Cardiodysrhythmic potassium-sensitive periodic paralysis (Andersen-Tawil syndrome) is a sub-type of familial long QT syndrome. Patients with mutations in the KCNJ2 gene are designated as ATS type 1 (LQT7), whereas patients with unknown mutations are designated as ATS type 2 (PMID:24383070). Recently, a mutation in KCNJ5 has been described (PMID:24574546). It is characterized by cardiac arrhythima, muscle weakness (periodic paralysis) and craniofacial and skeletal anomalies (PMID:20301308).
Andersen-Tawil syndrome is an autosomal dominant multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, and distinctive dysmorphic facial or skeletal features. Hypoplastic kidney and valvular heart disease have also been reported. The disorder shows marked intrafamilial variability and ... Andersen-Tawil syndrome is an autosomal dominant multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, and distinctive dysmorphic facial or skeletal features. Hypoplastic kidney and valvular heart disease have also been reported. The disorder shows marked intrafamilial variability and incomplete penetrance (summary by Davies et al., 2005).
Tawil et al. (1994) used the designation Andersen syndrome for a clinical triad consisting of potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. (This Andersen syndrome is not to be confused with Andersen disease, type IV glycogen storage ... Tawil et al. (1994) used the designation Andersen syndrome for a clinical triad consisting of potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. (This Andersen syndrome is not to be confused with Andersen disease, type IV glycogen storage disease (232500).) They found reports of 10 patients and added 4 new patients in 3 kindreds. All the patients had potassium-sensitive periodic paralysis without myotonia indistinguishable from other forms of hyperkalemic periodic paralysis (170500). In 1 family, a 45-year-old mother and her 22-year-old son were affected. The son had short stature, low-set ears, hypoplastic mandible, clinodactyly, and scoliosis. The mother was said to have the same dysmorphic features. Tawil et al. (1994) emphasized the variability of both the dysmorphic features and the cardiac manifestations. A variable prolongation of the QT interval, ventricular bigeminy, and short runs of bidirectional ventricular tachycardia were observed. Sudden death in this syndrome was reported by Levitt et al. (1972). Andersen et al. (1971) reported the case of an 8-year-old boy who was short of stature and had hypertelorism, broad nasal root, mandibular hypoplasia, scaphocephaly, and clinodactyly V, as well as a defect of the soft and hard palate. Stubbs (1976) described a 31-year-old housewife with bidirectional ventricular tachycardia whose mother died of 'heart failure' at age 37. Kramer et al. (1979) described a 19-year-old man who had episodes of cardiac dysfunction associated with tetraparesis. A brother had died at age 16 from a heart condition and an older surviving brother suffered from a 'heart condition' similar to that in the proband. The father had experienced attacks of weakness that decreased in frequency with advancing age. Tawil et al. (1994) showed that the Andersen syndrome is distinct from other forms of potassium-sensitive periodic paralysis by demonstrating lack of genetic linkage and concluded that it is probably distinct from the long QT syndrome (192500) on the same basis. Sansone et al. (1997) reported 11 patients from 5 kindreds with the classic triad of potassium-sensitive periodic paralysis, ventricular arrhythmia, and an unusual facial appearance. In these patients, periodic paralysis was associated with low, normal, or high serum potassium levels. A long QTc was observed in almost every case, suggesting this as a minimal diagnostic sign. Canun et al. (1999) suggested that recognition of the characteristic face in Andersen syndrome permits an early diagnosis and the detection of the severe systemic manifestations associated with the syndrome. They described a family in which 10 persons in 3 generations had Andersen syndrome. Facial photographs of 10 affected members of the family were presented. Severity of the facial involvement was not correlated with the severity of heart or muscle involvement of the affected members. Age of onset of periodic paralysis ranged from 4 to 18 years. All affected members with periodic paralysis were responsive to oral potassium except 