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Published on: July 18, 2019
The spectrum of rippling muscle disease
Hebatallah R Rashed1, Margherita Milone1
1Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
Abstract:
Rippling muscle disease (RMD) is a rare disorder of muscle hyperexcitability. It is characterized by rippling wave-like muscle contractions induced by mechanical stretch or voluntary contraction followed by sudden stretch, painful muscle stiffness, percussion-induced rapid muscle contraction (PIRC), and percussion-induced muscle mounding (PIMM). RMD can be hereditary (hRMD) or immune-mediated (iRMD). hRMD is caused by pathogenic variants in caveolin-3 (CAV3) or caveolae-associated protein 1/ polymerase I and transcript release factor (CAVIN1/PTRF). CAV3 pathogenic variants are autosomal dominant or less frequently recessive while CAVIN1/PTRF pathogenic variants are autosomal recessive. CAV3-RMD manifests with a wide spectrum of clinical phenotypes, ranging from asymptomatic creatine kinase elevation to severe muscle weakness. Overlapping phenotypes are common. Muscle caveolin-3 immunoreactivity is often absent or diffusely reduced in CAV3-RMD. CAVIN1/PTRF-RMD is characterized by congenital generalized lipodystrophy (CGL, type 4) and often accompanied by several extra-skeletal muscle manifestations. Muscle cavin-1/PTRF immunoreactivity is absent or reduced while caveolin-3 immunoreactivity is reduced, often in a patchy way, in CAVIN1/PTRF-RMD. iRMD is often accompanied by other autoimmune disorders, including myasthenia gravis. Anti-cavin-4 antibodies are the serological marker while the mosaic expression of caveolin-3 and cavin-4 is the pathological feature of iRMD. Most patients with iRMD respond to immunotherapy. Rippling, PIRC, and PIMM are usually electrically silent. Different pathogenic mechanisms have been postulated to explain the disease mechanisms. In this article, we review the spectrum of hRMD and iRMD, including clinical phenotypes, electrophysiological characteristics, myopathological findings, and pathogenesis.
Insights
Rippling muscle disease (RMD) is a rare muscle hyperexcitability disorder with hereditary and immune-mediated forms. This review covers RMD
Area of Science:
- Neurology
- Muscle Disorders
- Genetics
Background:
- Rippling muscle disease (RMD) is a rare neuromuscular disorder characterized by muscle hyperexcitability, presenting with rippling contractions, stiffness, and percussion-induced phenomena.
- RMD encompasses hereditary (hRMD) and immune-mediated (iRMD) subtypes, each with distinct genetic or immunological underpinnings.
- hRMD results from mutations in CAV3 or CAVIN1/PTRF, while iRMD is associated with autoimmune conditions and anti-cavin-4 antibodies.
Purpose of the Study:
- To comprehensively review the clinical phenotypes, electrophysiological characteristics, myopathological findings, and pathogenesis of both hereditary and immune-mediated Rippling Muscle Disease.
- To elucidate the genetic basis of hRMD, including CAV3 and CAVIN1/PTRF variants and their associated phenotypes.
- To describe the immunological features of iRMD, its serological markers, and response to immunotherapy.
Main Methods:
- Review of existing literature on Rippling Muscle Disease, focusing on clinical case studies and research articles.
- Analysis of genetic data for hereditary RMD, including CAV3 and CAVIN1/PTRF mutations.
- Examination of immunological findings in iRMD, including antibody detection and muscle biopsy results.
Main Results:
- hRMD presents a spectrum of phenotypes, from asymptomatic hyperCKemia to severe weakness, linked to CAV3 or CAVIN1/PTRF gene variants.
- CAV3-RMD shows variable caveolin-3 expression, while CAVIN1/PTRF-RMD is associated with congenital generalized lipodystrophy and altered caveolin-3/cavin-1 expression.
- iRMD is linked to autoimmune disorders, characterized by anti-cavin-4 antibodies and mosaic caveolin-3/cavin-4 expression, often responding to immunotherapy.
Conclusions:
- Rippling muscle disease comprises distinct hereditary and immune-mediated forms with specific genetic and immunological profiles.
- Understanding the underlying pathogenesis, including genetic mutations and autoimmune responses, is crucial for accurate diagnosis and management of RMD.
- Further research into RMD pathogenesis may reveal novel therapeutic targets for this rare muscle disorder.
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