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With the increasing concern about malignant hyperthermia and with the inclusion of creatine kinase determination in the automated blood chemistry profile, performed as part of health screening, the number of subjects with raised serum creatine kinase (hyperCKaemia) without clinical signs of neuromuscular disease is continuously increasing. In 1980 Rowland et al coined the term “idiopathic hyperCKaemia” to describe patients with consistently increased serum creatine kinase who may complain of myalgia or tiredness but do not have weakness or other abnormalities on neurological examination, electromyography, and muscle biopsy.1 Extensive ancillary investigations may lead to the diagnosis of a subclinical neuromuscular disorder in a variable percentage of subjects but in others hyperCKaemia remains unexplained even after complete studies.
Merlini et al2 reported on an 18 year old man and his 49 year old mother with persistent hyperCKaemia, no muscle symptoms and signs, muscle caveolin-3 deficiency, and a novel mutation (P28L) in the caveolin-3 (CAV3) gene. Recently two unrelated asymptomatic children (4 and 6 years old) with hyperCKaemia, reduced expression of caveolin-3 in muscle fibres and the same de novo CAV3 mutation (R26Q) have been also described.3 Although the absolute number of reported subjects was small caveolin-3 deficiency has been indicated as a cause of sporadic and familial “isolated” hyperCKaemia without any signs or symptoms of myopathy.2,3
To investigate the relative frequency of caveolin-3 deficiency in hyperCKaemia we reviewed the clinical records and muscle biopsy specimens of 56 consecutive subjects with persistent hyperCKaemia (more than twice the normal value) and normal neurological examination referred to our centre for neuromuscular diseases. Extensive investigations showed that subclinical neuromuscular disorders (dystrophinopathy and carrier state of dystrophinopathy, adult maltase acid deficiency, inflammatory myopathy, mitochondrial myopathy, motor neurone disease, hypothyroidism, hypoparathyroidism) accounted for 20 cases, not included in the study. In the remainder 36 subjects (34 male), with CK increased from 2 to 18 times, muscle biopsy was completely normal (15 cases) or showed only minimal and non-specific alterations such as mild increase variability of fibre size or increased percentage of internal nuclei. Mean age was 27 years (range 2–62). Three patients were younger than 15 years. Nine subjects belonged to nine different families with autosomal dominant hyperCKaemia without clinical signs reported in at least two subjects of two generations. Ten subjects complained of mild myalgias or feeling fatigued. EMG was normal in 35 of 35 tested subjects. Histochemistry for myofosforilase and myoadenilate deaminase, immunohistochemistry for dystrophin, sarcoglycans, laminins, desmin, and biochemical investigations for glycogen and lipid metabolism enzymes were all normal. In these 36 subjects, we labelled as idiopathic hyperCKaemia, we also performed immunofluorescence on frozen muscle sections using monoclonal antibody against caveolin-3 (BD Transduction laboratories). Biopsy specimens from normal subjects and patients with known diseases were used as controls. All 36 subjects showed a uniform sarcolemmal staining for caveolin-3, not different from controls. No staining was found inside muscle fibres in both groups.
CAV3 gene mutations have been associated with an autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C),4 rippling muscle disease (RMD),5 distal myopathy,6 and isolated hyperCKaemia.2,3 Different phenotypes may share the same mutation. For example, the P104L mutation may lead to LGMD-1C or RMD phenotype and the R26Q mutation, found in the two children with isolated hyperCKaemia,3 also causes RMD.5 This implies that other genes or regulating factors may be involved in determining the clinical phenotype and that, especially in paediatric cases, isolated hyperCKaemia may be a presymptomatic stage of other caveolinopathies.
All the muscle caveolinopathies described up to now showed a reduced intensity of sarcolemmal staining, with sometimes abnormal punctuated cytosolic staining.2–6 Therefore immunohistochemistry, by itself, should be a reliable enough technique to exclude in our series caveolin-3 deficiency.
In conclusion, our study on a large consecutive series of patients with idiopathic hyperCKaemia suggests that caveolin-3 deficiency is not a common cause of sporadic and familial hyperCKaemia without muscular signs. The other possible causes of this intriguing phenomenon remain to be unveiled.