Transient thyrotoxicosis‐aggravated attacks of paralysis in a patient with hereditary hypokalemic periodic paralysis type 2

We report a case with hereditary hypokalemic paralysis type 2 in whom thyrotoxicosis aggravated his attacks of paralysis. He experienced paralytic attacks several times a year from 24 years of age and was clinically diagnosed with hypokalemic periodic paralysis. At 49 years of age, a laboratory examination showed normal thyroid function. At 57 years of age, transient thyrotoxicosis was accompanied with an increase of the frequency and severity of attacks. Gene analysis revealed a missense mutation (c.2015G>A, p.R672H) in SCN4A, a known pathogenic mutation for hypokalemic paralysis type 2. This case highlights the importance of checking thyroid function when the frequency and severity of attacks are increased in patients with periodic paralysis.


| INTRODUC TI ON
The majority of patients with periodic paralysis can be classified into hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP) according to serum potassium levels during paralytic attacks. Glucose and potassium have opposite effects in HyperPP and HypoPP. Patients with HypoPP tend to have more prolonged and severe attacks of weakness (several hours to days) while patients with HyperPP typically have attacks with a shorter duration, which may be less severe. Symptom onset is typically in the second decades for HypoPP while HyperPP tends to present earlier in childhood. Myotonia is often associated with HyperPP, but is not found in HypoPP. 1 Most hereditary HypoPP cases are caused by a mutation in either CACNA1S, encoding the pore-forming α1-subunit of the dihydropyridine receptor Cav1.1 (HypoPP type 1), 2,3 or SCN4A, encoding the pore-forming α-subunit of the skeletal muscle voltage-gated sodium channel Nav1.4 (HypoPP type 2). 4 The clinical features of type 1 and 2 HypoPP are indistinguishable. 5 In Europe, the former is found in 70%-80% of patients, while the latter is observed in 10%. Conversely, up to 10% of men of Southeast Asian background with thyrotoxicosis may have thyrotoxic periodic paralysis (TPP). 6 The clinical features of HypoPP and TPP are similar.
Carbohydrate-rich meals and rest after exercise can trigger both conditions. Patients with TPP develop attacks only under thyrotoxicosis, regardless of etiology. Nearly all cases of TPP are sporadic, 6 although mutations in KCNJ18 are reportedly associated with TPP. 7 Here, we report a case with hereditary HypoPP type 2 harboring a c.2015G>A, p.R672H mutation in SCN4A in whom thyrotoxicosis  He had neither exophthalmos nor goiter. Anti-thyroid-stimulating hormone receptor and anti-thyroid-stimulating antibodies were negative. Technetium-99m pertechnetate thyroid scintigraphy and thyroid echography were normal. In the interictal phase, the electromyography study of the right rectus femoris muscle showed no myotonic discharge and demonstrated a reduced number of motor units. A long exercise test with the right ulnar nerve indicated that the baseline compound muscle action potentials before and after the test for 60 minutes were 6.8 mV and 5.0 mV, respectively, that is, a normal result. His hyperthyroidism changed to hypothyroidism after 9 weeks, and then to euthyroidism at 24 weeks after admission without treatment (Table 1)

| D ISCUSS I ON
Except for thyrotoxic symptoms, the clinical features of HypoPP and TPP are similar. 6 The mutation identified in this case (c.2015G>A, p.R672H) has been reported as a common pathogenic mutation for HypoPP type 2. 1,8 A patient with TPP associated with an SCN4A mutation, presenting with body weight loss prior to the recognition of hyperthyroidism, has been reported. 9 In our patient, disease history and thyroid function tests aided the recognition of transient thyrotoxicosis. No aggravated attacks have occurred since day 4 after admission.
Once a potential trigger effects, extracellular potassium levels are reduced in patients with HypoPP. In patients with SCN4A mutations, the two outmost arginine residues in domain II of Nav1.4 cause a leak current, which only manifests at hyperpolarized resting membrane potentials, is very small, and lead to a minor shift of resting muscle membrane potential. 1 In TPP patients, excess triiodothyronine, increased activity of 3Na + /2K + ATPase pumps, and/or insulin can exert additional alterations to sodium channel behavior during thyrotoxicosis. 6 In conclusion, we reported a patient with hereditary HypoPP type 2 in whom repeated thyroid function tests revealed that transient thyrotoxicosis aggravated his attacks.

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to report relevant to the paper.