NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Andersen-Tawil Syndrome

, MD, , MD, and , MD, PhD.

Author Information
, MD
Department of Neurology
University of Kansas Medical Center
Kansas City, Kansas
, MD
Department of Neurology
University of Rochester Medical Center
Rochester, New York
, MD, PhD
Department of Clinical Neurological Sciences
London Health Sciences Centre
University of Western Ontario
London, Ontario

Initial Posting: ; Last Revision: September 3, 2015.

Summary

Clinical characteristics.

Andersen-Tawil syndrome (ATS) is characterized by a triad of episodic flaccid muscle weakness (i.e., periodic paralysis), ventricular arrhythmias and prolonged QT interval, and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) have been described.

Diagnosis/testing.

The diagnosis of ATS is suspected in an individual with characteristic clinical and ECG findings. A pathogenic variant in KCNJ2, encoding the inward rectifier potassium channel 2 protein (Kir2.1), is identified in approximately 60% of individuals with ATS. The presence of a pathogenic variant in KCNJ2 confirms the diagnosis.

Management.

Treatment of manifestations: For episodic weakness: if serum potassium concentration is low (<3.0 mmol/L), administration of oral potassium (20-30 mEq/L) every 15-30 minutes (not to exceed 200 mEq in a 12-hour period) until the serum concentration normalizes; if a relative drop in serum potassium within the normal range causes episodic paralysis, an individual potassium replacement regimen with a goal of maintaining serum potassium levels in the high range of normal can be considered; if serum potassium concentration is high, ingesting carbohydrates or continuing mild exercise may shorten the attack.

Prevention of primary manifestations: Reduction in frequency and severity of episodic attacks of weakness with lifestyle/dietary modification to avoid known triggers; use of carbonic anhydrase inhibitors; daily use of slow-release potassium supplements; implantable cardioverter-defibrillator for those with tachycardia-induced syncope. Empiric treatment with flecainide should be considered for significant, frequent ventricular arrhythmias in the setting of reduced left ventricular function.

Prevention of secondary complications: Cautious use of antiarrhythmic drugs (particularly class I drugs) that may paradoxically exacerbate the neuromuscular symptoms.

Surveillance: Annual screening of asymptomatic individuals with a KCNJ2 pathogenic variant with a 12-lead ECG and 24-hour Holter monitoring.

Agents/circumstances to avoid: Medications known to prolong QT intervals; salbutamol inhalers (may exacerbate cardiac arrhythmias); thiazide and other potassium-wasting diuretics (may provoke drug-induced hypokalemia and could aggravate the QT interval).

Evaluation of relatives at risk: Molecular genetic testing if the pathogenic variant is known, otherwise detailed neurologic and cardiologic evaluation, 12-lead ECG, and 24-hour Holter monitoring can be done to reduce morbidity and mortality through early diagnosis and treatment in at-risk relatives.

Genetic counseling.

ATS is inherited in an autosomal dominant manner. At least 50% of individuals diagnosed with ATS have an affected parent. Up to 50% of affected individuals have ATS as the results of a de novo pathogenic variant. Each child of an individual with ATS has a 50% chance of inheriting the disorder. Prenatal diagnosis for pregnancies at increased risk is possible if the KCNJ2 pathogenic variant has been identified in an affected family member.

Diagnosis

Suggestive Findings

Andersen-Tawil syndrome (ATS) should be suspected in individuals with either A or B:

A.

Two of the following three criteria:

  • Periodic paralysis
  • Symptomatic cardiac arrhythmias or electrocardiographic 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 eyes
    • Small mandible
    • Fifth-digit clinodactyly
    • Syndactyly of toes 2 and 3
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].

Supportive Findings

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.

  • Serum 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.

Establishing the Diagnosis

The diagnosis of ATS is established in a proband with the above clinical criteria and/or when a heterozygous pathogenic variant is identified in KCNJ2 (see Table 1).

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and genomic testing.

  • Serial single-gene testing can be considered if (1) mutation of a particular gene accounts for a large proportion of the disease or (2) clinical findings, laboratory findings, ancestry, or other factors indicate that mutation of a particular gene is most likely. Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes KCNJ2, KCNJ5, and other genes of interest (see Differential Diagnosis and Long QT Syndrome) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • Genomic testing may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of ATS. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

    For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Andersen-Tawil Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
KCNJ2Sequence analysis 3~60% 4
Gene-targeted deletion/duplication analysis 5Unknown 6
Unknown 7NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.

