Contribution of Asian Haplotype of KCNJ18 to Susceptibility to and Ethnic Differences in Thyrotoxic Periodic Paralysis.

CONTEXT AND OBJECTIVES: Thyrotoxic periodic paralysis (TPP) is an acute complication of thyrotoxicosis that can be lethal. TPP is rare in Caucasians but often affects young men in East Asian populations. This study aimed to clarify the contribution of KCNJ18 to susceptibility to TPP in East Asian populations. PARTICIPANTS AND METHODS: The study comprised 635 participants including 13 Japanese patients with TPP, 208 Japanese patients with Graves disease without TPP, and 414 healthy control subjects from the Japanese (n = 208), Korean (n = 111), and Caucasian populations (n = 95). DNA samples from 29 participants (13 with TPP, 8 with Graves disease, and 8 controls) were sequenced for KCNJ18, and all participants (n = 635) were genotyped for six variants of KCNJ18 and a polymorphism of KCNJ2 (rs312691). RESULTS: Six single-nucleotide variants (SNVs) with amino acid substitutions were identified by direct sequencing of KCNJ18. Among these, four SNVs comprised three haplotypes under strong linkage disequilibrium. Haplotype 1 (AAAG) of KCNJ18 was significantly associated with susceptibility to TPP in the Japanese population (OR = 19.6; 95% CI, 1.5 to 256.9; P = 0.013). Haplotype frequencies in the general East Asian (Japanese and Korean) and Caucasian populations differed significantly (haplotype 1: 80.8% vs 48.4%, P = 1.1×10-27). CONCLUSION: A major haplotype of KCNJ18 in East Asian populations is significantly associated with susceptibility to TPP. The haplotype is much more common in East Asian than Caucasian populations, suggesting its contribution to the high prevalence of TPP in East Asian populations.

Periodic paralysis with normokalemia in a patient with hyperthyroidism: A case report.

RATIONALE: Thyrotoxic periodic paralysis is characterized by a sudden onset of hypokalemia and paralysis. This condition mainly affects the lower extremities and is secondary to thyrotoxicosis. The underlying hyperthyroidism is often subtle without typical symptoms such as palpitations, tremors, anxiety, and weight loss; this causes a difficulty in early diagnosis. Here, we reported a case of periodic paralysis in a patient with hyperthyroidism whose potassium level was within the normal range. PATIENT CONCERNS: A 33-year-old Taiwanese man presented to the emergency department with bilateral limb weakness (more severe in the lower limbs than in the upper limbs). On arrival, the patient's vital status was stable with clear consciousness. He denied experiencing recent trauma, back pain, chest pain, abdominal pain, headache or dizziness, or a fever episode. Physical examination showed no specific findings. Neurological examination showed weakness in the muscles of the bilateral upper and lower limbs. Muscle weakness was more severe in the proximal site than in the distal site. DIAGNOSIS: Blood examination showed normal complete blood count, normal renal and liver function, and normal potassium (3.5 mmol/L, normal range 3.5-5.1 mmol/L), sodium, and calcium levels; however, the examination showed impaired thyroid function (thyroid stimulating hormone: 0.04 uIU/mL, normal range 0.34-5.60 uIU/mL; free T4: 1.96 ng/dL, normal range 0.61-1.12 ng/dL). Brain computed tomography without contrast showed no obvious intra-cranial lesion. INTERVENTIONS: Intravenous potassium infusion (20 mEq/L) with normal saline was prescribed for the patient. OUTCOMES: After treatment, the patient felt a decrease in limb weakness. He was discharged from our emergency department with a scheduled follow-up in the endocrine outpatient department. LESSONS: TPP should be considered as a differential diagnosis in young Asian men presenting with limb paralysis that is more severe in the proximal site and in the lower limbs than in the distal site and in the upper limbs, respectively. It is important for emergency department physicians to consider TPP as a differential diagnosis as it can occur even if the patient's potassium level is within the normal range.

Is thyrotoxic periodic paralysis a disease caused by muscle membrane dysfunction?

