Genetic Screening of Patients with Thyrotoxic Hypokalemic Periodic Paralysis: An Experience from a Tertiary Care Hospital in the Northeast of Brazil.

BACKGROUND: Thyrotoxic Hypokalemic Periodic Paralysis (THPP) is a rare neuromuscular disease characterized by recurrent episodes of skeletal muscle weakness associated with hypokalemia. Alterations in protein-encoding genes that are part of ion channels seem to be related to the development of this disease. However, the pathogenic potential of some variants in these genomic regions is not yet fully understood. The aim of this study was to screen genetic alterations in regions coding for calcium (cav1.1), sodium (nav1.4), and potassium (Kir2.6) channels, evaluating its impact on the phenotype of patients with THPP. METHODS: Four patients with a diagnosis of THPP followed by the Endocrinology Service of the University Hospital of the Federal University of Maranhão (Brazil) were investigated for the presence of molecular abnormalities in CACNA1S, SCN4A, and KCNJ18 genes. RESULTS: The KCNJ18 analysis revealed at least one polymorphic variant in each patient. Considering the haplotypic classification of R39Q, R40H, A56E, and I249V variants, two cases were named Kir2.6_RRAI and the other two patients were named Kir2.6_QHEV. No patient had point mutations in the regions evaluated for CACNA1S and SCN4A genes. CONCLUSION: The identification of the Kir2.6_RRAI and Kir2.6_QHEV haplotypes reinforces the existence of two main haplotypes involving these four loci of the KCNJ18gene. On the other hand, point mutations in CACNA1S, SCN4A, and KCNJ18 genes do not seem to be the main mechanism of pathogenesis of THPP, indicating that many questions about this topic still remain unclear. So, the diagnosis of this rare disorder should still be based on clinical and biochemical aspects presented by the patient.

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands.

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.

Clinical and Aetiological Spectrum of Hypokalemic Flaccid Paralysis in Western Odisha.

OBJECTIVE: To study the clinical profile of hypokalemic flaccid paralysis (HKFP) and to evaluate its causes. METHODS: Fifty cases of hypokalemic flaccid paralysis (HKFP) admitted between November 2012 to October 2014 were taken up in the study. Serum potassium level < 3.5 mmol/ltr has been taken as hypokalemia. All cases were studied for spot and/or 24 hour urinary sodium / potassium, serum potassium / calcium / magnesium. Hypokalemic periodic paralysis (HPP) were diagnosed if there was spot/24 hour urine potassium excretion < 20mmol/ltr in presence of hypokalemia and flaccid weakness without other causes. EMG and nerve conduction study were done to exclude polyneuropathy and myopathic cases. RESULTS: Out of 50 cases of HKFP, male gender predominated (88%). Maximum number of cases (70%) occurred in 21 to 40 years of age. It occurred in all seasons but more in summer (58%). The precipitating factors were present in 76% of cases out of which high carbohydrate meal (28%), vomiting (16%), excessive sweating (8%), diarrhea (8%) and increased urination (12%) were present. Twenty percent of cases had recurrence (2 to 3 episodes most often) and 6% of cases had family history. Quadriparesis was seen in (54%), paraparesis (36%), hemiparesis (10%) and neck muscle weakness (32%). No case was present with respiratory paralysis or cranial nerve palsy. Twenty-one cases (42%) have very low potassium < 2.5 mmol/ltr, 11 cases (22%) with potassium level between 2.5 to 2.9 mmol/ltr and 18 cases (36%) with 3 to 3.5 mmol/ltr. There was no correlation between severity weakness and potassium level. Eleven cases (22%) had thyrotoxicosis and 3 cases (6%) were hypothyroid. Thirteen cases (26%) have excess urinary loss of potassium (≥20 mmol/ltr) of which 5 cases (10%) were distal renal tubular acidosis (dRTA), four cases (8%) were Gitelman's syndrome (GS) and in 4 cases exact cause could not be diagnosed. Non-renal / prior renal loss of potassium like diarrhea and excessive sweating was responsible in 8% cases each and vomiting in 10% of cases. One unique case of hypernatraemic hypokalemic paralysis (HHP) was found. Only 9 (18%) cases are hypokalemic periodic paralysis (HPP). CONCLUSIONS: HKFP is a hetergenous group of disease of which a significant number of patients had thyroid disorders mostly in the form of thyrotoxicosis followed by renal tubular dysfunctions like dRTA and GS; non-renal and prior renal loss of potassium like diarrhea, excessive sweating and vomiting respectively. Early recognition and prompt management of these conditions will give gratifying result and prevent further attacks in some cases.

Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis.

OBJECTIVE: To identify susceptibility genes to nonfamilial hypokalemic periodic paralysis (hypoKPP) consisting of thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP) and explore the potential pathogenic mechanisms. METHODS: We enrolled patients with nonfamilial hypoKPP not carrying mutations in CACNA1S, SCN4A, KCNJ18, or KCNJ2 and conducted genome-wide association analyses comparing 77 patients with TPP and 32 patients with SPP with 1,730 controls in a Han Chinese population in Taiwan. Replication was performed using an independent Han Chinese cohort of 50 patients with TPP, 22 patients with SPP, and 376 controls. RESULTS: We identified 4 single nucleotide polymorphisms (rs312692, rs312736, rs992072, rs393743) located about 100 Kb downstream of KCNJ2 on chromosome 17q24.3 associated with both TPP and SPP reaching genome-wide significance (p < 9 × 10(-8)). rs312736 was mapped to CTD-2378E21.1, a lincRNA, and direct sequencing revealed an exon variant rs312732 (risk allele A) highly associated with both TPP (p = 1.81 × 10(-12); odds ratio [OR] 3.22 [95% confidence interval (CI) 2.36-4.40]) and SPP (p = 8.6 × 10(-12); OR 5.4 [95% CI 3.17-9.18]). Overexpression of C (normal allele) CTD-2378E21.1 in C2C12 skeletal muscle cell, but not A (risk allele) CTD-2378E21.1, showed significantly decreased Kcnj2 expression, indicating A-type CTD-2378E21.1 has lost the ability to regulate Kcnj2. CONCLUSIONS: Our study reveals a shared genetic predisposition between TPP and SPP. CTD-2378E21.1 is a novel disease-associated gene for both TPP and SPP and may negatively regulate KCNJ2 expression. These findings provide new insights into the pathogenesis of nonfamilial hypoKPP.

Rare disease centers for periodic paralysis: China versus the United States and United Kingdom.

INTRODUCTION: We have developed a rare disease center in China. METHODS: In this study we analyzed how patients with periodic paralysis accessed centers in China vs. in the USA and UK. RESULTS: A total of 116 patients with periodic paralysis were evaluated in Beijing and Hangzhou (2003-2012). These patients traveled long distances for outpatient specialist care without an appointment or physician referral. In contrast, at the University of Rochester in the USA, >90% of patients were referred from physicians throughout the country by identifying physician expertise or by referrals from a patient advocacy group. In the UK, a single center, supported by the National Health Service, provides assessment/genetic testing for all UK patients. CONCLUSIONS: Rare disease centers in China require: (1) establishing a center for clinical characterization of the disease (e.g., periodic paralysis); (2) establishing a genetic diagnostic platform; (3) placing the center at a major city hospital; and (4) facilitating patient access through internet websites.

Prevalence study of genetically defined skeletal muscle channelopathies in England.

OBJECTIVES: To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders. METHODS: Analysis of demographic, clinical, electrophysiologic, and genetic data of all patients assessed at our national specialist channelopathy service. Only patients living in the United Kingdom with a genetically defined diagnosis of nondystrophic myotonia or periodic paralysis were eligible for the study. Prevalence rates were estimated for England, December 2011. RESULTS: A total of 665 patients fulfilled the inclusion criteria, of which 593 were living in England, giving a minimum point prevalence of 1.12/100,000 (95% confidence interval [CI] 1.03-1.21). Disease-specific prevalence figures were as follows: myotonia congenita 0.52/100,000 (95% CI 0.46-0.59), paramyotonia congenita 0.17/100,000 (95% CI 0.13-0.20), sodium channel myotonias 0.06/100,000 (95% CI 0.04-0.08), hyperkalemic periodic paralysis 0.17/100,000 (95% CI 0.13-0.20), hypokalemic periodic paralysis 0.13/100,000 (95% CI 0.10-0.17), and Andersen-Tawil syndrome (ATS) 0.08/100,000 (95% CI 0.05-0.10). In the whole sample (665 patients), 15 out of 104 different CLCN1 mutations accounted for 60% of all patients with myotonia congenita, 11 out of 22 SCN4A mutations for 86% of paramyotonia congenita/sodium channel myotonia pedigrees, and 3 out of 17 KCNJ2 mutations for 42% of ATS pedigrees. CONCLUSION: We describe for the first time the overall prevalence of genetically defined skeletal muscle channelopathies in England. Despite the large variety of mutations observed in patients with nondystrophic myotonia and ATS, a limited number accounted for a large proportion of cases.

Novel etiopathophysiological aspects of thyrotoxic periodic paralysis.

Thyrotoxicosis can lead to thyrotoxic periodic paralysis (TPP), an endocrine channelopathy, and is the most common cause of acquired periodic paralysis. Typically, paralytic attacks cease when hyperthyroidism is abolished, and recur if hyperthyroidism returns. TPP is often underdiagnosed, as it has diverse periodicity, duration and intensity. The age at which patients develop TPP closely follows the age at which thyrotoxicosis occurs. All ethnicities can be affected, but TPP is most prevalent in people of Asian and, secondly, Latin American descent. TPP is characterized by hypokalemia, suppressed TSH levels and increased levels of thyroid hormones. Nonselective ß adrenergic blockers, such as propranolol, are an efficient adjuvant to antithyroid drugs to prevent paralysis; however, an early and definitive treatment should always be pursued. Evidence indicates that TPP results from the combination of genetic susceptibility, thyrotoxicosis and environmental factors (such as a high-carbohydrate diet). We believe that excess T(3) modifies the insulin sensitivity of skeletal muscle and pancreatic ß cells and thus alters potassium homeostasis, but only leads to a depolarization-induced acute loss of muscle excitability in patients with inherited ion channel mutations. An integrated etiopathophysiological model is proposed based on molecular findings and knowledge gained from long-term follow-up of patients with TPP.

[An analysis of the risk factors for the severity of paralysis in patients with hypokalemic periodic paralysis].

OBJECTIVES: To analyze the independent factors for the severity of paralysis in the patients with hypokalemic periodic paralysis (HOPP). METHODS: Eighty patients admitted with HOPP were reviewed. Using univariate analysis and multivariate analysis, the independent factors for the severity of paralysis were revealed. RESULTS: A total of 76 cases were male and 4 female with a mean age of (26.3 +/- 4.5) years. Univariate analysis showed that patients with low serum magnesium level, low serum potassium level, high serum creatine kinase level, changes of electrocardiogram, chest distress and palpitation, nausea and vomiting as well as muscular soreness had more severe paralysis, while multivariate analysis revealed that serum magnesium < 0.8 mmol/L (OR 8.3, 95%CI 1.0 - 68.4, P < 0.05), serum potassium 1.5 - 1.8 mmol/L (OR 1.3, 95% CI 1.1 - 16.0, P < 0.01) and serum creatine kinase > 200 U/L (OR 1.1, 95%CI 1.0 - 1.1, P < 0.01) were the independent factors for the severity of paralysis. CONCLUSION: Low serum magnesium level, low serum potassium level and high serum creatine kinase level are the independent risk factors for more severe paralysis in patients with HOPP.

Thyrotoxic periodic paralysis admitted to the medical department in Qatar.

OBJECTIVES: In this study we describe the clinical presentation and electrolyte disturbances of thyrotoxic periodic paralysis (TPP) in patients admitted to the Department of Medicine at Hamad General Hospital. METHODS: Retrospective descriptive study involving patients admitted to the medical department of Hamad General Hospital with paralysis and hyperthyroidism. RESULTS: Eighteen patients with TPP were identified over a three-year period (2004-2007). Their mean age was 32.4 +/- 8.52 years (range 21 to 48 years); all were males. Eleven patients were from the Philippines, five were from Nepal, one was Indian and one was from Sri Lanka. Fourteen patients (77.8%) had the attack in the summer while the remaining four in winter. Nine had a history of severe exertion, five had ingested a heavy carbohydrate meal, two had a sore throat, one had ingested alcoholic and one was without a precipitating cause. Fifteen patients had no previous history of hyperthyroidism. Later on, all patients proved to have hyperthyroidism. All patients were hypokalaemic, while seven patients had hypophosphataemia and three had hypomagnesaemia. Urinary potassium was <20 mmol/l in all patients. Fifteen patients had ECG changes. All patients had proximal myopathy. Twelve patients had signs of hyperthyroidism in the form of goitre, warm sweaty palms, tachycardia, and tremor. Nine patients had attacks of paralysis before diagnosis. After discharge, ten patients had recurrences within one to seven months. CONCLUSION: The causes of hypokalaemia and lower-extremity paralysis are numerous; TPP should be taken into consideration in the differential diagnosis of all acute episodes of motor paralysis, especially in young Asian male patients.