1, who had normal potassium levels during an attack of paralysis. Two members of the family had no periodic paralysis but had hyperthyroidism. Canun et al. (1999) found a long QTc in only 3 of 8 affected members studied. Canun et al. (1999) did not find short stature; low weight and a slender constitution were found in several relatives. Tristani-Firouzi et al. (2002) presented extensive clinical and in vitro electrophysiologic studies on a total of 17 kindreds with 10 different mutations. Among mutation carriers, the frequency of periodic paralysis was 64% (23 of 36 individuals). Unlike hypokalemic periodic paralysis (170400), in which attacks are precipitated by carbohydrate ingestion, no consistent trigger could be identified in Andersen syndrome. Rest following physical exertion was a common trigger, as in the classic forms of periodic paralysis. At least 2 dysmorphic features were present in 28 of 36 KCNJ2 mutation carriers (78%): 14 of 36 (39%) had low-set ears, 13 of 36 (36%) had hypertelorism, 16 of 36 (44%) had small mandibles, 23 of 36 (64%) had clinodactyly, and 4 of 36 (11%) had syndactyly. Cleft palate was identified in 3 of 36 Andersen syndrome subjects (8%) and scoliosis in 4 of 36 (11%). Dysmorphic features were most often mild and nondisfiguring, and were easily overlooked on routine physical examination. This is relevant given that in individuals with cardiac involvement, one-sixth demonstrated mild dysmorphic features as the only other clue to the diagnosis of Andersen syndrome. In this series, LQT was present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. Andelfinger et al. (2002) identified a heterozygous missense mutation (R67W; 600681.0006) in the KCNJ2 gene in 41 members of a kindred with ventricular arrhythmias (13 of 16 female members, 81%) and periodic paralysis (10 of 25 male members, 40%) segregating as autosomal dominant traits with sex-specific variable expressivity. Some mutation carriers exhibited dysmorphic features, including hypertelorism, small mandible, syndactyly, clinodactyly, cleft palate, and scoliosis, which, together with cardiodysrhythmic periodic paralysis, constitute Andersen syndrome. However, no individual exhibited all manifestations of Andersen syndrome, and this diagnosis was not considered in the proband until other family members were examined. Other features seen in this kindred included unilateral dysplastic kidney and cardiovascular malformation (i.e., bicuspid aortic valve, bicuspid aortic valve with coarctation of the aorta, or valvular pulmonary stenosis), which had not previously been associated with Andersen syndrome. Nonspecific electrocardiographic abnormalities were identified in some individuals, but none had a prolonged QT interval. Davies et al. (2005) reported 22 affected individuals from 11 unrelated families with ATS. Most patients showed the common clinical triad of hypokalemic periodic paralysis, ventricular arrhythmias, and dysmorphic features, such as hypertelorism, broad-based nose, hypoplastic mandible, and clinodactyly. Other unusual clinical features included poor dentition with abnormal enamel formation in 2 families, high-pitched voice in 1 family, learning disabilities in 1 family, gait ataxia in 1 patient, and renal tubular defects in 1 patient, Genetic analysis identified 9 different pathogenic mutations in the KCNJ2 gene, including 6 novel mutations. In vitro functional expression studies of 5 of the mutant proteins showed a dominant-negative effect on the wildtype allele. In a father and 2 daughters with Andersen syndrome, Lu et al. (2006) identified heterozygosity for a missense mutation in the KCNJ2 gene (T75R; 600681.0011). The mutation was not found in the girls' unaffected mother and brother. In vitro studies revealed that the mutant channel was nonfunctional, and T75R transgenic mice had bidirectional ventricular tachycardia after induction and longer QT intervals. All 3 affected individuals had ventricular arrhythmias and dysmorphic features, but only 2 had periodic paralysis. None of the family members had a prolonged QTc interval, but prominent U waves could be observed in the 3 affected members. Yoon et al. (2006) prospectively evaluated 10 individuals with confirmed mutations in the KCNJ2 gene and identified a characteristic pattern of craniofacial features and dental and skeletal anomalies. These included broad forehead, short palpebral fissures, relatively