INTRODUCTION: Thyrotoxic periodic paralysis (TPP) is characterized by recurrent episodes of reversible paralysis with hyperthyroidism. It is clinically similar to hypokalemic periodic paralysis (HOPP), which features significant ion-channel dysfunction and reduced muscle fiber conduction velocity (MFCV). However, the muscle membrane function in TPP is not known. METHODS: For 13 patients with TPP and 15 age-matched controls, clinical assessment and serial neurophysiological testing, including nerve conduction, prolonged exercise (PE) testing, and MFCV. were performed. RESULTS: MFCV values were elevated up to 1 year from the paralytic attack in TPP patients. In the group with a positive PE test, MFCV values were higher. There was no significant relationship between MFCV values and either hypokalemia or hyperthyroidism. CONCLUSIONS: Although clinical manifestations in TPP are similar to those observed in HOPP, TPP appears to feature an alternate pathogenic mechanism. Specifically, MFCV values increased rather than decreased. Further studies are needed to support these findings. Muscle Nerve, 2016 Muscle Nerve 56: 780-786, 2017.

Andersen-Tawil syndrome: report of 3 novel mutations and high risk of symptomatic cardiac involvement.

INTRODUCTION: Andersen-Tawil syndrome (ATS) is a potassium channelopathy affecting cardiac and skeletal muscle. Periodic paralysis is a presenting symptom in some patients, whereas, in others, symptomatic arrhythmias or prolongation of QT in echocardiographic recordings will lead to diagnosis of ATS. Striking intrafamilial variability of expression of KCNJ2 mutations and rarity of the syndrome may lead to misdiagnosis. METHODS: We report 15 patients from 8 Polish families with ATS, including 3 with novel KCNJ2 mutations. RESULTS: All patients had dysmorphic features; periodic paralysis affected males more frequently than females (80% vs. 20%), and most attacks were normokalemic. Two patients (with T75M and T309I mutations) had aborted sudden cardiac death. An implantable cardioverter-defibrillator was utilized in 40% of cases. CONCLUSIONS: KCNJ2 mutations cause a variable phenotype, with dysmorphic features seen in all patients studied, a high penetrance of periodic paralysis in males and ventricular arrhythmia with a risk of sudden cardiac death.

[Normokalemic periodic paralysis lasting for two weeks: a severe form of sodium channelopathy with M1592V mutation].

A 73-year-old man with recurrent periodic paralytic episodes lasting for two weeks each admitted to our hospital because of the leg weakness and the elevated value of serum creatine kinase. On admission, weakness in the proximal legs and mild eye lid myotonia were noted. Needle electromyography revealed abundant myotonic discharges. The prolonged exercise test showed a continuous reduction of compound muscle action potentials in the abductor digiti minimi muscle. Direct sequencing of SCN4A in the proband showed a G-to-A alteration at position 4774 that results in a change of 1592(nd) methionine to valine (M1592V). Cosegregation regarding the M1592V mutation and paralytic phenotype in this family was confirmed. Two cardinal features in this family were longer paralytic episodes compared to classical hyperkalemic/normokalemic periodic paralysis and the normal potassium value during the paralytic episodes. This study together with antecedent reports indicates that M1592V mutation shares a much greater clinical diversity ranging from congenital paramyotonia to periodic paralysis with a longer duration.

Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations.

OBJECTIVE: To report that homoplasmic deleterious mutations in the mitochondrial DNA MT-ATP6/8 genes may be responsible for acute episodes of limb weakness mimicking periodic paralysis due to channelopathies and dramatically responding to acetazolamide. METHODS: Mitochondrial DNA sequencing and restriction PCR, oxidative phosphorylation functional assays, reactive oxygen species metabolism, and patch-clamp technique in cultured skin fibroblasts. RESULTS: Occurrence of a typical MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome in a single member of a large pedigree with episodic weakness associated with a later-onset distal motor neuropathy led to the disclosure of 2 deleterious mitochondrial DNA mutations. The MT-ATP6 m.9185T>C p.Leu220Pro mutation, previously associated with Leigh syndrome, was present in all family members, while the MT-TL1 m.3271T>C mutation, a known cause of MELAS syndrome, was observed in the sole patient with MELAS presentation. Significant defect of complexes V and I as well as oxidative stress were observed in both primary fibroblasts and cybrid cells with 100% m.9185T>C mutation. Permanent plasma membrane depolarization and altered permeability to K(+) in fibroblasts provided a link with the paralysis episodes. Screening of 9 patients, based on their clinical phenotype, identified 4 patients with similar deleterious MT-ATP6 mutations (twice m.9185T>C and once m.9176T>C or m.8893T>C). A fifth patient presented with an original potentially deleterious MT-ATP8 mutation (m.8403T>C). All mutations were associated with almost-normal complex V activity but significant oxidative stress and permanent plasma membrane depolarization. CONCLUSION: Homoplasmic mutations in the MT-ATP6/8 genes may cause episodic weakness responding to acetazolamide treatment.

Episodes of paralysis in Chinese men with thyrotoxic periodic paralysis are associated with elevated serum testosterone.

BACKGROUND: The strong predilection for thyrotoxic periodic paralysis (TPP) to occur in males suggests androgen may contribute to its pathogenesis. We therefore sought to determine if serum total and free testosterone (TT and FT) concentrations differed among patients with TPP during episodes of paralysis, patients with TPP between episodes of paralysis, and patients with Graves' disease (GD) not having TPP. METHODS: A total of 105 Chinese men were included in the study, and were divided into three groups. Group 1 consisted of men with TPP who were studied during episodes of paralysis; group 2 consisted of men with TPP who were studied between episodes of paralysis; group 3 consisted of men with GD not having TPP. Patients in each were different persons. Serum electrolytes, free triiodothyronine (FT3), free thyroxine (FT4), TT, and FT were measured. Multiple regression analyses and analysis of covariance were performed to analyze the relationship of serum parameters, group status, and age. RESULTS: One multiple regression analysis was used to determine if serum TT concentrations were associated with age, FT3, FT4, or group status. This analysis indicated that age, FT4 level, and group status were significantly and independently associated with serum TT concentrations. With regard to group status, patients in group 1 had serum TT concentrations 0.92 ng/mL higher than patients in group 3 (p=0.033). As to FT4 level, TT concentrations increased by 0.016 ng/mL for each additional pmol/L of FT4 (p=0.002). Another multiple regression analysis was used to determine if serum FT concentrations were associated with age, FT3, FT4, group status, or serum TT concentrations. This analysis revealed that serum TT concentrations and group status were significantly and independently associated with serum FT concentrations. In terms of group status, patients in group 1 had serum FT concentrations of 2.11 pg/mL greater on average than patients in group 3 (p=0.006). CONCLUSIONS: We infer that episodes of paralysis in Chinese men with TPP are associated with elevated serum testosterone. We also found serum TT and FT concentrations of men with GD are both affected by group status; serum TT rather than FT concentrations are associated with thyroid function.

Thyrotoxic periodic paralysis: clinical and molecular aspects.

Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism that most often affects young East Asian males but increasingly also in other ethnic groups. The typical presentation is acute attacks varying from mild weakness to total paralysis starting at night or in the early morning a few hours after a heavy meal, alcohol abuse or strenuous exercise with complete recovery within 72 h. Signs and symptoms of hyperthyroidism may not be obvious. The hallmark is hypokalemia from increased cellular sodium/potassium-ATPase pump activity with transport of potassium from the extracellular to the intracellular space in combination with reduced potassium output. Recently, KCNJ18 gene mutations which alter the function of an inwardly rectifying potassium channel named Kir2.6 have been detected in 0-33 % of cases. Hence, the pathophysiology in TPP includes a genetic predisposition, thyrotoxicosis and environmental influences and the relative impact from each of these factors may vary. The initial treatment, which is potassium supplementation, should be given with caution due to a high risk of hyperkalemia. Propranolol is an alternative first-line therapeutic option based on the assumption that hyperadrenergic activity is involved in the pathogenesis. If thyroid function tests are unobtainable in the acute situation the diagnosis is supported by the findings of hypokalemia, low spot urine potassium excretion, hypophosphatemia with hypophosphaturia, high spot urine calcium/phosphate ratio, and electrocardiographic abnormalities as tachycardia, atrial fibrillation, high QRS voltage, and atrioventricular block. Definitive treatment is cure of the hyperthyroidism. The underlying mechanisms of TPP remain, however, incompletely understood awaiting further studies.

Genome-wide association study identifies a susceptibility locus for thyrotoxic periodic paralysis at 17q24.3.

Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of thyrotoxicosis. We conducted a genome-wide association study (GWAS) and a replication study with a total of 123 southern Chinese with TPP (cases) and 1,170 healthy controls and identified a susceptibility locus on chromosome 17q24.3 near KCNJ2 (rs312691: odds ratio (OR) = 3.3; P(meta-analysis) = 1.8 × 10(-14)). All subjects with TPP also had Graves' disease, and subsequent TPP versus Graves' disease comparison confirmed that the association at 17q24.3 was specific to TPP. The area under the curve (AUC) of rs312691 genotype for risk prediction of TPP in subjects with Graves' disease was 0.73. Expression quantitative trait locus (eQTL) analysis identified SNPs in the region flanking rs312691 (±10 kb) that could potentially affect KCNJ2 expression (P = 0.0001). Our study has identified a susceptibility locus associated with TPP and provides insight into the causes of TPP.

Aetiological, clinical and metabolic profile of hypokalaemic periodic paralysis in adults: a single-centre experience.

BACKGROUND: Hypokalaemic periodic paralysis constitutes a heterogeneous group of disorders that present with acute muscular weakness. In this analysis, we discuss the aetiological factors that appear to be more common in the Indian population. METHODS: From 1995 to 2001, 31 patients presented with periodic paralysis (mean age 34.5 years, range 11-68 years). Of the 31 patients, 19 were men. The clinical and laboratory data of these patients were analysed. Patients were investigated for possible secondary causes of hypokalaemla. RESULTS: There were 13 patients (42%) with renal tubular acidosis, 13 with primary hyperaldosteronism (42%), 2 each with thyrotoxic periodic paralysis and sporadic periodic paralysis, and I with Gitelman syndrome. Of the 13 patients with renal tubular acidosis, 10 had proximal and 3 distal renal tubular acidosis. Three of these patients with renal tubular acidosis had Sjogren syndrome. The patients diagnosed to have renal tubular acidosis had significantly lower serum bicarbonate (18.7 [14.6] v. 29.6 [5.0] mEq/L; p < 0.05) and higher levels of chloride (107.5 [6.0] v. 99.5 [3.4] mEq/L; p < 0.05) compared with those who had primary hyperaldosteronism, although the potassium values were similar (2.4 [0.65] v. 2.26 [0.48] mEq/L; p = 0.43). All patients with primary hyperaldosteronism had hypertension at presentation and were proven to have adrenal adenomas. CONCLUSION: A significant number of patients in this study had secondary and potentially reversible causes of hypokalaemic periodic paralysis. The common causes were renal tubular acidosis and primary hyperaldosteronism. A detailed work-up for secondary causes should be undertaken in Indian patients with hypokalaemic periodic paralysis.

Thyrotoxic periodic paralysis in a Maori patient.

A case of thyrotoxic periodic paralysis (TPP) in a patient of Maori heritage is described. The epidemiology, aetiology and pathogenesis of TPP are discussed. The case demonstrates that neurological examination and biochemical findings may be normal between episodes of paralysis. Given that there is much racial variation in the prevalence of TPP, and the suggestion that non-thyrotoxic periodic paralysis may be more prevalent in Maori, the case highlights the need for more research into the prevalence and pathogenesis of TPP in Maori patients.

Andersen syndrome: the newest variant of the hereditary-familial long QT syndrome.

Andersen's Syndrome is a rare disease, hereditary with autosomal dominant transmission, of the ion channels of the sarcolemmal membranes of the cardiac and skeletal muscles (channelopathy), which affects chromosome 17 of the KCNJ2 gene, responsible for encoding the outward potassium delayed rectifier current KIR2.1, resulting in a loss or suppression of the function of this channel.

An unrecognized cause of paralysis in ED: thyrotoxic normokalemic periodic paralysis.

Hypokalemic paralysis associated with hyperthyroidism (TPP) is a well-known acute electrolyte and muscle function disorder. Lesser known is normokalemic periodic paralysis associated with hyperthyroidism. We describe two cases of young men with acute muscular paralysis and bilateral impairment of sensation over the lower legs who had normal plasma potassium concentrations. They were initially misdiagnosed as having Guillain-Barré syndrome or hysterical paralysis. However, thyroid function tests showed elevated serum T(3) and T(4) and markedly depressed thyroid-stimulating hormone findings consistent with hyperthyroidism. Control of the hyperthyroidism completely abolished their periodic paralysis. Thyrotoxic normokalemic periodic paralysis (TNPP) should be kept in mind as a cause of acute muscle weakness to avoid missing a treatable and curable condition.