The spectrum of rippling muscle disease

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.

Keywords: CAV3; CAVIN1/PTRF; Caveolin‐3; cavin‐4; rippling muscle disease.