long nose with fullness along the bridge and bulbous tip, malar, maxillary, and mandibular hypoplasia, thin upper lip, high-arched or cleft palate, triangular facies, and mild facial asymmetry. Dental anomalies were identified in all patients and consisted of delayed eruption of permanent dentition, oligodontia, and dental root anomalies. Jaw characteristics included small maxilla and mandible, narrow upper and lower dental arches, and antegonial notching of the lower border of the mandible. Skeletal anomalies included hand and foot size at the lower limits of normal, brachydactyly, 2-3 toe syndactyly, and toe clinodactyly. Yoon et al. (2006) proposed that the diagnostic dysmorphology criteria of ATS be extended to include these features. Bendahhou et al. (2007) reported 2 unrelated families with periodic paralysis and cardiac dysrhythmias without significant dysmorphic features. The 19-year-old male proband in 1 family had a small chin but no other noticeable dysmorphism. His first episode of periodic paralysis was triggered by corticosteroid treatment of a skin condition, with improvement after discontinuation of corticosteriods; since that time, he had several more attacks, including another one triggered by corticosteroids. Electromyography showed a typical hypokalemic periodic paralysis pattern. The other proband was a 23-year-old woman with no noticeable dysmorphic features who had difficulty playing sports in childhood, with pain in the lower extremities that made it difficult to walk for a few days afterward. On examination, she had full strength of upper limbs but a permanent motor deficit of the lower limbs. Electrocardiography showed ventricular arrhythmia, bidirectional tachycardia, and extrasystoles. Her mother, maternal aunt, and maternal grandmother all had a history of cardiac arrhythmias, and the grandmother had a pacemaker.
In a kindred with Andersen syndrome showing linkage to 17q23, Plaster et al. (2001) identified a missense mutation in the KCNJ2 gene (600681.0001). They identified 8 additional mutations in the KCNJ2 gene in unrelated patients with Andersen syndrome ... In a kindred with Andersen syndrome showing linkage to 17q23, Plaster et al. (2001) identified a missense mutation in the KCNJ2 gene (600681.0001). They identified 8 additional mutations in the KCNJ2 gene in unrelated patients with Andersen syndrome (see, e.g., 600681.0002-600681.0005). Using targeted mutation, Lopes et al. (2002) established that mutations in KCNJ2 residues decreased the strength of channel interactions with phosphatidylinositol 4,5-bisphosphate (PIP2). They concluded that a decrease in channel-PIP2 interactions underlies the molecular mechanism of Andersen syndrome when these mutations are present in patients. Among 17 unrelated probands with clinical symptoms of ATS, Donaldson et al. (2003) identified 8 different mutations, including 6 novel mutations, in the KCNJ2 gene in 9 probands. Six probands possessed mutations of residues implicated in binding membrane-associated PIP2. Including previous reports, the authors determined that mutations in PIP2-related residues accounted for disease in 18 of 29 (62%) reported families with KCNJ2-related ATS. Donaldson et al. (2003) found no phenotypic differences between patients with mutations in the PIP2-related residues and those with mutations elsewhere in the gene. The authors suggested that genetic heterogeneity likely exists for this disorder. Choi et al. (2007) identified 2 different heterozygous missense mutations in the KCNJ2 gene in affected members of 2 Korean families with Andersen-Tawil syndrome. The authors stated that this was the first report of causative mutations in KCNJ2 in Korean ATS patients. In 2 unrelated probands with periodic paralysis and cardiac dysrhythmias, who were known to be negative for common CACNA1S and SCN4A mutations causing hypokalemic periodic paralysis, Bendahhou et al. (2007) identified heterozygosity for 2 different missense mutations in the KCNJ2 gene (600681.0012 and 600681.0013, respectively). Bendahhou et al. (2007) noted that except for a small chin in 1 proband, there were no dysmorphic features in these families, and suggested that KCNJ2 should be screened in patients with periodic paralysis even when the classic dysmorphic features of Andersen syndrome are not present.
The diagnosis of Andersen-Tawil syndrome (ATS) is suspected in individuals with either A or B: ...
