Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic
predisposition; however, the underlying genetic cause remains elusive in many cases.
Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including
limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy
and isolated hyperCKemia. Here we present a series of eight patients from seven families
presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3
diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7),
exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced
rapid muscle contractions (PIRCs) were seen in five out of six patients examined.
A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants
(p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was
normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of
caveolin-3 in five patients compared with controls. This case series demonstrates
that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations
and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting
was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry
in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and
rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical
clue for caveolinopathies, even in the absence of other "typical" features. The use
of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical
phenotypes may be attributed to well-known human disease genes.