3 and RMD2. The phenotype is consistent across independent cases, and no alternative genetic etiologies have been proposed for these patients. Functional data have not identified dominant-negative effects in RMD2, distinguishing it from autosomal dominant caveolinopathies. Thus, the evidence remains internally consistent and supportive of a recessive disease model.

Integration of genetic and experimental findings supports a ClinGen Moderate clinical validity classification for CAV3-associated RMD2. Two unrelated homozygous probands with concordant functional studies fulfill genetic and functional scoring thresholds short of full replication over time. Additional segregation or larger cohorts could elevate the classification to Strong. Nevertheless, current data justify molecular testing of CAV3 in patients with unexplained rippling muscle phenomena and guide interpretation of novel missense variants.

Key Take‐Home: Homozygous loss-of-function mutations in CAV3 cause RMD2 via an autosomal recessive mechanism, and combined genetic and histopathological evidence supports moderate clinical validity for diagnostic testing.

References

• Annals of neurology • 2003 • Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease PMID:12666119

Evidence Based Scoring (AI generated)