ORPHA: 79102;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q32.1 | {Thyrotoxic periodic paralysis, susceptibility to, 1} | 188580 | Autosomal dominant | 3 | CACNA1S | 114208 |
A number sign (#) is used with this entry because of evidence that susceptibility to thyrotoxic periodic paralysis-1 (TTPP1) is conferred by variation in the CACNA1S gene on chromosome 1q32.
Thyrotoxic periodic paralysis is a sporadic muscle disorder characterized by episodic attacks of weakness associated with hypokalemia in individuals with hyperthyroidism. The paralysis resolves upon treatment of hyperthyroidism. The disorder is most common among males of Asian descent, including Chinese, Japanese, Vietnamese, Filipino, and Koreans, although it occurs less commonly in individuals of Caucasian background. Thyrotoxic periodic paralysis is clinically similar to hereditary hypokalemic periodic paralysis (HOKPP; 170400), but the paralysis in TTPP occurs only in the presence of hyperthyroidism. TTPP can also be precipitated by factors that result in hypokalemia, such as carbohydrate ingestion and rest after exercise (review by Kung, 2006).
Genetic Heterogeneity of Thyrotoxic Periodic Paralysis
See also TTPP2 (613239), conferred by variation in the KCNJ18 gene (613236) on chromosome 17p11, and TTPP3 (614834), mapped to chromosome 17q24.
Among 1,366 consecutive Southern Chinese patients with thyrotoxicosis, McFadzean and Yeung (1967) found that 25 had a history of 1 or more attacks of periodic paralysis, and that 23 of the 25 were male.
Bernard et al. (1972) reported thyrotoxic periodic paralysis in 5 unrelated Californian males of Japanese, Mexican, and Filipino descent. The patients ranged in age from 18 to 36 years. All presented with a chief complaint of periodic muscle weakness and paralysis in the lower limbs, often occurring at night or in the morning or after a large meal. All were subsequently found to have variable clinical features of hyperthyroidism, including palpitations, hypertension, increased heart rate, nervousness, sweating, and weight loss. However, some of the patients had very mild features of hyperthyroidism. When measured, serum potassium was very low during the episodes. All patients had complete recovery after proper treatment for hyperthyroidism, and most had no significant family history. Bernard et al. (1972) noted that some patients may have subtle or even absent clinical signs of hyperthyroidism, which should be evaluated by laboratory studies.
Layzer and Goldfield (1974) observed periodic paralysis in a Japanese-American male who 'abused' thyroid hormone.
Ali (1975) reported a 30-year-old man of Scottish descent who presented with weight loss, palpitations, sweating, and heat intolerance over 18 months. He also reported episodic attacks of weakness in the legs that usually occurred after awakening, but could come at any time. He had no weakness between attacks. There was no relevant family history. Physical examination showed thyrotoxicosis, with exophthalmos, an enlarged thyroid gland, and hyperreflexia. During an attack, serum potassium was severely depleted and he had complete flaccid paralysis from the waist down associated with absent reflexes. Proper treatment of the hyperthyroidism resulted in complete clinical recovery with no further episodes of paralysis.
Leung (1985) observed thyrotoxicosis and periodic paralysis in 4 adult members of a Chinese family: a mother and 3 children, including 2 males and 1 female. Two had Graves disease (275000) and Hashimoto thyroiditis (140300) as evidenced by the presence of thyroid antibodies and elevated thyroxine levels. The other 2 were not available for study.
Kilpatrick et al. (1994) found 6 reports of thyrotoxic hypokalemic periodic paralysis in African Americans and described 4 additional cases, all in males. They concluded that the disorder may be more frequent in blacks than previously suspected and should be considered when patients present with unexplained hypokalemia, muscular weakness, and rhabdomyolysis.
A specific genetic basis for TTPP is suggested by the fact that although occasional cases occur in Caucasians (e.g., Ali, 1975; Shah et al., 1979), the disorder is seen predominantly in Asians.
Hsu (1978) stated that Chinese males with thyrotoxicosis who have HLA types BW22 and BW17 and do not have BW46 are most susceptible to periodic paralysis. Thus, thyrotoxic periodic paralysis may be due to a genetic peculiarity of muscle membranes.
Yeung (1981) stated that multiple cases in families had been observed.
Kung et al. (2004) studied 97 male patients with thyrotoxic periodic paralysis, 77 male patients with Graves disease without thyrotoxic periodic paralysis, and 100 normal male subjects, all Chinese. They detected 12 single-nucleotide polymorphisms (SNPs) in the CACNA1S gene, 3 of which were novel. Significant differences in the SNP genotype distribution between subjects with thyrotoxic periodic paralysis compared with Graves disease controls and normal controls were seen at a 5-prime flanking region SNP (114208.0005) and 2 intronic SNPs (114208.0006, 114208.0007). The authors concluded that because these SNPs lie at or near a thyroid hormone-responsive element (TRE), it is possible that they may affect the binding affinity of the TRE and modulate the stimulation of thyroid hormone on the Cav1.1 gene.
Associations Pending Confirmation
Dias Da Silva et al. (2002) identified an arg83-to-his (R83H; 604433.0001) substitution in the KCNE3 gene in 1 of 15 patients with thyrotoxic hypokalemic periodic paralysis. The patient was a 44-year-old Caucasian man of Portuguese descent who experienced episodic paralysis for 2 years before developing thyrotoxicosis caused by Graves disease (275000). Two of his 3 offspring, all asymptomatic, were found to have the same mutation. However, Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004) concluded that the R83H variant does not play a causative role in periodic paralysis and that it is a polymorphism. See 604433.0001 for further discussion. Tang et al. (2004) did not identify the R83H substitution, or any mutations in the KCNE3 gene, among 79 Chinese patients with thyrotoxic hypokalemic periodic paralysis.