Hypokalemic thyrotoxic periodic paralysis: clinical characteristics and predictors of recurrent paralytic attacks.

BACKGROUND AND PURPOSE: To study the clinical characteristics of hypokalemic thyrotoxic periodic paralysis (hoTPP) and identify the predictors of recurrent paralytic attacks before achieving the euthyroid status. METHODS: We retrospectively analyzed 45 hoTPP patients who were admitted during the 7-year study period. RESULTS: A tendency towards male predominance was observed among the 45 patients (91.1%, 41/45). The mean onset age was 32.9 +/- 10.0 years (range: 16-54 years). No significant differences were observed in the onset age between male and female patients. Precipitating factors included rest/sleep at night, hot weather, upper respiratory tract infections (URIs), and excessive physical activities. Atypical weakness was observed in nine (20%, 9/45) patients. One patient initially diagnosed with sporadic periodic paralysis eventually developed hoTPP. DISCUSSION: In provocative tests, hypokalemia was not a consistent finding during paralytic attacks. Before achieving the euthyroid status, the rate of recurrent attacks was as high as 62.2%, and peaked in the first 3 months after hoTPP was diagnosed. Patients with URIs exhibited a higher incidence of recurrent paralytic attacks than those without (odds ratio = 13.00; 95% confidence interval = 1.08-156.08; P = 0.04).

Thyrotoxic hypokalaemic periodic paralysis in a Turkish population: three new case reports and analysis of the case series.

OBJECTIVE: Thyrotoxic hypokalaemic periodic paralysis (THPP) is an uncommon condition with intermittent episodes of muscle weakness and occasionally severe paralysis. THPP is a common complication of hyperthyroidism in Asian populations, and has also been reported in other ethnic groups including Caucasians. This study aimed to conduct an analysis of THPP in a Turkish population, and is to our knowledge the first analysis of a homogeneous Caucasian group. SUBJECTS: Forty cases with THPP were identified in the Turkish population. Three out of the 40 were new cases and were assigned as index cases. Two cases were not included in the analysis because of lack of data. RESULTS: THPP was diagnosed in 10 cases during the first attack and was observed to have a significant shorter complete recovery time statistically in this group (P < 0.01). The majority of cases were hypokalaemic, while there were two normokalaemic cases. Classification of the cases according to their potassium (K) levels revealed that the group with K levels < 2.5 mEq/l had a statistically longer amelioration time than the group with K levels > or = 2.5 mEq/l. When the cases were classified according to intravenous or oral application of K, the mean amelioration time was 6.8 +/- 3.6 h for the intravenous group and 13.1 +/- 7.6 for the oral group. Mean complete recovery times of the groups were 29.4 +/- 16.2 h and 52.8 +/- 18.0 h, respectively. The intravenous group had a shorter amelioration time and complete recovery time, and both were statistically significant (P < 0.05 for each). CONCLUSIONS: THPP may be seen among Caucasians. Diagnosing THPP during the first attack might decrease the recovery time. The level of hypokalaemia seems to affect the recovery time and initial low K levels may lead to more deterioration in a patient's health compared with mild or near-normal levels. Intravenous, rather than oral, application of K may be advantageous for shortening both the amelioration and complete recovery times.

A case report of familial periodic paralysis.

A 20-year-old male was brought to the hospital with the complaints of severe weakness and inability to move the limbs of 12 hours duration. For the last 2 years he had the same episodes with spontaneous recovery. Family history strongly suggested involvement of other members of the family. Physical examination did not suggest any neurological deficit. All investigations were normal except serum potassium level being 2.2 meq/l during attack and 3.4 meq/l after the attack. He was treated with oral acetazolamide and potassium chloride. The case was diagnosed to be familial periodic paralysis belonged to the group 'episodic myasthenia'.

