A 20-year-old male visited our clinic complaining of myalgia, exercise-induced muscle stiffness, and fatigability with a 10-year history. He had been healthy until the age of 10 years, when he first experienced myalgia and stiffness in his proximal leg upon running, which made it difficult for him to exercise. Although the stiffness resolved rapidly within 10 seconds, he subsequently was unable to perform any intense exercise. He also complained of stiffness and myalgia when waking up, which meant that he could only walk on tiptoes for the first few minutes after getting out of bed. Light repetitive exercise such as walking and grasping alleviated the symptoms. He also noticed that briskly hitting a resting limb muscle produced a transient muscle contraction and focal swelling. He also complained of daytime fatigability that was worsen by continuous exercise. He reported no other problems, including fixed or transient muscle weakness.

A physical examination revealed bilateral calf hypertrophy and that tapping limb muscle using a reflex hammer provoked a transient rapid contraction (PIRC) and focal mounding of the muscle (PIMM) (Fig. 1), but myotonia and muscle rippling were not provoked. However, a neurological examination was unremarkable, including for the individual muscle powers, deep tendon reflexes, and sensory functions.

Laboratory tests revealed a high creatinine kinase level (1,543 U/L). The findings of a nerve conduction study was normal, and needle electromyography showed some small and short motor unit potentials without abnormal spontaneous activities in all tested muscles, suggesting the presence of inactive myopathy. It was particularly interesting that when we hit the surface of a needle-inserted muscle with a reflex hammer, transient positive sharp waves and fibrillation potentials were recorded. However, no myotonic or neuromyotonic discharges were observed, and a short exercise test did not reveal any abnormality. Biopsy of the biceps muscle revealed slight variations in fiber size, a few regenerating fibers, and a slight increase in the number of internalized myonuclei (Fig. 2). Dystrophin and dysferlin immunohistochemical staining was normal.

Focused exome sequencing identified a known pathogenic variant in CAV3 (c.80G>A [p.R27C, rs116840778]), which was confirmed by subsequent Sanger sequencing. Because the patient recalled that his older brother had enlarged calves, we performed a genetic study of his family members (father, mother, older brother, and younger sister) and identified the same mutation in his mother and elder brother. Physical examinations of his mother and older brother revealed muscle rippling, PIRC, and PIMM in both of them. Their clinical features are summarized in Table 1.

In 1994, Burns et al.² reported a family exhibiting muscle mounding and rippling in an autosomal dominant manner and noted its benign clinical course. They also performed an electrophysiological study in vivo and observed an abnormal after-contraction and sarcolemmal hyperexcitability, which they suggested was responsible for the rippling muscles. In 1998, mutations in CAV3 were first identified as a cause of limb-girdle muscular dystrophy type 1C (LGMD 1C).³ More than 64 different mutations have been identified, and they are associated mainly with skeletal muscle disorders.⁴ It is now generally accepted that there are four main distinctive phenotypes of skeletal muscle disease: limb-girdle muscle weakness, RMD, hyperCKemia, and distal myopathy.¹ It was recently proposed that LGMD 1C be excluded from the LGMD classification because its main clinical features are muscle rippling and myalgia, with RMD being proposed as a new nomenclature.⁵

Caveolin 3 is expressed in all cell types of muscle and its monomers oligomerize to form a high-molecular-mass scaffolding network that transforms sarcolemmal membranes into an invaginated structure called caveolae, which play an important role in membrane stabilization as a part of the dystrophin-glycoprotein complex, modulation of signaling pathways, and calcium and/or chloride transportation related to muscle contractions.⁶ Studies of a transgenic animal model have shown that CAV3 mutations produce pathological changes in muscles due to increased vulnerability to oxidative stress,⁷ hypersensitivity to stretch forces,⁶ and myofibril disorganization.⁸

The mutation identified in the present family (p.R27Q) is one of the common CAV3 mutations. Although p.R27Q is generally associated with a milder phenotype, some patients develop fixed muscle weakness, and families with significant phenotypic variability between members have also been reported.¹ The examinations of the present family members revealed a mild phenotype with all showing features of RMD with hyperCKemia, but it is noticeable that some features such as the presence of rippling, daytime fatigability, and myalgia were not shared by all of them. In a recent large cohort of patients with caveolinopathy, myalgia was the main symptom and rippling was present in only 60% of the patients regardless of the genotype. Moreover, 40% of those patients showed muscle weakness during a 3-decade follow-up, and none of them had any respiratory or cardiac problems, suggesting that it is a very mild muscle disease.⁹

Another interesting aspect of the present patient was a needle electromyographic findings. Although it is generally believed that electrical silence is observed in rippling muscle, there are a few reports of transient spontaneous activities being present during PIRC. Maki et al.¹⁰ observed transient bursts of asynchronous activity during PIRC, with individual potentials being very short (less than 2 milliseconds) and resembling fibrillation potentials. Those authors considered their finding suggestive of transient hyperexcitability of individual muscle fibers during PIRC. Our findings strongly support their ideas, and so further studies are warranted to elucidate this issue.

In summary, the present case shows that the clinical presentation of caveolinopathy can be highly variable with different overlapping conditions. This should be considered in the differential diagnosis of patients with mild muscle symptoms such as myalgia and idiopathic hyperCKemia.