The overall incidence of TTPP in Chinese and Japanese thyrotoxic patients had been estimated at 1.8 and 1.9%, respectively. In North America, the incidence is much lower, at about 0.1 to 0.2% in thyrotoxic patients. The male to female ratio ranges from 17:1 to 70:1 (review by Kung, 2006).
Ali, K. Hypokalaemic periodic paralysis complicating thyrotoxicosis. Brit. Med. J. 4: 503-504, 1975. [PubMed: 1192145] [Full Text: https://doi.org/10.1136/bmj.4.5995.503-a]
Au, K.-S., Yeung, R. T. T. Thyrotoxic periodic paralysis: periodic variation in the muscle calcium pump activity. Arch. Neurol. 26: 543-546, 1972. [PubMed: 4260573] [Full Text: https://doi.org/10.1001/archneur.1972.00490120083009]
Bernard, J. D., Larson, M. A., Norris, F. H., Jr. Thyrotoxic periodic paralysis in Californians of Mexican and Filipino ancestry. Calif. Med. 116: 70-74, 1972. [PubMed: 5059669]
Dias Da Silva, M. R., Cerutti, J. M., Arnaldi, L. A. T., Maciel, R. M. B. A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. J. Clin. Endocr. Metab. 87: 4881-4884, 2002. [PubMed: 12414843] [Full Text: https://doi.org/10.1210/jc.2002-020698]
Hsu, T. H. Personal Communication. Baltimore, Md. 2/27/1978.
Jurkat-Rott, K., Lehmann-Horn, F. Periodic paralysis mutation MiRP2-R83H in controls: interpretations and general recommendation. Neurology 62: 1012-1015, 2004. [PubMed: 15037716] [Full Text: https://doi.org/10.1212/01.wnl.0000119392.29624.88]
Kilpatrick, R. E., Seiler-Smith, S., Levine, S. N. Thyrotoxic hypokalemic periodic paralysis: report of four cases in black American males. Thyroid 4: 441-445, 1994. [PubMed: 7711509] [Full Text: https://doi.org/10.1089/thy.1994.4.441]
Kung, A. W. C., Lau, K. S., Fong, G. C. Y., Chan, V. Association of novel single nucleotide polymorphisms in the calcium channel alpha-1 subunit gene (Cav1.1) and thyrotoxic periodic paralysis. J. Clin. Endocr. Metab. 89: 1340-1345, 2004. [PubMed: 15001631] [Full Text: https://doi.org/10.1210/jc.2003-030924]
Kung, A. W. C. Clinical review: thyrotoxic periodic paralysis: a diagnostic challenge. J. Clin. Endocr. Metab. 91: 2490-2495, 2006. [PubMed: 16608889] [Full Text: https://doi.org/10.1210/jc.2006-0356]
Kusakabe, T., Yoshida, M., Nishikawa, M. Thyrotoxic periodic paralysis: a peculiar case with unusual dystonic behavior and variable relations of paralysis to serum potassium levels. J. Clin. Endocr. Metab. 43: 730-740, 1976. [PubMed: 977720] [Full Text: https://doi.org/10.1210/jcem-43-4-730]
Layzer, R. B., Goldfield, E. Periodic paralysis caused by abuse of thyroid hormone. Neurology 24: 949-952, 1974. [PubMed: 4472229] [Full Text: https://doi.org/10.1212/wnl.24.10.949]
Leung, A. K. C. Familial 'hashitoxic' periodic paralysis. J. Roy. Soc. Med. 78: 638-640, 1985. [PubMed: 3839536] [Full Text: https://doi.org/10.1177/014107688507800808]
McFadzean, A. J. S., Yeung, R. Periodic paralysis complicating thyrotoxicosis in Chinese. Brit. Med. J. 1: 451-455, 1967. [PubMed: 6017520] [Full Text: https://doi.org/10.1136/bmj.1.5538.451]
Ramsay, I. D. Thyrotoxic periodic paralysis. In: Thyroid Disease and Muscle Dysfunction. Chicago: Year Book Med. Publ. (pub.) 1974. Pp. 96-125.
Shah, N., Kussman, M. J., Tulgan, H. Familial periodic paralysis and hyperthyroidism. New York J. Med. 79: 1770-1771, 1979. [PubMed: 290877]
Sternberg, D., Tabti, N., Fournier, E., Hainque, B., Fontaine, B. Lack of association of the potassium channel-associated peptide MiRP2-R83H variant with periodic paralysis. Neurology 61: 857-859, 2003. [PubMed: 14504341] [Full Text: https://doi.org/10.1212/01.wnl.0000082392.66713.e3]
Tang, N. L. S., Chow, C. C., Ko, G. T. C., Tai, M. H. L., Kwok, R., Yao, X. Q., Cockram, C. S. No mutation in the KCNE3 potassium channel gene in Chinese thyrotoxic hypokalaemic periodic paralysis patients. Clin. Endocr. 61: 109-112, 2004. [PubMed: 15212652] [Full Text: https://doi.org/10.1111/j.1365-2265.2004.02079.x]
Yeung, R. T. T., Tse, T. F. Thyrotoxic periodic paralysis: effect of propranolol. Am. J. Med. 57: 584-590, 1974. [PubMed: 4432863] [Full Text: https://doi.org/10.1016/0002-9343(74)90010-2]
Yeung, R. T. T. Personal Communication. Hong Kong 10/9/1981.