6.

Large deletions of KCNJ2 are reported [Lestner et al 2012, Vergult et al 2012, Marquis-Nicholson et al 2014]. The prevalence of large deletions is unknown.

7.

One individual with periodic paralysis, ventricular arrhythmias, no history of hypertension, and normal plasma aldosterone levels was found to have a p.Gly387Thr variant in KCNJ5. Of individuals with suspected ATS in whom a KCNJ2 pathogenic variant was not identified, 1/21 had a p.Thr158Ala KCNJ5 variant identified [Kokunai et al 2014].

Clinical Characteristics

Clinical Description

Andersen-Tawil syndrome (ATS) is characterized by a triad of features:

  • Episodic flaccid muscle weakness
  • Ventricular arrhythmias and prolonged QT interval
  • Distinctive dysmorphic features

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. The phenotype is highly variable. Approximately 60% of affected individuals manifest the complete triad of cardinal features and up to 80% express two of the three cardinal features [Tristani-Firouzi et al 2002, Haruna et al 2007].

Weakness. 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]. Affected individuals can develop fixed proximal weakness over time.

Ventricular arrhythmias including bidirectional ventricular tachycardia (VT), polymorphic VT, and multifocal premature ventricular contractions may be asymptomatic, or may manifest (most commonly) as palpitations. 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 ATS 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]. A retrospective multicenter French study of 36 individuals with ATS followed for an average of 9.5 years, reported no deaths in follow up; four individuals experienced syncope and one individual had a non-fatal cardiac arrest [Delannoy et al 2013].

Dilated cardiomyopathy was observed in two of three affected individuals in a single kindred with the p.Arg218Trp pathogenic variant [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 pathogenic variants [Davies et al 2005].

Detailed, prospectively collected data in ten individuals with confirmed KCNJ2 pathogenic variants 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, wide nasal bridge with bulbous nose, hypoplasia of maxilla and mandible, thin upper lip, and a triangular face.
  • 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.

Note: 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 pathogenic variant 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 molecularly confirmed ATS [Haruna et al 2007].

Genotype-Phenotype Correlations

Whether a KCNJ2 pathogenic variant is present or not, individuals with clinically defined ATS are phenotypically indistinguishable [Tristani-Firouzi et al 2002, Donaldson et al 2003].

In a case series that evaluated for KCNJ2 pathogenic variants in individuals with typical (>2 ATS features) and atypical (only 1 ATS feature or catecholaminergic polymorphic ventricular tachycardia [CPVT]) features of 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 pathogenic variant, 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].

A large five-generation family was found to have a deletion in KCNJ2 (c.271_282del12;p.Ala91_Leu94del) and more severe cardiac manifestations, including 4/10 individuals receiving an implantable cardioverter-defibrillator and 5/10 reporting life-threatening ventricular arrhythmias in childhood [Fernlund et al 2013]. These individuals had characteristic mild dysmorphic features, but only one had periodic paralysis.

Two pathogenic variants in KCNJ2 associated with a reduction in Kir2.1 current but without a dominant-negative effect on normal channels (p.Asn318Ser and p.Trp322Cys) were described in three individuals with an isolated cardiac phenotype: with premature ventricular contractions, ventricular tachycardia, or ventricular fibrillation [Limberg et al 2013].

Penetrance

Non-penetrance is evident in 6%-20% of individuals with an identifiable pathogenic variant [Andelfinger et al 2002, Tristani-Firouzi et al 2002, Donaldson et al 2003].

Nomenclature

Although listed in OMIM, the following names for ATS are no longer in clinical use:

  • Periodic paralysis, potassium-sensitive cardiodysrhythmic type
  • Andersen cardiodysrhythmic periodic paralysis

Prevalence

The prevalence is not known. ATS is diagnosed in fewer than 10% of individuals with primary periodic paralysis. The incidence of periodic paralysis is also unknown and estimated to be at most 1:100,000.