DiagnosisClinical DiagnosisThe diagnosis of Andersen-Tawil syndrome (ATS) is suspected in individuals with either A or B: A.Two of the following three criteria:Periodic paralysis Symptomatic cardiac arrhythmias or electrocardiographic (ECG) evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval Characteristic facies, dental anomalies, small hands and feet, and at least two of the following: Low-set ears Widely spaced eyesSmall mandible Fifth-digit clinodactyly Syndactyly B.One of the above three in addition to at least one other family member who meets two of the three criteria [Tawil et al 1994, Sansone et al 1997, Tristani-Firouzi et al 2002].The presence of a pathogenic KCNJ2 sequence variant confirms the diagnosis of Andersen-Tawil syndrome type 1 (ATS1).TestingSerum potassium concentration during episodes of weakness may be elevated, normal, or, most commonly, reduced (<3.5 mmol/U) [Tawil et al 1994, Sansone et al 1997, Canún et al 1999, Tristani-Firouzi et al 2002]. Routine nerve conduction electrophysiology is normal between episodes. A more sensitive electrophysiologic study, the long exercise protocol, may reveal an immediate post-exercise increment followed by an abnormal decrement in the compound motor action potential amplitude (>40%) [Katz et al 1999] or area (>50%) 20-40 minutes post-exercise [Kuntzer et al 2000, Fournier et al 2004]. In a study of 11 individuals with ATS, 82% met long-exercise amplitude decrement criteria for abnormal testing [Tan et al 2011].Electrocardiogram may reveal characteristic abnormalities including prominent U waves, prolonged Q-U intervals, premature ventricular contractions, polymorphic ventricular tachycardia, and bidirectional ventricular tachycardia [Zhang et al 2005]. 24-hour Holter monitoring is important to document the presence, frequency, and duration of ventricular tachycardia (VT) and the presence or absence of associated symptoms. Molecular Genetic TestingGene. KCNJ2, encoding the inward rectifier potassium channel 2 protein (Kir2.1), is the only gene in which mutations are known to cause Andersen syndrome type 1 (ATS1). Evidence for locus heterogeneity. To date, no other loci have been identified to account for ATS (termed Andersen syndrome type 2, or ATS2) in the 40% of kindreds not linked to KCNJ2.Clinical testing Table 1. Molecular Genetic Testing Used in Andersen Syndrome Type 1View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityKCNJ2Sequence analysisSequence variants 2~60% 3Clinical Mutation scanning 4UnknownDeletion / duplication analysis 5Partial- or whole-gene deletions / duplicationsUnknown, none reported1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Approximately 60% of individuals with ATS have a missense mutation or a small intragenic deletion in KCNJ2; more than 20 missense mutations have been described to date [Plaster et al 2001, Ai et al 2002, Andelfinger et al 2002, Tristani-Firouzi et al 2002, Donaldson et al 2003, Hosaka et al 2003]. The mutation p.Arg218Trp is considered a potential hotspot for disease-causing mutations [Davies et al 2005]. 4. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead ECG, a 24-hour Holter monitor, and possibly the long exercise protocol.In approximately 60% of individuals, molecular genetic testing confirms the clinical diagnosis (see Genotype-Phenotype Correlations). To date there is no known role for routine deletion/duplication analysis. 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) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with mutations in KCNJ2.
Andersen-Tawil syndrome (ATS) is characterized by the triad of episodic flaccid muscle weakness, distinctive dysmorphic features, and ventricular arrhythmias and prolonged QT interval. Affected individuals present initially with either periodic paralysis or cardiac symptoms (palpitations and/or syncope) in the first or second decade [Tawil et al 1994, Tristani-Firouzi et al 2002]; however, prospective standardized natural history data are not yet available. ...
Natural HistoryAndersen-Tawil syndrome (ATS) is characterized by the triad of episodic flaccid muscle weakness, distinctive dysmorphic features, and ventricular arrhythmias and prolonged QT interval. Affected individuals present initially with either periodic paralysis or cardiac symptoms (palpitations and/or syncope) in the first or second decade [Tawil et al 1994, Tristani-Firouzi et al 2002]; however, prospective standardized natural history data are not yet available. Intermittent weakness occurs spontaneously, or alternatively may be triggered by prolonged rest or rest following exertion. The attack frequency, duration, and severity are variable between and within affected individuals. Mild permanent weakness is common [Tawil et al 1994, Sansone et al 1997, Canún et al 1999, Tristani-Firouzi et al 2002]. Ventricular arrhythmias, including bidirectional ventricular tachycardia (VT), polymorphic VT, and multifocal premature ventricular contractions may be asymptomatic or manifest as palpitations most commonly. Less common symptomatic presentations include syncope, cardiac arrest, or sudden death [Andelfinger et al 2002, Tristani-Firouzi et al 2002, Donaldson et al 2003]. While the ECG may reveal a long QTc (LQT) interval, characteristic T-U patterns including enlarged U waves, a wide T-U junction, and prolonged terminal T-wave downslope distinguish ATS1 from other LQT syndromes [Zhang et al 2005, Haruna et al 2007]. A large case series found no significant difference in the incidence of ventricular tachyarrhythmias between individuals with typical and atypical presentations of ATS [Kimura et al 2012].Dilated cardiomyopathy was observed in two of three affected individuals in a single kindred with the p.Arg218Trp mutation [Schoonderwoerd et al 2006]; whether this is an uncommon phenotypic manifestation or a consequence of chronic tachycardia remains to be seen [Tristani-Firouzi 2006]. Distinctive physical features recognized initially included low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, broad nasal root, and scoliosis [Andersen et al 1971, Tristani-Firouzi et al 2002, Donaldson et al 2003]. Dental enamel discoloration was noted in two kindreds with the p.Gly300Asp and p.Arg218Trp mutations [Davies et al 2005]. Detailed, prospectively collected data in ten individuals with confirmed KCNJ2 mutations have expanded the phenotype to include a characteristic facies and dental and skeletal anomalies [Yoon et al 2006a]. Characteristic facies include broad forehead, short palpebral fissures, full nasal bridge with bulbous tip, hypoplasia of maxilla and mandible, thin upper lip, and a triangular shape. Dental findings include (among others) persistent primary dentition, multiple missing teeth (oligodontia), and dental crowding. Skeletal findings include mild syndactyly of toes 2 and 3 as well as fifth-digit clinodactyly. Novel findings include small hands and feet (<10th centile for age) and joint laxity. Isolated reports of renal anomalies include unilateral hypoplastic kidney [Andelfinger et al 2002] and renal tubular defect [Davies et al 2005]. Mild learning difficulties have been described [Davies et al 2005]. A distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) has been recognized in individuals with a KCNJ2 mutation despite IQ levels similar to those of their unaffected sibs [Yoon et al 2006b]. Afebrile seizures occurring only in infancy were reported in 4/23 (17%) of a Japanese cohort with ATS1 [Haruna et al 2007].
Individuals with clinically defined ATS are phenotypically indistinguishable, regardless of the presence of a KCNJ2 mutation (ATS1) or absence of a KCNJ2 mutation (ATS2) [Tristani-Firouzi et al 2002, Donaldson et al 2003]. ...
Genotype-Phenotype CorrelationsIndividuals with clinically defined ATS are phenotypically indistinguishable, regardless of the presence of a KCNJ2 mutation (ATS1) or absence of a KCNJ2 mutation (ATS2) [Tristani-Firouzi et al 2002, Donaldson et al 2003]. In a case series that evaluated for KCNJ2 mutations in typical (>2 ATS features) and atypical (only 1 ATS feature or catecholaminergic polymorphic ventricular tachycardia) individuals with ATS, mutation-positive rates were 75% (15/20) in those with typical ATS, 71% (5/7) in those with the cardiac phenotype alone, 100% (2/2) in those with periodic paralysis, and 7% (2/28) in those with CPVT [Kimura et al 2012].In a single large kindred with the KCNJ2 p.Arg67Trp mutation, periodic paralysis was observed only in men, cardiac symptoms only in women, and congenital anomalies in both [Andelfinger et al 2002]. However, this apparent sex-limited bias in clinical presentation has not been confirmed [Donaldson et al 2003, Davies et al 2005].
Table 2. Long QT syndrome: OMIM Phenotypic Series...
Differential DiagnosisTable 2. Long QT syndrome: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype MIM NumberGene/LocusGene/Locus MIM Number{Acquired long QT syndrome, reduced susceptibility to} 613688 ALG10, KCR1 603313 Cardiac arrhythmia, ankyrin-B-related 600919 ANK2, LQT4 106410 Long QT syndrome-1 192500 KCNQ1, KCNA9, LQT1, KVLQT1, ATFB3, SQT2 607542 {Long QT syndrome 1, acquired, susceptibility to} 192500 KCNQ1, KCNA9, LQT1, KVLQT1, ATFB3, SQT2 607542 Long QT syndrome-2 613688 KCNH2, LQT2, HERG, SQT1 152427 {Long QT syndrome-2, acquired, susceptibility to} 613688 KCNH2, LQT2, HERG, SQT1 152427 Long QT syndrome-3 603830 SCN5A, LQT3, VF1, HB1, SSS1, CMD1E, CDCD2 600163 Long QT syndrome-4 600919 ANK2, LQT4 106410 Long QT syndrome-5 613695 KCNE1, JLNS, LQT5, JLNS2 176261 Long QT syndrome-6 613693 KCNE2, MIRP1, LQT6, ATFB4 603796 Long QT syndrome-7 170390 KCNJ2, HHIRK1, KIR2.1, IRK1, LQT7, SQT3, ATFB9 600681 Long QT syndrome-9 611818 CAV3, LGMD1C, LQT9 601253 Long QT syndrome-10 611819 SCN4B 608256 Long QT syndrome-11 611820 AKAP9, YOTIAO, AKAP450 604001 Long QT syndrome 12 612955 SNT1, LQT12 601017 Long QT syndrome 13 613485 KCNJ5, GIRK4, KATP1, LQT13 600734 Timothy syndrome 601005 CACNA1C, CACNL1A1, CCHL1A1, TS 114205 Data from Online Mendelian Inheritance in ManAndersen-Tawil syndrome (ATS) should be considered in any individual presenting with periodic paralysis and ventricular arrhythmias or enlarged U waves. Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead ECG, a 24-hour Holter monitor, and possibly the long exercise protocol. The differential diagnosis depends on the initial presentation and includes the primary and secondary periodic paralyses and thyrotoxic periodic paralysis. Episodes of flaccid paralysis Hypokalemic periodic paralysis is the most common periodic paralysis. Affected individuals have episodes of reversible, flaccid paralysis associated with reduced serum potassium concentrations (<3.5 mmol/U) and/or slowly progressive proximal weakness. The onset, duration, and severity of attacks, with the associated triggers, are similar to those in individuals with ATS. Respiratory muscles are spared. Weakness is improved with oral potassium ingestion. The cardiac and dysmorphic features of ATS are, however, absent in hypokalemic periodic paralysis. Molecular testing identifies mutations in CACNA1S or SCN4A in approximately 80% of affected individuals after secondary causes such as thyrotoxicosis, diuretic use, and renal (e.g., hyperaldosteronism, distal tubular acidosis) or gastrointestinal (e.g., vomiting, diarrheal illness) causes have been ruled out. Inheritance is autosomal dominant. Hyperkalemic periodic paralysis is characterized by episodes of flaccid paralysis associated with normal or elevated ictal serum potassium concentrations (>5.0 mmol/U) and aggravated by potassium ingestion. Onset is in the first decade; episodes are briefer than those that occur in individuals with hypokalemic periodic paralysis. Electrical myotonia is evident in 50% of affected individuals. The cardiac and dysmorphic features of ATS are absent. Molecular testing reveals one of seven common mutations in SCN4A in approximately 50% of individuals. Secondary forms of hyperkalemic periodic paralysis to rule out include adrenal insufficiency, hypoaldosteronism, and adverse effects of certain medications (e.g., ACE inhibitors, spironolactone, nonsteroidal anti-inflammatory drugs). Inheritance is autosomal dominant. Thyrotoxic periodic paralysis is a consideration in any individual with severe weakness and marked hypokalemia. Men, particularly Asians, are affected in greater numbers; however, thyrotoxic periodic paralysis may be seen in all races. Diagnosis is established by measurement of serum TSH, T4, and T3 concentrations. A mutation in an inwardly rectifying potassium (Kir) channel (encoded by KCNJ18) has been identified in approximately one third of affected individuals in one series [Ryan et al 2010].Palpitations, syncope, or cardiac arrest. Syncopal episodes are often interpreted as a neurologic problem rather than arrhythmia. Physical examination and ECG should be part of the evaluation of syncope. Bidirectional ventricular tachycardia demonstrated on ECG may be seen with ATS, digitalis toxicity, and catecholaminergic polymorphic ventricular tachycardia (CPVT). A normal resting ECG with exercise-induced polymorphic arrhythmias is a clue to CPVT. Mutations in RYR2 and CASQ2 are causative. Inheritance is autosomal dominant [Tristani-Firouzi & Etheridge 2010].