There are 2 dominantly inherited, clinically similar types of episodic flaccid generalized weakness, HOKPP and HYPP, that are distinguished by the changes in serum potassium levels during paralytic attacks. In contrast to HYPP, myotonia is usually not present ... There are 2 dominantly inherited, clinically similar types of episodic flaccid generalized weakness, HOKPP and HYPP, that are distinguished by the changes in serum potassium levels during paralytic attacks. In contrast to HYPP, myotonia is usually not present in HOKPP (Jurkat-Rott et al., 2000). Hypokalemic periodic paralysis may also occur as a rare complication of thyrotoxicosis (see TTPP1, 188580), a disorder with a high frequency in individuals of Asian descent (Kung, 2006).
The classic picture of HOKPP is episodic weakness accompanied by low serum potassium levels. The attacks are aborted by administration of potassium or by exercise and are precipitated by insulin or glucose administration. Hypokalemic periodic paralysis shows markedly ... The classic picture of HOKPP is episodic weakness accompanied by low serum potassium levels. The attacks are aborted by administration of potassium or by exercise and are precipitated by insulin or glucose administration. Hypokalemic periodic paralysis shows markedly reduced penetrance in females, although penetrance is 100% in males. For this reason, some pedigree patterns have suggested X-linked recessive inheritance (Sagild, 1959). Ropers and Szliwowski (1979) described a family in which an unaffected male had 2 daughters, each by a different wife, with this disorder. One of the affected daughters had an affected son. Buruma et al. (1985) reported a large family with HOKPP with 28 affected patients in 4 generations. All patients investigated showed permanent muscle weakness. Ma et al. (1986) reported the unusual occurrence of high frequency of periodic paralysis among Chinese patients with primary hyperaldosteronism and resultant hypokalemia due to adrenal cortical adenoma. Among 50 consecutive patients with an adenoma, 42% presented with periodic paralysis. Other features included palpitations (30%) and syncope (12%). Those with paralysis had significantly lower mean serum potassium and significantly higher aldosterone levels than those without paralysis. Ma et al. (1986) also noted that hypokalemic paralysis can occur in Orientals with barium poisoning, and as a side-effect of gossypol, a fertility regulating agent used in China. Raskin et al. (1981) and Pun et al. (1989) observed periodic paralysis with Sjogren syndrome (270150), which can be complicated by distal renal tubular acidosis and hypokalemia. Boerman et al. (1995) reported a large Dutch family in which 55 members had HOKPP inherited in an autosomal dominant pattern. Nineteen patients had typical episodic attacks of paralysis, whereas 14 had muscle weakness without attacks. Reduced muscle fiber conduction velocity was present. Age of onset ranged from 9 to 19 years of age. In a review of 71 patients from 56 kindreds with HOKPP, Miller et al. (2004) found that 64% of kindreds had mutations in either the CACNA1S or SCN4A genes. The arg1239-to-his (R1239H; 114208.0001) and arg528-to-his (R528H; 114208.0003) mutations of the CACNA1S gene were the most common mutations, each found in 42% of kindreds. Five kindreds had SCN4A mutations. No mutations were identified in 20 kindreds. HOKPP patients with mutations had a significantly earlier age at disease onset (10 years) compared to those without mutations (22 years); however, 2 patients with mutations presented at ages 23 and 26 years, respectively. Among those with mutations, the disease was most severe during the teenage years, and 72% of patients had residual muscle weakness. Muscle biopsies showed vacuolar changes in 80% of patients with CACNA1S mutations; these changes were not seen in any patients without mutations. Treatment with acetazolamide was beneficial in 85% of those with mutations and 100% of those without mutations. In a diagnostic flow chart for the periodic paralyses, Miller et al. (2004) indicated that HOKPP shows onset in childhood to adolescence and is characterized by infrequent but severe attacks, often lasting up to 24 hours, and decreased serum potassium. Myotonia is not a feature. Chabrier et al. (2008) reported a Turkish boy, born of consanguineous parents, with very early onset of HOKPP at 1 year of age. He showed hypotonia and respiratory insufficiency at birth, which the authors postulated may have been related to the disorder. Although oral potassium supplementation was initiated, he was still symptomatic and showed chronic global muscle weakness at age 6 years. - Clinical Variability Abbott et al. (2001) reported a male proband with atypical HOKPP who was negative for mutations in the SCN4A and CACNA1S genes. He had onset of episodic paralytic weakness at the age of 14 years. Episodes were characterized by weakness primarily affecting the lower extremities and lasting hours to days, and were usually precipitated by strenuous exercise followed by rest or after prolonged sitting. Carbohydrate ingestion did not precipitate attacks, alcohol intake appeared to facilitate recovery from an attack, and potassium had no effect. He was classified as having hypokalemic periodic paralysis because of the typical age of onset, paralytic attacks that most often occurred after exercise, a low potassium level during a spontaneous attack, and the ability to precipitate an attack with insulin and glucose on 1 occasion. Atypical for this diagnosis was that a second provocative test was negative and that attacks usually occurred while awake.