Differential Diagnosis

Andersen-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, thyrotoxic periodic paralysis, and conditions associated with long QT.

Episodes of flaccid paralysis

  • Hypokalemic periodic paralysis is the most common periodic paralysis. Affected individuals may experience paralytic episodes with concomitant hypokalemia (<2.5 mmol/L), and occasionally may develop late-onset proximal myopathy. The paralytic attacks are characterized by reversible flaccid paralysis usually leading to paraparesis or tetraparesis but typically sparing the respiratory muscles and heart. The onset, duration, and severity of attacks, with the associated triggers, are similar to those in individuals with ATS. Weakness is improved with oral potassium ingestion. The cardiac and dysmorphic features of ATS are, however, absent in individuals with hypokalemic periodic paralysis. Molecular testing identifies pathogenic variants 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 pathogenic variants in SCN4A in approximately 60% of individuals. Inheritance is autosomal dominant. 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).
  • Thyrotoxic periodic paralysis (OMIM 188580, 613239, 614834) 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 thyroid-stimulating hormone (TSH), T4, and T3 concentrations. A pathogenic variant in an inwardly rectifying potassium (Kir) channel (encoded by KCNJ18) was identified in approximately one third of affected individuals in one series [Ryan et al 2010].

Long QT syndromes. See Long QT Syndrome, a review of similar phenotypes that are genetically diverse.

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. Pathogenic variants in RYR2 or CASQ2 are causative. Inheritance is autosomal dominant [Tristani-Firouzi & Etheridge 2010].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 long QT (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 TSH concentration is within normal limits
  • Medical genetics consultation

Treatment of Manifestations

Management 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 (not to exceed 200 mEq in a 12-hour period) until the serum concentration normalizes often shortens the attack. As dysphagia is almost never a problem during attacks of paralysis, oral potassium replacement is the safest route. If intravenous potassium replacement is needed, a 5% mannitol solution instead of a saline or glucose solution (both of which may exacerbate weakness) is recommended. Close monitoring of serum potassium concentrations and ECG is necessary during potassium replacement therapy in an emergency setting to avoid secondary hyperkalemia.
  • Whether a relative drop in serum potassium within the normal range causes episodic paralysis is not clear. If such cases are suspected, affected individuals can work with their physician to devise an individual potassium replacement regimen, with a goal of maintaining serum potassium levels in the high range of normal.
  • 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 Manifestations

Prophylactic 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]. A prospective open label study in ten individuals with ATS and a confirmed KCNJ2 pathogenic variant tested the effect of flecainide, a type 1c antiarrhythmic, for the prevention of cardiac arrhythmias [Miyamoto et al 2015]. Outcomes included a 24-hour Holter monitor before and after treatment, and a treadmill exercise test. Flecainide was found to significantly reduce the number of ventricular arrhythmias seen on Holter monitor, and to suppress exercise-induced ventricular arrhythmias. Individuals were then followed for a mean of 23 months and no syncope or cardiac arrest was documented. The study concluded that flecainide may reduce cardiac arrhythmias in ATS – however the ultimate benefit of flecainide for prevention of medically significant cardiac arrhythmias is still unknown.

Prevention of Secondary Complications

Cardiologists 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.

Surveillance

For asymptomatic individuals with a KCNJ2 pathogenic variant, 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 Avoid

Affected individuals should avoid medications known to prolong QT intervals. See CredibleMeds® 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 evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures:

  • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, detailed neurologic and cardiologic evaluation, 12-lead ECG, and 24-hour Holter monitoring can be used to clarify the disease status of at-risk relatives.

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 individual care and anticipation of increased risk (as can be seen in those with long QT syndrome) seems reasonable.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Andersen-Tawil syndrome (ATS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • At least 50% of individuals diagnosed with ATS have an affected parent.
  • A proband with ATS may have the disorder as the result of a de novo KCNJ2 pathogenic variant. The proportion of cases caused by de novo mutation of KCNJ2 may be as high as 50%.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include a detailed neurologic and cardiologic evaluation, 12-lead ECG, 24-hour Holter monitoring, and molecular genetic testing for the KCNJ2 pathogenic variant identified in the proband.
  • The family history of some individuals diagnosed with ATS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent not attributed to the disease, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic and cardiologic evaluations and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected and/or has the KCNJ2 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the KCNJ2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been reported in ATS [Hasegawa et al 2015].

Offspring of a proband. Each child of an individual with ATS has a 50% chance of inheriting the KCNJ2 pathogenic variant.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with ATS has the pathogenic variant or clinical evidence of the disorder, the KCNJ2 pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the KCNJ2 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the KCNJ2 pathogenic variant has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Periodic Paralysis Association (PPA)
    155 West 68th Street
    Suite 1732
    New York NY 10023
    Phone: 407-339-9499
    Email: lfeld@cfl.rr.com
  • Sudden Arrhythmia Death Syndromes (SADS) Foundation
    508 East South Temple
    Suite #202
    Salt Lake City UT 84102
    Phone: 800-786-7723 (toll-free); 801-531-0937
    Email: sads@sads.org
  • Consortium for Clinical Investigation of Neurologic Channelopathies Contact Registry
  • Long QT Syndrome (LQTS) Registry
    An ongoing research study with the goal of contributing to a better understanding of the genetics, natural history, and treatment of LQTS. Currently enrolling families in which a mutation has already been identified.
    University of Rochester Medical Center
    265 Crittenden Boulevard
    CU 420653
    Rochester NY 14642-0653
    Phone: 585-276-0016
    Fax: 585-273-5283

Molecular Genetics

Information 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 Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)

170390ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS
600681POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 2; KCNJ2
600734POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 5; KCNJ5

KCNJ2

Gene structure. KCNJ2 has two exons spanning 5.4 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. See Table A, Locus Specific and HGMD. The p.Arg218Trp pathogenic variant is considered a potential hotspot for pathogenic variants [Davies et al 2005]. The majority of pathogenic variants in KCNJ2 are missense changes. A small number of in-frame deletions and a duplication have also been reported.

Table 2.

KCNJ2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.199C>Tp.Arg67Trp 1NM_000891​.2
NP_000882​.1
c.271_282del12p.Ala91_Leu94del 1
c.652C>Tp.Arg218Trp 2
c.899G>Ap.Gly300Asp 2
c.953A>Gp.Asn318Ser 1
c.966G>Cp.Trp322Cys 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

Normal gene product. KCNJ2 encodes the inward rectifier potassium channel 2 protein (Kir2.1), with 427 amino acid residues and 48-kd molecular weight. Kir2.1 is 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].

Abnormal gene product. Pathogenic variants in KCNJ2 cause dominant-negative suppression of Kir2.1 current [Plaster et al 2001, Tristani-Firouzi et al 2002, 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] and affect channel-PIP2 interactions [Donaldson et al 2003]. Several pathogenic variants 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 pathogenic variants 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].

KCNJ5

Pathogenic allelic variants. One individual with clinical criteria of ATS and a novel pathogenic variant in KCNJ5 (p.Gly387Arg) has been described. The proband had periodic paralysis and ventricular arrhythmias, with a family history of ventricular arrhythmias on his father’s side. A review of 21 individuals in a Japanese cohort (in whom ATS was suspected but no KCNJ2 pathogenic variant was found) idenitifed one additional patient with a novel variant in KCNJ5 (p.Thr158Ala) [Kokunai et al 2014]. The ultimate frequency of KCNJ5 pathogenic variants in patients who meet clinical criteria for ATS but do not have a KCNJ2 variant remains to be determined.

Table 3.

KCNJ5 Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.472A>Gp.Thr158AlaNM_000890​.3
NP_000881​.3
c.1159G>Cp.Gly387Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. KCNJ5 codes a G-protein activated inwardly rectifying potassium channel protein 4 (Kir3.4). Expression studies show that KCNJ5 is expressed in cardiac and skeletal muscle.

Abnormal gene product. Functional studies on the p.Gly387Arg pathogenic variant in KCNJ5 also demonstrated a dominant-negative effect on Kir2.1 function [Kokunai et al 2014].

References

Literature Cited

  1. Ai T, Fujiwara Y, Tsuji K, Otani H, Nakano S, Kubo Y, Horie M. Novel KCNJ2 mutation in familial periodic paralysis with ventricular dysrhythmia. Circulation. 2002;105:2592–4. [PubMed: 12045162]
  2. Airey KJ, Etheridge SP, Tawil R, Tristani-Firouzi M. Resuscitated sudden cardiac death in Andersen-Tawil syndrome. Heart Rhythm. 2009;6:1814–7. [PMC free article: PMC2789273] [PubMed: 19959136]
  3. Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr, Benson DW. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002;71:663–8. [PMC free article: PMC379203] [PubMed: 12148092]
  4. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand. 1971;60:559–64. [PubMed: 4106724]
  5. Ballester LY, Benson DW, Wong B, Law IH, Mathews KD, Vanoye CG, George AL Jr. Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome. Hum Mutat. 2006;27:388. [PubMed: 16541386]
  6. Barajas-Martinez H, Hu D, Ontiveros G, Caceres G, Desai M, Burashnikov E, Scaglione J, Antzelevitch C. Biophysical and molecular characterization of a novel de novo KCNJ2 mutation associated with Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry. Circ Cardiovasc Genet. 2011;4:51–7. [PMC free article: PMC3041844] [PubMed: 21148745]
  7. Bendahhou S, Donaldson MR, Plaster NM, Tristani-Firouzi M, Fu YH, Ptácek LJ. Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. J Biol Chem. 2003;278:51779–85. [PubMed: 14522976]
  8. Bökenkamp R, Wilde AA, Schalij MJ, Blom NA. Flecainide for recurrent malignant ventricular arrhythmias in two siblings with Andersen-Tawil syndrome. Heart Rhythm. 2007;4:508–11. [PubMed: 17399642]
  9. Cannon SC. An expanding view for the molecular basis of familial periodic paralysis. Neuromuscul Disord. 2002;12:533–43. [PubMed: 12117476]
  10. Canún S, Pérez N, Beirana LG. Andersen syndrome autosomal dominant in three generations. Am J Med Genet. 1999;85:147–56. [PubMed: 10406668]
  11. Chun TU, Epstein MR, Dick M 2nd, Andelfinger G, Ballester L, Vanoye CG, George AL Jr, Benson DW. Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm. 2004;1:235–41. [PubMed: 15851159]
  12. Davies NP, Imbrici P, Fialho D, Herd C, Bilsland LG, Weber A, Mueller R, Hilton-Jones D, Ealing J, Boothman BR, Giunti P, Parsons LM, Thomas M, Manzur AY, Jurkat-Rott K, Lehmann-Horn F, Chinnery PF, Rose M, Kullmann DM, Hanna MG. Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation. Neurology. 2005;65:1083–9. [PubMed: 16217063]
  13. Delannoy E, Sacher F, Maury P, Mabo P, Mansourati J, Magnin I, Camous JP, Tournant G, Rendu E, Kyndt F, Haïssaguerre M, Bézieau S, Guyomarch B, Le Marec H, Fressart V, Denjoy I, Probst V. Cardiac characteristics and long-term outcome in Andersen-Tawil syndrome patients related to KCNJ2 mutation. Europace. 2013;15:1805–11. [PubMed: 23867365]
  14. Doi T, Makiyama T, Morimoto T, Haruna Y, Tsuji K, Ohno S, Akao M, Takahashi Y, Kimura T, Horie M. A novel KCNJ2 nonsense mutation, S369X, impedes trafficking and causes a limited form of Andersen-Tawil syndrome. Circ Cardiovasc Genet. 2011;4:253–60. [PubMed: 21493816]
  15. Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar T, Escolar DM, Fu YH, Ptácek LJ. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology. 2003;60:1811–6. [PubMed: 12796536]
  16. Donaldson MR, Yoon G, Fu YH, Ptacek LJ. Andersen-Tawil syndrome: a model of clinical variability, pleiotropy, and genetic heterogeneity. Ann Med. 2004;36 Suppl 1:92–7. [PubMed: 15176430]
  17. Fernlund E, Lundin C, Hertervig E, Kongstad O, Alders M, Platonov P. Novel mutation in the KCNJ2 gene is associated with a malignant arrhythmic phenotype of Andersen-Tawil syndrome. Ann Noninvasive Electrocardiol. 2013;18:471–8. [PubMed: 24047492]
  18. Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B, Willer JC, Tabti N, