Alternative titles; symbols
ORPHA: 206599; DO: 0111338;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p25.3 | Creatine phosphokinase, elevated serum | 123320 | Autosomal dominant | 3 | CAV3 | 601253 |
A number sign (#) is used with this entry because of evidence that some cases of hyperCKemia are caused by heterozygous mutation in the CAV3 gene (601253) on chromosome 3p25.
The existence of a 'normal' high serum creatine phosphokinase (CPK) was discussed by Emery and Spikesman (1970) in the context of 'subclinical Duchenne muscular dystrophy.' Patients may describe muscle cramps with exertion, but there is no evidence of neuromuscular disease: muscle biopsy and exercise lactic acid production are normal. This familial trait can plague the physician and medical geneticist who are counseling a family with muscular dystrophy.
In the course of studying exercise physiology, Michael Brook of St. Louis (Drachman, 1980) found that he, as well as a number of other normal physicians, developed markedly elevated CPK levels after bicycle ergometer exercise.
Bertorini et al. (1980) described a man with carnitine palmitoyltransferase I deficiency (255120) who had no clinical difficulties until age 51 years. However, at age 46 he had been found to have elevated CPK for no apparent reason.
Sunohara et al. (1984) studied 3 unrelated Japanese adult men with what the authors termed 'idiopathic hyperCKemia.' One was the father of a girl who had survived malignant hyperthermia (145600); his parents were first cousins and his mother, a sister, and a daughter of the sister also had high serum CK activity. Sensitivity to caffeine of muscles in vitro, as in malignant hyperthermia, was seen in this man and in one other.
Frydman et al. (1995) described a 7-month-old boy with gross motor delay and failure to thrive who presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization, the ECG changed from normal sinus rhythm to a type I Wolff-Parkinson-White pattern. Duchenne muscular dystrophy (DMD; 310200) was suspected based on elevated creatine kinase serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analyses which documented a deletion in the dystrophin gene (300377) in the propositus, and in an affected male cousin of his mother. 'Idiopathic' hyperCKemia was found in the propositus, his father, and 5 of his relatives. Frydman et al. (1995) suggested that the unusually early and severe manifestations of DMD in this patient may be related to the coincidental inheritance of a maternal DMD gene and of a paternal gene causing hyperCKemia.
Differential Diagnosis
Afifi (1998) pointed out that reports of idiopathic hyperCKemia had dramatically diminished since the discovery of dystrophin and its gene and the subsequent development of knowledge regarding the variable presentations of dystrophinopathies. About 75% of reported cases have been male. Clinical and/or histopathologic evidence of a neuromuscular disorder developed between 1 and 7 years after detection of hyperCKemia in about one-third of the cases. Diagnoses included distal myopathy, myoadenylate deaminase deficiency, polymyositis, mitochondrial myopathy, sarcoid myopathy, McArdle disease, central core disease, multicore disease, inclusion body myopathy, and Duchenne muscular dystrophy carrier status.
Della Marca et al. (2009) reported 7 patients with severe myalgia in the lower limbs and hyperCKemia who were found to have severe restless legs syndrome with severe periodic limb movements in sleep (RLS; 102300). Treatment of RLS resulted in improved serum creatine kinase levels in 6 patient who underwent treatment. The authors concluded that some severe cases of RLS can result in increased serum CK, and discussed the possible overlap of the 2 disorders.
From study of 14 monozygotic twins and 14 dizygotic twins, Meltzer et al. (1978) found evidence of significant heritability of plasma CPK level.
Carbone et al. (2000) identified a de novo recurrent sporadic mutation in the CAV3 gene (601253.0007) in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia) without muscle weakness. They concluded that their data indicate that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia.
Afifi, A. K. Idiopathic hyperCKemia revisited. (Editorial) J. Child Neurol. 13: 251-252, 1998. [PubMed: 9660505] [Full Text: https://doi.org/10.1177/088307389801300601]
Bertorini, T., Yeh, Y.-Y., Trevisan, C., Stadlan, E., Sabesin, S., DiMauro, S. Carnitine palmityltransferase deficiency: myoglobinuria and respiratory failure. Neurology 30: 263-271, 1980. [PubMed: 7189025] [Full Text: https://doi.org/10.1212/wnl.30.3.263]
Carbone, I., Bruno, C., Sotgia, F., Bado, M., Broda, P., Masetti, E., Panella, A., Zara, F., Bricarelli, F. D., Cordone, G., Lisanti, M. P., Minetti, C. Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia. Neurology 54: 1373-1376, 2000. [PubMed: 10746614] [Full Text: https://doi.org/10.1212/wnl.54.6.1373]
Della Marca, G., Dittoni, S., Catteruccia, M., Frusciante, R., Madia, F., Losurdo, A., Testani, E., Vollono, C., Servidei, S. Restless legs syndrome with periodic limb movements: a possible cause of idiopathic hyperCKemia. Neurology 73: 643-645, 2009. [PubMed: 19704085] [Full Text: https://doi.org/10.1212/WNL.0b013e3181b38995]
Drachman, D. B. Personal Communication. Baltimore, Md. 1980.
Emery, A. E. H., Spikesman, A. Evidence against the existence of a subclinical form of X-linked Duchenne muscular dystrophy. J. Neurol. Sci. 10: 523-533, 1970. [PubMed: 5422556] [Full Text: https://doi.org/10.1016/0022-510x(70)90185-1]
Frydman, M., Straussberg, R., Shomrat, R., Goebel, H., Legum, C., Shiloh, Y. Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family. Am. J. Med. Genet. 58: 209-212, 1995. [PubMed: 8533818] [Full Text: https://doi.org/10.1002/ajmg.1320580302]
Meltzer, H. Y., Dorus, E., Grunhaus, L., Davis, J. M., Belmaker, R. Genetic control of human plasma creatine phosphokinase activity. Clin. Genet. 13: 321-326, 1978. [PubMed: 566176] [Full Text: https://doi.org/10.1111/j.1399-0004.1978.tb01187.x]
Sunohara, N., Takagi, A., Nonaka, I., Sugita, H., Satoyoshi, E. Idiopathic hyperCKemia. Neurology 34: 544-547, 1984. [PubMed: 6538316] [Full Text: https://doi.org/10.1212/wnl.34.4.544]