In 11 of 33 probands with HOKPP, Ptacek et al. (1994) identified mutations in the CACNL1A3 gene (114208.0001; 114208.0002) that occurred at 1 of 2 adjacent nucleotides within the same codon. This was the first human disease to ... In 11 of 33 probands with HOKPP, Ptacek et al. (1994) identified mutations in the CACNL1A3 gene (114208.0001; 114208.0002) that occurred at 1 of 2 adjacent nucleotides within the same codon. This was the first human disease to be related to DHP receptor mutations. In a large Dutch family with HOKPP, Boerman et al. (1995) identified a mutation in the CACNL1A3 gene (114208.0003). Davies et al. (2001) found that 11 of 36 families with HOKPP harbored mutations in the CACNA1S gene (114208.0001 and 114208.0003), whereas only 1 family had a mutation in the SCN4A gene (603967.0020), suggesting that SCN4A mutations are an uncommon cause of HOKPP in the U.K. Among 58 independent index cases of HOKPP, Sternberg et al. (2001) found that 40 were linked to the CACNA1S gene and 5 to the SCN4A gene, all of which were in the same codon (see, e.g., 603967.0016). Thirteen families remained without known mutations, indicating genetic heterogeneity. Chabrier et al. (2008) identified a de novo mutation in the CACNA1S gene (114208.0008) in a Turkish boy with very early onset of HOKPP. Matthews et al. (2009) identified mutations in the CACNA1S or SCN4A gene in 74 (almost 90%) of 83 patients with HOKPP. All of the mutations, including 3 novel mutations, affected arginine residues in the S4 voltage sensing region in 1 of the transmembrane domains of each gene. The most common mutations affected residues arg528 (25 cases) and arg1239 (39 cases) in CACNA1S (see, e.g., R1239H; 114208.0001 and R528H; 114208.0003). The most common mutations in SCN4A affected residues arg672 (see, e.g., 603967.0016) and arg1132. The findings supported the hypothesis that loss of positive charge in S4 voltage sensors is important to the pathogenesis of this disorder. (Sokolov et al., 2007).
The two distinct forms of muscle involvement observed in hypokalemic periodic paralysis (HOKPP), paralytic episodes and fixed myopathy, may occur separately or together. The pure paralytic episodic form occurs most commonly; the combination of paralytic episodes and a slowly progressive myopathy is less common; the pure myopathic form without paralytic episodes is rare:...
DiagnosisClinical DiagnosisThe two distinct forms of muscle involvement observed in hypokalemic periodic paralysis (HOKPP), paralytic episodes and fixed myopathy, may occur separately or together. The pure paralytic episodic form occurs most commonly; the combination of paralytic episodes and a slowly progressive myopathy is less common; the pure myopathic form without paralytic episodes is rare:Paralytic episodes. The primary symptom consists of attacks of reversible flaccid paralysis with a concomitant hypokalemia that usually leads to paraparesis or tetraparesis but spares the respiratory muscles.Myopathic form. The myopathic form results in slowly progressive, fixed muscle weakness that begins as exercise intolerance predominantly of the lower limbs; it usually does not lead to severe disability. This fixed weakness must be distinguished from the reversible weakness that exists between attacks in some affected individuals.TestingIn individuals who have had one or more paralytic episodes, several tests can be used to differentiate between the other possible causes and primary HOKPP resulting from a genetic skeletal muscle membrane ion channel defect.Serum concentration of potassium during paralytic attack. During an attack, the serum concentration of potassium ranges from 0.9 to 3.0 mmol/L (normal range: 3.5-5.0 mmol/L).Note: Measurement of the serum concentration of potassium during an attack is needed to classify a paralytic episode as hypokalemic.Transtubular potassium concentration gradient and potassium-creatinine ratio during paralytic attack. The following can be used to distinguish between hypokalemia caused by renal (urinary) losses and hypokalemia caused by intracellular muscular shift of potassium (as occurs in primary HOKPP caused by a genetic ion channel defect) [Lin et al 2004]:Urinary potassium concentration >20 mmol/L indicates urinary loss of potassium. Note: The threshold value of 20 mmol/L is not sufficient to distinguish between renal and non-renal hypokalemia.Urinary potassium/creatinine ratio of >2.5 indicates urinary loss of potassium.A transtubular potassium concentration gradient (TTKG)* >3.0 suggests hypokalemia of renal origin. * The ratio: [urine potassium/plasma potassium]/[urine osmolality/blood osmolality]Note: In the case of associated dysmorphic traits and intercritic-associated cardiac arrhythmia, the diagnosis of Andersen-Tawil syndrome must be considered as a differential diagnosis.Serum concentration of thyroid-stimulating hormone and free thyroxine and triiodothyronine. Thyrotoxic periodic paralysis (TPP) is a major differential diagnosis of primary genetic HOKPP. Therefore, in case of attacks of weakness with hypokalemia, it is recommended to quantify the following:Plasmatic thyroid-stimulating hormone (TSH): Reference range: 0.45-4.5 µU/mL Free thyroxine (FT4): Reference range: 8-20 pg/mLFree triiodothyronine (FT3): Reference range: 1.4-4 pg/mL A low level of TSH together with high levels of FT3 and FT4 indicates that hyperthyroidism is present and is the very probable (and treatable) cause of paralytic attacks. TPP is curable by treatment for hyperthyroidism. TPP is distinct from familial genetic hypokalemic periodic paralysis (FHOKPP); however, at least two cases of genetically defined FHOKPP for which hyperthyroidism was an additional trigger for hypokalemic paralytic episodes have been reported [Lane et al 2004, Vicart et al 2004].Electromyogram (EMG) During an attack, EMG findings are not specific; EMG demonstrates a reduced number of motor units and possibly myopathic abnormalities.Between attacks, EMG may exhibit myopathic abnormalities in individuals with fixed myopathy.Myotonic discharges are typically absent in HOKPP; however, one family