such symptoms occur in only half of all cases. The most common type of hyperthyroidism, Graves' disease, may additionally cause eye problems (Graves' ophthalmopathy) and skin changes of the legs (pretibial myxedema). Thyroid disease may also cause muscle weakness in the form of thyrotoxic myopathy, but this is constant rather than episodic. Causes Genetics Genetic mutations in the L-type calcium channel α1-subunit (Cav1.1) have been described in Southern Chinese with TPP. The mutations are located in a different part of the gene from those described in the related condition familial periodic paralysis. In TPP, the mutations described are single-nucleotide polymorphisms located in the hormone response element responsive to thyroid hormone, implying that transcription of the gene and production of ion channels may be altered by increased thyroid hormone levels. Furthermore, mutations have been reported in the genes coding for potassium voltage-gated channel, Shaw-related subfamily, member 4 (Kv3.4) and sodium channel protein type 4 subunit alpha (Na41.4). Of people with TPP, 33% from various populations were demonstrated to have mutations in KCNJ18, the gene coding for Kir2.6, an inward-rectifier potassium ion channel. This gene, too, harbors a thyroid response element. Certain forms of human leukocyte antigen (HLA)—especially B46, DR9, DQB1*0303, A2, Bw22, AW19, B17, and DRW8—are more common in TPP. Linkage to particular forms of HLA, which plays a central role in the immune response, might imply an immune system cause, but it is uncertain whether this directly causes TPP or whether it increases the susceptibility to Graves' disease, a known autoimmune disease. Thyroid disease The most common underlying form of thyroid disease associated with TPP is Graves' disease, a syndrome due to an autoimmune reaction that leads to overproduction of thyroid hormone. TPP has also been described in people with other thyroid problems such as thyroiditis, toxic nodular goiter, toxic adenoma, TSH-producing pituitary adenoma, excessive ingestion of thyroxine or iodine, and amiodarone-induced hyperthyroidism. Mechanism The muscle weakness and increased risk of irregular heart beat in TPP result from markedly reduced levels of potassium in the bloodstream. Potassium is not in fact lost from the body, but increased Na+/K+-ATPase activity (the enzyme that moves potassium into cells and keeps sodium in the blood) leads to shift of potassium into tissues, and depletes the circulation. In other types of potassium derangement, the acid-base balance is usually disturbed, with metabolic alkalosis and metabolic acidosis often being present. In TPP, these disturbances are generally