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Andersen-Tawil syndrome (ATS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Andersen-Tawil syndrome (ATS), the following evaluations are recommended:Baseline assessments by a neurologist and cardiologist familiar with periodic paralysis and LQT respectively Serum potassium concentrations at baseline and during attacks of weakness 12-lead ECG and 24-hour Holter monitor Electrophysiologic studies including the long exercise protocol [Kuntzer et al 2000, Fournier et al 2004] Verification that serum concentration of thyroid-stimulating hormone (TSH) is within normal limits Medical genetics consultationTreatment of ManifestationsManagement of individuals with ATS requires the coordinated input of a neurologist familiar with the treatment of periodic paralysis and a cardiologist familiar with the treatment of cardiac arrhythmias. To date, no randomized clinical therapeutic trials have been conducted on ATS.Management of attacks of episodic weakness depends on the associated serum potassium concentration:If the serum potassium concentration is low (<3.0 mmol/L), administration of oral potassium (20-30 mEq/L) every 15-30 minutes until the serum concentration normalizes often shortens the attack. Monitoring of serum potassium concentrations and ECG may be useful during potassium replacement therapy in an emergency setting to avoid secondary hyperkalemia. Attacks of weakness when serum potassium concentration is high usually resolve within 60 minutes. Episodes may be shortened by ingesting carbohydrates or continuing mild exercise. Intravenous calcium gluconate is rarely necessary for management in an individual seen in an emergency setting. Vasovagal syncope in individuals with ATS mandates a careful cardiology assessment [Airey et al 2009].Prevention of Primary ManifestationsProphylactic treatment aimed at reduction of attack frequency and severity can be achieved, as in other forms of periodic paralysis, with the following:Lifestyle and dietary modification to avoid known triggers Use of carbonic anhydrase inhibitors (acetazolamide 250-500 mg/1-2x/day or dichlorphenamide 50-100 mg/1-2x/day) Daily use of slow-release potassium supplements, which may also be helpful in controlling attack rates in individuals prone to hypokalemia. Elevating the serum potassium concentration (>4 mEq/L) has the added benefit of narrowing the QT interval, thus reducing the risk of LQT-associated arrhythmias. An implantable cardioverter-defibrillator in individuals with tachycardia-induced syncope [Chun et al 2004] Empiric treatment with flecainide [Bökenkamp et al 2007, Fox et al 2008, Pellizzón et al 2008] should be considered for significant, frequent ventricular arrhythmias in the setting of reduced left ventricular function [Tristani-Firouzi & Etheridge 2010].Prevention of Secondary ComplicationsCardiologists should be aware that some antiarrhythmic drugs, particularly class I drugs, may paradoxically exacerbate the neuromuscular symptoms and should be used cautiously in individuals with ATS. Although malignant hyperthermia has not been reported in ATS, appropriate anesthetic precautions should be undertaken as with individuals with other forms of periodic paralysis. SurveillanceFor asymptomatic individuals with a pathogenic KCNJ2 mutation, annual screening including a 12-lead ECG and 24-hour Holter monitoring is desirable, followed by referral to a cardiologist if abnormalities are identified. Agents/Circumstances to AvoidAffected individuals should avoid medications known to prolong QT intervals. See www.azcert.org [Woosley 2001] for a complete and updated list.Salbutamol inhalers, which may be used in the treatment of primary hyperkalemic periodic paralysis, should be avoided because of the potential for exacerbation of cardiac arrhythmias. Thiazide and other potassium-wasting diuretics may provoke drug-induced hypokalemia and could aggravate the QT interval.Evaluation of Relatives at Risk It is appropriate to offer molecular genetic testing to at-risk relatives if the disease-causing mutation is identified in an affected family member, so that morbidity and mortality can be reduced by early diagnosis and treatment.If the disease-causing mutation in the family is not known, it is appropriate to offer clinical diagnostic evaluations to at-risk family members in order to permit early diagnosis and treatment.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management The rarity of ATS and the paucity of reports pertaining to pregnancy in women with ATS make an evidence-based approach to pregnancy management difficult to formulate. One case study reported an uneventful pregnancy, with increased episodes of weakness but reduced ventricular ectopy compared to the pre-pregnancy period [Subbiah et al 2008]. However, as data are limited, a multidisciplinary approach to patient care and anticipation of increased risk (as can be seen in those with long QT syndrome) seems reasonable. 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. Andersen-Tawil Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDKCNJ217q24.3Inward rectifier potassium channel 2Gene Connection for the Heart - KCNJ2 KCNJ2 @ ZAC-GGM KCNJ2 homepage - Mendelian genesKCNJ2Data 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 Andersen-Tawil Syndrome (View All in OMIM) View in own window 170390ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS 600681POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 2; KCNJ2Molecular Genetic PathogenesisKCNJ2 encodes the inward rectifier potassium channel 2, or Kir2.1 [Plaster et al 2001], expressed primarily in skeletal muscle, heart, and brain. Kir2.1 is involved in setting and stabilizing the resting membrane potential in skeletal and cardiac muscle and has a major role in the terminal repolarization phase of the cardiac action potential [Plaster et al 2001, Tristani-Firouzi et al 2002]. The majority of mutations exert a dominant-negative effect on channel current [Lange et al 2003, Donaldson et al 2004, Davies et al 2005, Ballester et al 2006, Barajas-Martinez et al 2011, Marrus et al 2011]. Several mutations affect trafficking of the mutant channel to the cell surface for reasons that are not clear [Ballester et al 2006]. One study identified loss of an endoplasmic reticulum export motif [Doi et al 2011]. The majority traffic normally to the cell surface but fail to conduct normally [Bendahhou et al 2003]. Phosphatidylinositol 4,5 bisphosphate (PIP2) is an important regulator of Kir2.1 channel function; many KCNJ2 mutations alter PIP2 binding [Lopes et al 2002, Donaldson et al 2003]. Flaccid paralysis results from failure to propagate action potentials in the muscle membrane as a result of sustained membrane depolarization [Cannon 2002]. The modestly prolonged QT interval and ventricular arrhythmias are caused by impaired cardiac ventricular repolarization; the reduced inward rectifying potassium current results in distinct T-U wave morphology [Tristani-Firouzi et al 2001, Zhang et al 2005].While the role of Kir2.1 in skeletal development remains to be clarified, consistent craniofacial, dental, and skeletal anomalies are present [Yoon et al 2006a]. Targeted disruption of Kir2.1 in a knockout mouse is fatal, with complete cleft of the secondary palate [Zaritsky et al 2000]. Normal allelic variants. KCNJ2 has two exons spanning 5.4 kb. Pathologic allelic variants. See Table A, Locus Specific and HGMD. Normal gene product. KCNJ2 encodes the inward rectifier potassium channel 2 protein (Kir2.1), with 427 amino acid residues and 48-kd molecular weight. Abnormal gene product. Mutations in KCNJ2 cause dominant-negative suppression of Kir2.1 current [Plaster et al 2001, Tristani-Firouzi et al 2002] and affect channel-PIP2 interactions [Donaldson et al 2003].