with combined heat-induced myotonia and cold-induced hypokalemic periodic paralysis has been described [Sugiura et al 2000].Specific exercise tests can assist with the diagnosis of periodic paralyses and nondystrophic myotonias [Fournier et al 2004]:Short exercise test (SET). SET consists of recording evoked compound muscle action potential (CMAP) every ten seconds over one minute after a short effort (5-12 seconds) [Streib 1987].Long exercise test (LET). LET consists of recording evoked CMAP over 30-45 minutes, every one to two minutes and then every five minutes, after a long effort (2-5 minutes, with brief 3- to 4-second rest periods every 15-45 seconds) [McManis et al 1986].Five patterns (I-V) of abnormal responses to SET and/or LET in periodic paralyses and nondystrophic myotonias have been described [Fournier et al 2004]. Genetically defined periodic paralyses specifically result in:Pattern IV (no or rare myotonic discharges, increase of CMAP in SET, immediate increase and late marked decrease in LET), more commonly seen in the hyperkalemic type ORPattern V (no myotonic discharges, normal response to SET, no immediate increase but late marked decrease in LET), more commonly seen in the hypokalemic typeA false negative normal pattern may be noted in some individuals who have a disease-causing mutation, especially in asymptomatic individuals or those who have not recently had a paralytic attack [Tengan et al 2004].Muscle biopsy. In individuals with the myopathic form of HOKPP, muscle biopsy with adequate histochemical and histoenzymologic staining has been the mainstay of diagnosis. Light microscopy shows vacuoles [Pearson 1964, Olivariusbde & Christensen 1965, Martin et al 1984] or sometimes tubular aggregates [Faugere et al 1981]. Although the latter are less specific to HOKPP, they are the only lesions in some cases. Note: Electron microscopy is not necessary.Molecular Genetic TestingGenes. Two genes are known to be associated with hypokalemic periodic paralysis (HOKPP):CACNA1S, accounting for approximately 55%-70% of HOKPPSCN4A, accounting for approximately 8%-10% of HOKPPOther loci. One study suggested that mutations in another potassium channel gene, KCNE3, cause HOKPP [Abbott et al 2001] and thyrotoxic periodic paralysis [Dias Da Silva et al 2002a]; however, two further studies did not support this hypothesis, showing that this missense variant is present in 0.8%-1.5% of the healthy population [Sternberg et al 2003, Jurkat-Rott & Lehmann-Horn 2004]. The nine most common mutations in CACNA1S and SCN4A do not account for about 20%-36% of individuals with clinically diagnosed HOKPP, indicating possible further allelic heterogeneity and/or genetic heterogeneity of the disorder [Sternberg et al 2001, Miller et al 2004]; however, no other loci have been identified.Clinical testingCACNA1S (hypokalemic periodic paralysis type 1)Targeted mutation analysis. Four mutations (p.Arg528His, p.Arg1239His, p.Arg1239Gly, p.Arg528Gly), clustered in exons 11 and 30, are present in approximately 55%-70% of individuals with HOKPP [Jurkat-Rott et al 1994, Ptacek et al 1994a, Sternberg et al 2001, Miller et al 2004, Wang et al 2005]. Mutations p.Arg528His and p.Arg1239His are far more common than p.Arg1239Gly and p.Arg528Gly. A fifth mutation in exon 21 (p.Arg897Ser) has been described recently [Chabrier et al 2008]. Sequence analysis of select exons. Alternately, exons 11 and 30 can be analyzed by direct sequencing, which detects the four common mutations and any additional sequence variants in these exons. Sequencing of exon 21 should also be performed [Chabrier et al 2008]. Sequence analysis of entire coding region may also be considered when targeted mutation analysis or sequencing of select exons is negative (see Testing Strategy).SCN4A (hypokalemic periodic paralysis type 2)Sequence analysis of select exon(s). Sequence analysis of exon 12 detects five mutations (p.Arg669His, p.Arg672Ser, p.Arg672His, p.Arg672Gly, p.Arg672Cys) that account for approximately 10% of individuals with HOKPP [Bulman et al 1999, Jurkat-Rott et al 2000b, Sternberg et al 2001, Bendahhou et al 2001, Davies et al 2001, Kim et al 2004]. Sequence analysis of exon 18, in which a sixth mutation (p.Arg1132Gln) has been described, should also be performed [Carle et al 2006]. Sequence analysis / mutation scanning of entire coding region of SCN4A may detect rare or de novo mutations, such as the one reported by Sugiura et al [2000] in a family with a combination of heat-induced myotonia and cold-induced paralysis.Table 1. Summary of Molecular Genetic Testing Used in Hypokalemic Periodic ParalysisView in own windowGene SymbolTest MethodMutations DetectedProportion of HOKPP Diagnosed with This Test MethodTest AvailabilityCACNA1STargeted mutation analysisp.Arg528His, p.Arg1239His, p.Arg1239Gly, p.Arg528Gly p.Arg897Ser 155%-70%Clinical Sequence analysis of exons 11, 21 and 30 2Sequence variants 355%-70%Sequence analysis of entire coding regionSequence variants 3UnknownSCN4ATargeted mutation analysisp.Arg669His, p.Arg672Ser, p.Arg672His, p.Arg672Gly, p.Arg672Cys p.Arg1132Gln 48%-10%Clinical Sequence analysis exon 12 and 18Sequence variants 38%-10%Sequence analysis of entire coding regionSequence variants 3Unknown1. Mutations tested may vary among laboratories.2. Exons sequenced may vary among laboratories.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Includes, but not limited to, detection of variants p.Arg669His, p.Arg672Ser, p.Arg672His, p.Arg672Gly, p.Arg672Cys, p.Arg1132Gln. Mutations detected may vary among laboratories.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming the diagnosis in a proband. One approach to molecular genetic testing is the following:1.Test for common mutations in exons 11 and 30 of CACNA1S by targeted mutation analysis or sequencing of select exons.2.If no mutation is identified, sequence exon 12 and 18 of SCN4A and exon 21 of CACNA1S.3.If no mutation is identified, sequence all coding regions of SCN4A to search for mutations associated with normokalemic and hyperkalemic periodic paralysis (in case the diagnosis of HOKPP is incorrect).4.If no mutation is identified, sequence all coding regions of CACNA1S in search of a novel/rare mutation.5.If no mutation is identified, sequence the coding region of KCNJ2 for a mutation that could cause Andersen-Tawil syndrome, which can mimic HOKPP.Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersCACNA1S. While missense mutations in exons 11 and 30 can cause HOKPP type 1, missense mutations in exon 26 (p.Arg1086Cys, p.Arg1086His) have been shown to cause autosomal dominant malignant hyperthermia susceptibility (MHS) without HOKPP in at least two families [Monnier et al 1997, Jurkat-Rott et al 2000a]. One family with combined HOKPP and MHS caused by an unidentified mutation has been reported [Rajabally & El Lahawi 2002]. Mutations in CACNA1S account for 1% of all individuals with MHS [Stewart et al 2001].MHS is a pharmacogenetic disorder of skeletal muscle calcium regulation. MH-susceptible individuals respond to volatile anesthetics (halothane, sevoflurane, desflurane, enflurane, isoflurane) or depolarizing muscle relaxants (succinylcholine) with uncontrolled skeletal muscle hypermetabolism. The triggering substances release calcium stores from the sarcoplasmic reticulum, causing contracture of skeletal muscles, glycogenolysis, and increased cell metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, hypoxemia, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk of cardiac arrhythmia or even arrest, and myoglobinuria with a risk of renal failure. In almost all cases, the first manifestations of MH occur in the operating room. Death results unless the individual is promptly treated.SCN4A. While missense mutations in exon 12 cause HOKPP type 2, a large number of missense mutations in other exons have been shown to cause autosomal dominant disorders characterized by hyperexcitability of the sarcoplasmic membrane [Ptacek et al 1991, Rojas et al 1991, Plassart et al 1994, Ptacek et al 1994b]:Hyperkalemic periodic paralysis type 1 (HyperPP1). HyperPP1 is characterized by: attacks of flaccid limb weakness (possibly including muscle weakness of the eyes, throat, and trunk as well); hyperkalemia (>5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake; normal serum potassium and muscle strength between attacks; onset before age 20 years; and absence of paramyotonia (muscle stiffness aggravated by cold and exercise). The attacks of flaccid muscle weakness usually begin in the first decade of life. Initially infrequent, the attacks increase in frequency and severity over time until approximately age 50 years, after which the frequency declines considerably. Potassium-rich food or rest after exercise may precipitate an attack. A cold environment, emotional stress, glucocorticoids, and pregnancy provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to an hour, and then disappears. Usually, cardiac arrhythmia and respiratory insufficiency do not occur during the attacks. Between attacks, HyperPP1 is usually associated with mild myotonia (muscle stiffness) that does not impede voluntary movements. Many older individuals with HyperPP1 develop a chronic progressive myopathy.Paramyotonia congenita (PC). PC in general is characterized by myotonic symptoms followed by weakness; symptoms are worsened by repeated movements and triggered or aggravated by exposure to cold [Plassart et al 1994, Ptacek et al 1994b]. It is caused mainly by mutations at codons 1313 and 1448 of SCN4A.Potassium-aggravated myotonias (PAM) and related disorders. This group of diseases is characterized by myotonic symptoms that are neither clearly ameliorated by exercise (as in myotonia congenita) nor worsened by exercise and cold (as in paramyotonia congenita). Symptoms may fluctuate (myotonia fluctuans) or be permanent (myotonia permanens) and/or be aggravated by potassium. They may respond to acetazolamide (acetazolamide-responsive myotonias) [Trudell et al 1987]. PAM and related disorders are caused mainly by mutations at codon 1306 of SCN4A. These myotonic syndromes are distinct from myotonic dystrophy type 1 (DM1), caused by a trinucleotide repeat expansion in DMPK, and myotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM), caused by a tetranucleotide repeat expansion in ZNF9. Diseases caused by mutations in SCN4A may also be intermediate or compound forms of HyperPP and PC, or PC and PAM.Malignant hyperthermia susceptibility. Moslehi et al [1998] described a large kindred in which affected individuals had hyperkalemic periodic paralysis with or without MHS. None had MHS alone. The causative SCN4A allele was later characterized as having a double mutation, p.[Phe1490Leu + Met1493Ile] [Bendahhou et al 2000]. Vita et al [1995] described a kindred with succinylcholine-induced masseter muscle rigidity, a complication of anesthesia other than malignant hyperthermia susceptibility that was caused by a missense mutation of SCN4A, p.Gly1306Ala.Congenital myasthenic syndromes. Congenital myasthenic syndromes (CMS) are characterized by fatigable weakness involving ocular, bulbar, and limb muscles with onset at or shortly after birth. In some types of CMS, myasthenic symptoms may be mild; but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may occur, precipitated by fever, infections, or excitement. If symptoms start in the neonatal period, the major findings include: feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Respiratory insufficiency with sudden apnea and cyanosis may occur. Individuals with onset later in childhood show abnormal muscle fatigability with difficulty in running or climbing stairs. Motor milestones may be delayed. Affected individuals present with fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Cardiac and smooth muscle are not involved. Tsujino et al [2003] reported a single individual with a particular endplate functioning abnormality caused by a missense mutation of SCN4A that caused markedly enhanced fast inactivation.
The two different forms of hypokalemic periodic paralysis (HOKPP) are the paralytic form and the myopathic form. The natural history of the disorder varies among individuals....
Natural HistoryThe two different forms of hypokalemic periodic paralysis (HOKPP) are the paralytic form and the myopathic form. The natural history of the disorder varies among individuals.Paralytic form. The primary symptom of the paralytic form is an attack of reversible flaccid paralysis with concomitant hypokalemia usually leading to paraparesis or tetraparesis but sparing the respiratory muscles and heart. No correlation between serum potassium concentration and severity of weakness exists. Some individuals have only one episode in a lifetime; more commonly, attacks repeat daily, weekly, monthly, or less often. The interval between crises may vary and may be prolonged by preventive treatment with potassium salts or acetazolamide.The age of onset of the first attack ranges from one to 20 years. The mean age of onset of the first paralytic episode in symptomatic individuals depends on the mutation (see Genotype-Phenotype Correlations) and gender; on average, onset is earlier by two to three years in females than in males. Generally, the frequency of attacks is highest between ages 15 and 35 years and then decreases with age.The major factors triggering attacks are carbohydrate-rich meals and rest after exercise. The triggering threshold appears to differ from one individual to another, some having a small number of attacks in their lifetime, triggered by a very unusual effort, a significant stress, a long trip, or a medical intervention (such as glucose perfusion or surgery); and others having frequent crises, triggered by ordinary nocturnal rest (crises often begin during the night or at awakening), rest following participation in sports, digestion of a carbohydrate meal, or menstruation.Acute paralytic crises usually last at least several hours and sometimes several days. In some affected individuals, abortive or full attacks in close succession may lead to permanent muscle weakness and severe handicap, including inability to play sports or even to perform routine daily activities [Links et al 1990].Between paralytic attacks, some individuals experience subacute weakness that may be reversed by treatment with potassium salts and acetazolamide or may resolve spontaneously. It may be difficult to differentiate this subacute weakness from the permanent muscle weakness of the myopathic form. By contrast, some individuals have no limitation of activity or exercise between attacks. Severity of disability in HOKPP thus varies both over the individual's lifetime and between individuals.Myopathic form. The myopathic form of HOKPP, which develops in approximately 25% of individuals with HOKPP, results in a progressive, fixed muscle weakness that begins at extremely variable ages as exercise intolerance predominantly in the lower limbs. Muscle weakness occurs independent of paralytic symptoms and may be the sole manifestation of HOKPP [Buruma & Bots 1978].Increased risk for malignant hyperthermia (MH). Individuals with HOKPP have an increased risk of unknown magnitude for malignant hyperthermia, though not as great a risk as in those individuals with true autosomal dominant malignant hyperthermia susceptibility. Results of in vitro contracture tests performed on muscle obtained from individuals with HOKPP are not abnormal but are often equivocal [Lehmann-Horn & Iaizzo 1990, Lambert et al 1994], and three individuals with HOKPP who developed malignant hyperthermia have been reported to date [Lambert et al 1994, Rajabally & El Lahawi 2002, Marchant et al 2004]; however, in one individual, the cause was clearly a coincidental mutation in RYR1 [Marchant et al 2004] (see Prevention of Secondary Complications). Increased risk for pre- or post-anesthetic weakness. Individuals with HOKPP are often reported to have pre- or post-anesthetic weakness [Siler & Discavage 1975, Horton 1977, Melnick et al 1983], the risk for which requires preventive measures and careful anesthetic follow-up (see Management).Muscle histology. Histologic findings associated with the myopathy may depend on the specific mutation. In individuals with the p.Arg528His CACNA1S mutation, it usually consists of vacuoles. Two male members of a family with the p.Arg672Gly SCNA4 mutation presented only with tubular aggregates [Sternberg et al 2001].
Age of onset of paralytic attacks. Retrospective analysis of a significant number of probands with the p.Arg528His or p.Arg1239His mutation in CACNA1S or the p.Arg672His mutation in SCN4A allows definition of trends for the age of onset for each mutation:...
Genotype-Phenotype CorrelationsAge of onset of paralytic attacks. Retrospective analysis of a significant number of probands with the p.Arg528His or p.Arg1239His mutation in CACNA1S or the p.Arg672His mutation in SCN4A allows definition of trends for the age of onset for each mutation:Age of onset is lower for individuals with the p.Arg1239His mutation (age 10±5 years [Sternberg et al 2001]; age 7±4 years [Miller et al 2004]) than for individuals with the p.Arg528His mutation (age 14±3 years [Sternberg et al 2001]; age 14±5 years [Miller et al 2004]).Mean age of onset is higher for individuals with SCN4A mutations (age 16±5 years [Sternberg et al 2001, Miller et al 2004]).A case of de novo p.Arg897Ser mutation in CACNA1S was associated with an unusually young age of onset [Chabrier et al 2008]Serum concentration of potassium during paralytic attacks. In the series of Miller et al [2004], the serum concentration of potassium noted during paralytic attacks is the lowest for the p.Arg1239His mutation in CACNA1S (1.9±0.4 mmol/L), higher for the SCN4A mutations (2.2±0.8 mmol/L), and still higher for the p.Arg528His mutation in CACNA1S (2.9±0.7 mmol/L). Conversely, Sternberg et al [2001] found that percritic serum concentration of potassium was lower for individuals with the p.Arg528His mutation (1.69±0.49 mmol/L) than for individuals with the p.Arg1239His mutation (2.23±0.86 mmol/L).Frequency, duration, and triggering factors of paralytic attacks. Miller et al [2004] showed that:Frequency of attacks did not differ among symptomatic individuals with the p.Arg528His or p.Arg1239His mutation in CACNA1S or with SCN4A mutations.Duration of attacks was shorter in individuals with SCN4A mutations (average: 1 hour) than in individuals with either CACNA1S mutation (average: 10 hours). The most frequent precipitant of attacks was:Rest after exercise for individuals with the p.Arg1239His mutation or an SCN4A mutationHigh carbohydrate meal or sweets for individuals with the p.Arg528His mutation.Response to treatment. Response to acetazolamide may also be mutation dependent:SCN4A. Treatment with acetazolamide resulted in exacerbation of symptoms in several individuals in a family with the p.Arg672Gly mutation [Sternberg et al 2001] and one individual with the p.Arg672Ser mutation [Bendahhou et al 2001]. However, Venance et al [2004] showed that exacerbation of symptoms by acetazolamide was not predictable in individuals with SCN4A mutations, as symptoms improved in at least four individuals with either the p.Arg669His or p.Arg672Ser mutation. Treatment was not effective in a Chinese individual with the p.Arg672His mutation [Ke et al 2006].CACNA1S. Acetazolamide treatment is frequently beneficial in individuals with the p.Arg528His or p.Arg1239His mutations.Muscle histologyCACNA1S. Vacuoles (or less frequently, nonspecific myopathic changes), but not tubular aggregates, were the histologic lesions seen in individuals with the p.Arg528His or p.Arg1239His mutation.SCN4A. Tubular aggregates seem to be the main histologic lesion in individuals with the p.Arg672Gly mutation [Sternberg et al 2001]; however, vacuoles may be the main lesion in those with other SCN4A mutations [Miller et al 2004].