Thyrotoxic periodic paralysis and anesthesia report of a case and literature review.

Thyrotoxic periodic paralysis (TPP) is a disease characterized by recurrent episodes of paralysis and hypokalemia during a thyrotoxic state. The disease primarily affects people of Asian descent, but can affect other ethnic groups. In Asians, the symptoms of thyrotoxicosis are distinct and usually precede the first paralytic episode, whereas in non-Asian populations, paralysis is the presenting symptom. If TPP has not been diagnosed and the patient has a surgical procedure during general or regional anesthesia, symptoms of the disease may be confused with other adverse perioperative events such as delayed recovery from neuromuscular paralysis. No specific anesthetic regimen is superior. Current TTP treatment recommendations involve treating the underlying hyperthyroid state. Other modalities such as beta-blockade and potassium replacement are also important in the acute paralytic state. Future diagnostic and treatment innovations may lie in the genetic and molecular understanding of this disease. We present a case of an Asian male with known TPP undergoing general anesthesia, a brief case series involving 5 patients, and a review of the literature.

Hypokalaemia and paralysis in the Thai population.

BACKGROUND: Hypokalaemia with paralysis is a syndrome common in Thailand. This syndrome may result from hypokalaemic periodic paralysis (HypoPP), thyrotoxic periodic paralysis (TPP) or distal renal tubular acidosis (dRTA). We prospectively investigated the nature of this syndrome in afflicted Thai patients. METHODS: Blood and urine samples were collected from 47 patients during attacks for multiple biochemical and thyroid function tests. A long acid loading test was performed in all euthyroid patients. Mutation analyses were done in all HypoPP and TPP patients. RESULTS: Of the subjects, 34 completed the study. Of those, 11 (32%), eight (24%) and 15 (44%) had TPP, dRTA and HypoPP, respectively. Patients with dRTA and TPP were older than those with HypoPP. Males were more prevalent than females in HypoPP and TPP; the reverse was true for dRTA. Two-thirds of the HypoPP cases were sporadic. The majority of the HypoPP and dRTA patients resided in northeastern Thailand. Of the 11 TPP patients, nine (82%) had no previous thyroid disease. Moreover, four out of 11 patients (36%) had subtle clinical signs of hyperthyroidism; three of eight dRTA patients had renal stones, nephrocalcinosis or both. Only two patients had metabolic acidosis at the time of presentation. No common mutations were found in the HypoPP and TPP patients. CONCLUSIONS: In most of our patients, HypoPP is sporadic and not associated with the common mutations reported previously. Clinical clues that can assist in differentiating between the causes of hypokalaemia and paralysis are age at onset, gender and geographic region residence of the patients. However, the absence of previous histories of thyroid disease or overt thyrotoxicosis, and of stone disease/nephrocalcinosis or metabolic acidosis does not exclude the diagnosis of TPP or dRTA.

Clinical and molecular analysis of chinese patients with thyrotoxic periodic paralysis.

Although sporadic thyrotoxic periodic paralysis (TPP) has a much higher prevalence in Asian than in all the other populations studied so far, it is also increasingly being seen at the emergency departments of the West, hence, it is vital to stress the importance of recognizing it. TPP shares some similarities with hypokalemic periodic paralysis (HOKPP). However, the pathophysiology of TPP and the reasons for this higher incidence are not known. We hypothesized that some mutations in the CACNA1S gene, which has been implicated in familial HOKPP, might play a role in TPP. We present 5 Chinese patients who suffer from TPP and demonstrate typical clinical features. No mutation was found on the whole CACNA1S gene. Therefore other molecular mechanisms will have to be examined in order to explain the different TPP incidences.

Thyrotoxic, hypokalaemic periodic paralysis in Australasian men.

Abstract The present study describes the clinical and laboratory features of 11 patients with thyrotoxic, hypokalaemic periodic paralysis, presenting to five Melbourne teaching hospitals between 1991 and 2000. All 11 patients were Asian or Polynesian men aged 18-41 years, and most had experienced previous episodes of acute, unexplained paralysis. All cases resolved without significant morbidity. Thyrotoxic, hypokalaemic periodic paralysis is a potentially life-threatening and terrifying condition, which is often under-recognized and will present with increasing frequency in the community. The diagnosis should be considered in any Asian-Australian male presenting with sudden onset paralysis.