Hypokalemic periodic paralysis (HOKPP) is the most common cause of periodic paralysis. Four major differential diagnoses exist:...
Differential DiagnosisHypokalemic periodic paralysis (HOKPP) is the most common cause of periodic paralysis. Four major differential diagnoses exist:Normo- and hyperkalemic paralysis(normo/HyperPP) differ in several ways from HOKPP:Serum concentration of potassium during the paralytic attacks is normal or elevated.Some triggering factors for HOKPP attacks (e.g., carbohydrate-rich meals) are not found.Age of onset of paralytic attacks is lower.Duration of attacks is usually shorter.Electromyography shows myotonic discharges in most individuals between attacks; however, the response patterns for short exercise test (SET) and long exercise test (LET) may be indiscernible; i.e., pattern IV or V defined by Fournier et al [2004] may be caused by both hypokalemic and normo/hyperkalemic periodic paralysis.HyperPP type 1 is caused by point mutations in SCN4A encoding the voltage-gated skeletal muscle sodium channel. Usually, the distinction between HOKPP and normo/hyperPP can be made on the basis of clinical, biologic (percritic kalemia), and EMG findings and confirmed by molecular genetic testing [Miller et al 2004, Vicart et al 2004].Thyrotoxic periodic paralysis (TPP) is most often not familial, but in some instances there may be a familial predisposition. The clinical and biologic picture of TPP is identical to that of the paralytic episodes of HOKPP. Furthermore, the EMG response patterns for SETs and LETs (i.e., patterns IV or V defined by Fournier et al [2004]) for familial genetic HOKPP and TPP are identical when thyrotoxicosis is present. Males of Asian origin, and possibly people of Latin American and Afro-American origin, are at greater risk than people of other ethnic/racial origins for developing periodic paralysis as a consequence of thyrotoxicosis.Although TPP is not usually caused by classic HOKPP-causing mutations [Dias da Silva et al 2002b, Ng et al 2004], the association of TPP with genetically-defined HOKPP and normoPP has been reported [Lane et al 2004, Vicart et al 2004]. An association with CACNA1S 5'UTR and intronic SNPs has been suggested but not confirmed [Kung et al 2004].Because thyrotoxicosis may be a precipitating factor of genetically defined hypokalemic or normokalemic periodic paralysis [Lane et al 2004, Vicart et al 2004], the following should be measured in anyone with weakness and hypokalemia:Plasma thyroid-stimulating hormone (TSH) (reference range: 0.45-4.5 µU/mL)Free thyroxine (FT4) (reference range: 8.0-20.0 pg/mL)Free triiodothyronine (FT3) (reference range: 1.4-4.0 pg/mL)Note: Low TSH together with high FT3 and FT4 are diagnostic of hyperthyroidism. Treatment of hyperthyroidism cures TPP.Andersen-Tawil syndrome in its full clinical presentation is characterized by developmental abnormalities (short stature, scoliosis, tapered curved fingers, hypertelorism [wide-set eyes], micrognathia, broad forehead, cleft palate, missing teeth), periodic weakness, and long QT interval predisposing to ventricular tachyarrhythmias, together with episodes of hypo-, normo-, or hyperkalemic weakness [Andersen et al 1971]. Incomplete clinical presentations are possible: Andersen-Tawil syndrome may express itself as pure HOKPP. An electrocardiogram or a Holter-ECG recording between attacks of weakness is necessary to evaluate for the possibility of Andersen-Tawil syndrome. The EMG response patterns for short and long exercise tests may be identical; i.e., patterns IV or V defined by Fournier et al [2004] may be caused by Andersen-Tawil syndrome as well as HOKPP. Mutations in KCNJ2 are causative [Plaster et al 2001]. Inheritance is autosomal dominant with reduced penetrance and variable expressivity.Hypokalemia caused by reduced potassium intake, enhanced renal excretion, or digestive loss. Because the clinical manifestations of hypokalemia are mainly muscle weakness, it may be difficult, in some cases, to discriminate between a paralytic attack of HOKPP and an episode of weakness associated with hypokalemia of another cause. In that case, the diagnosis relies on the correct interpretation of findings such as blood pressure, urinary concentration of potassium, and blood concentration of bicarbonate (Table 2).See also Testing, Transtubular potassium concentration gradient and potassium-creatinine ratio during paralytic attack.Table 2. Orientation for Detection of Cause of Secondary HypokalemiaView in own windowBlood PressureUrinary PotassiumBlood BicarbonateDiagnostic ExplanationsHigh Primary or secondary inappropriate (pseudo) hyperaldosteronism Secondary hyperaldosteronism (increased renin blood concentration): renin secreting tumor, renal artery stenosis, malignant hypertension Hyperglucocorticism (normal renin blood concentration) Licorice (normal renin blood concentration)>25 mmol/LHighLiddle syndrome (tubulopathy)Normal<25 mmol/LHighPast treatment with diureticsLow or normal Gastrointestinal losses Insufficient potassium intake>25 mmol/LHighVomiting Present treatment with diuretics Bartter syndrome (tubulopathy with normo- or hypercalcuria, normomagnesemia) Gitelman syndrome (tubulopathy with hypocalciuria, hypomagnesemia)LowDistal tubular acidosis type 1, 2 (but not 4, in which there is hyperkalemia) Diabetic acidosis
To establish the extent of disease in an individual diagnosed with hypokalemic periodic paralysis (HOKPP), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with hypokalemic periodic paralysis (HOKPP), the following evaluations are recommended:Neurologic examination to assess muscle strength in the legsMeasurement of the following thyroid functions:Plasma thyroid-stimulating hormone (TSH)Free thyroxine (FT4)Free triiodothyronine (FT3)Treatment of ManifestationsParalytic crisis. The treatment of a paralytic crisis in an individual with HOKPP has two aims: (1) to normalize the serum concentration of potassium; and, (2) to shorten the paralytic episode. Normalization of the serum concentration of potassium and resolution of muscle weakness are not strictly parallel. The serum concentration of potassium may normalize several hours before weakness begins to resolve.Treatment of the paralytic crisis is thus far from perfect, as the only tool is the administration of potassium by mouth or IV, which treats the hypokalemia directly but the weakness only indirectly:Potassium in doses of 0.2 to 0.4 mmol/kg is administered orally every 15 to 30 minutes over one to three hours.If the individual is unable to swallow or does not tolerate potassium by mouth, potassium may be administered intravenously. In that case, it must be diluted in 5% mannitol rather than in glucose or sodium chloride, which trigger crises in individuals with HOKPP. The concentration of potassium administered intravenously must not exceed 40 mmol/L, and the flow must not exceed 20 mmol/hour or 200-250 mmol/day; administration must be stopped when the serum potassium concentration is normalized, even if weakness persists.Because the hypokalemia and subsequent changes in potassium concentration induced by treatment may result in cardiac arrhythmias, it is important to monitor the electrocardiogram (ECG) before, during, and after treatment and to have repeated assessment of blood potassium concentration. In particular, a prominent increase in the amplitude of the U wave on ECG, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as torsades de pointes. Some individuals exhibit serious arrhythmias with only mild hypokalemia.Monitoring of the ECG and blood potassium concentration must be continued some hours after normalization of the serum potassium concentration, in order to detect a relapse of hypokalemia or development of hyperkalemia secondary to an excessive potassium load.Myopathy. No preventive or curative treatment is known for fixed myopathy in HOKPP. The prevention of paralytic attacks does not seem to prevent the development of myopathy. The effects of muscle weakness are managed as in other disorders with similar manifestations.Prevention of Primary ManifestationsPreventive treatment is intended to decrease the frequency and intensity of paralytic attacks. Triggering factors need to be identified and, if possible, avoided.A diet rather low in sodium and carbohydrate and rich in potassium is recommended.Oral intake of potassium salts (10-20 mmol/dose, three doses/day) can prevent attacks, especially if the dose of potassium is taken some hours before the usual time of the attack (i.e., a nocturnal dose if crises occur at awakening).Acetazolamide is highly effective in individuals with the CACN1AS mutations p.Arg528His and p.Arg1239His. However, the role of acetazolamide in treating individuals with SCN4A mutations is less clear; although it may aggravate crises in individuals with the p.Arg672Gly and p.Arg672Ser mutations, it may be effective in individuals with other SCN4A mutations [Venance et al 2004]. Acetazolamide is started at 125 mg/day and may be increased over some weeks to as much as 1000 mg/day. Sufficient fluid intake must be maintained during treatment in order to prevent the development of renal calculi.Alternatives to acetazolamide. If acetazolamide is not tolerated or if it is not effective after prolonged use, alternatives include dichlorphenamide (50-200 mg/day), triamterene (50-150 mg/day), and spironolactone (25-100 mg/day).Prevention of Secondary ComplicationsPre- or postoperative paralysis. Because of the risk of paralysis preceding or following anesthesia, precautions should be taken during administration of anesthesia to individuals with HOKPP. Individuals with HOKPP should be considered as susceptible to malignant hyperthermia and managed with a non-triggering anesthetic technique, although general anesthesia using volatile anesthetics and succinylcholine has been reported as safe in a small number of individuals with HOKPP.General guidelines for perioperative care include the following [Hofer et al 2001]:Close control of serum potassium concentrationLow carbohydrate intakeAvoidance of large glucose and salt loadsMaintenance of body temperature and acid-base balanceCareful use of neuromuscular blocking agents with continuous monitoring of neuromuscular functionSurveillanceThe frequency of consultations needs to be adapted to the individual's signs and symptoms and response to preventive treatment. Neurologic examination with attention to muscle strength in the legs should be performed, in order to detect permanent weakness associated with myopathy.Questionnaires completed by the affected individual may be used to evaluate disease severity without treatment and/or response to medication.Agents/Circumstances to AvoidFactors such as the following can trigger paralytic attacks and thus should be avoided when possible:Unusually strenuous effortExcess of carbohydrate-rich mealsSweetsAlcoholOral or intravenous corticosteroids may induce paralytic attacks and should be used with care in individuals with HOKPP.Glucose infusion may induce paralytic attacks and should be replaced by another type of infusion.Evaluation of Relatives at RiskWhen a disease-causing mutation is identified in a proband, molecular genetic testing of at-risk, asymptomatic family members is appropriate because of the risk for unexpected acute paralysis and/or malignant hyperthermia.When the results of presymptomatic testing are not known, the at-risk family members must be considered at risk for complications; and precautions must be taken, particularly in the administration of anesthesia and avoidance of risk factors.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hypokalemic Periodic Paralysis: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSCN4A17q23.3Sodium channel protein type 4 subunit alpha Sodium channel, voltage-gated, type IV, alpha subunit (SCN4A) @ LOVDSCN4ACACNA1S1q32.1Voltage-dependent L-type calcium channel subunit alpha-1SCalcium channel, voltage-dependent, L type, alpha 1S subunit (CACNA1S) @ LOVDCACNA1SData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hypokalemic Periodic Paralysis (View All in OMIM) View in own window 114208CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1S SUBUNIT; CACNA1S 170400HYPOKALEMIC PERIODIC PARALYSIS, TYPE 1; HOKPP1 603967SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, ALPHA SUBUNIT; SCN4AMolecular Genetic PathogenesisVoltage-gated ion channels are transmembrane proteins that share a common structure and were highly conserved throughout evolution [Catterall 1988, Ackerman & Clapham 1997, Greenberg 1997, Celesia 2001]. Sodium and calcium channels consist of a major alpha subunit responsible for most of the channel properties and of accessory subunits that have regulatory roles. Alpha subunits are made of four domains (DI to DIV), each of them comprising six transmembrane segments (S1 to S6). The four domains cooperate in forming the ion pore. Upon depolarization, modification of the channel protein conformation allows ion fluxes through the plasma membrane by opening the ion pore (activation). Activation of the channel is promptly followed by closure of the pore (inactivation). Inactivation of voltage-gated ion channels may occur on the timescale of milliseconds (fast inactivation) or seconds (slow inactivation).The voltage-gated calcium channel of the skeletal muscle (Cav 1.1) is located in the T-tubule of the muscle fibers and is responsible for L-type calcium currents. It has the double function of regulating calcium entry into the muscle fiber and coupling (via voltage detection) muscle excitation and contraction. HOKPP-causing mutations are found in the S4 segment of both domain II (p.Arg528His) and domain IV (p.Arg1239Gly and p.Arg1239His). Segment S4 consists of a ring of positive charges every three amino acids and is thought to be the voltage sensor of the channel. Both mutations in segment 4 of domains II and IV replace a positively charged amino acid by a lesser charged amino acid. So far, segments 4 of domains II and IV are the only sites in the voltage-gated calcium channel in which mutations causing HOKPP have been described. Possible biophysical defects specific to CACNA1S mutations have been investigated by in vitro patch-clamp-based electrophysiologic studies of transiently or persistently transfected cells expressing mutated channels. HOKPP-causing mutations in CACNA1S result in a half-reduced calcium current density and a slowing in the rate of activation [Morrill & Cannon 1999]. A more recent investigation on homologous mutations of the cardiac rabbit channel confirmed those loss-of-function features [Kuzmenkin et al 2007]The voltage-dependent sodium channel of the skeletal muscle (Nav 1.4) is activated by membrane depolarization and is responsible for the upstroke of the action potential. It therefore plays a key role in muscle contraction, allowing a proper propagation of the action potential along the muscle membrane. Mutations causing HOKPP concern only the voltage-sensitive segment S4 of domain II of the sodium channel alpha subunit and change positively charged arginines to non-charged amino acid residues. Possible biophysical defects specific to SCN4A mutations have been investigated by in vitro patch-clamp-based electrophysiologic studies of transiently or persistently transfected cells expressing mutated channels. HOKPP-causing mutations in SCN4A enhance fast [Jurkat-Rott et al 2000b, Kuzmenkin et al 2002] and/or slow [Struyk et al 2000, Kuzmenkin et al 2002] inactivation and reduce current density [Jurkat-Rott et al 2000b]. Altogether, those defects reduce the fraction of available noninactivated sodium channels at the resting potential.Flaccid weakness in both types of HOKPP, as well as in hyperPP (see Hyperkalemic Periodic Paralysis), is caused by a paradoxical sustained membrane depolarization [Cannon 2002]. Paroxystic membrane depolarization in HOKPP is partially or totally coupled with paroxystic hypokalemia resulting from the transfer of potassium from the extracellular to the intracellular compartment of skeletal muscle cells, and with subtle hormonal changes. In HOKPP type 1 as well as in HOKPP type 2, muscle paradoxically depolarizes in response to hypokalemia, whereas normal muscle hyperpolarizes [Ruff 1999, Jurkat-Rott et al 2000b]. This paradoxical depolarization may be made possible by a reduction of inward rectifier potassium currents [Ruff 1999] and especially ATP-sensitive potassium channels [Tricarico et al 1999].Recent progress has been made in understanding the pathophysiology of HOKPP, by showing that HOKPP-causing mutations in Nav 1.4 S4 segments create an abnormal gating pore current, i. e. an accessory ionic transmembrane permeation pathway through the aqueous environment of S4 segment [Sokolov et al 2005, Sokolov et al 2007, Struyk & Cannon 2007]. This current is a low-amplitude inward current at the resting potential, and varies in its amplitude and selectivity according to the precise mutation and to the physiologic or pathologic conditions, thus contributing to membrane depolarization in pathologic circumstances [Struyk et al 2008]CACNA1SNormal allelic variants. CACNA1S has 44 exons.Pathologic allelic variants. See Table 3. The following are associated with HOKPP:c.1583G>A, p.Arg528Hisc.1582C>G, p.Arg528Glyc.3715C>G, p.Arg1239Glyc.3716G>A, p.Arg1239HisTable 3. Selected CACNA1S Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1583G>Ap.Arg528HisNM_000069.2 NP_000060.2c.1582C>Gp.Arg528Glyc.2691G>Tp.Arg897Serc.3716G>Ap.Arg1239Hisc.3715C>Gp.Arg1239Glyc.3256C>Tp.Arg1086Cys 1c.3257G>Ap.Arg1086His 1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Mutations associated with autosomal dominant malignant hyperthermia susceptibility [Monnier et al 1997, Jurkat-Rott et al 2000a]Normal gene product. CACNA1S codes for the voltage-dependent L-type calcium channel alpha-1S subunit.Normal gene product. See Molecular Genetic Pathogenesis.SCN4ANormal allelic variants. SCN4A has 24 exons.Pathologic allelic variants. See Table 4. Table 4. Selected SCN4A Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencec.2006G>Ap.Arg669HisNM_000334.4 NP_000325.4c.2014C>Ap.Arg672Serc.2014C>Gp.Arg672Glyc.2014C>Tp.Arg672Cysc.2015G>Ap.Arg672Hisc.3395 G >Ap.Arg1132Glnc.[4468T>C+4479G>A]p.[Phe1490Leu + Met1493Ile] 1c.3917G>Cp.Gly1306Ala 2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Mutation associated with hyperkalemic periodic paralysis with or without malignant hyperthermia susceptibility (see Genetically Related Disorders) [Bendahhou et al 2000]2. Mutation associated with masseter rigidity (see Genetically Related Disorders) [Vita et al 1995]Normal gene product. SCN4A codes for the sodium channel protein type 4 subunit alpha.Normal gene product. See Molecular Genetic Pathogenesis.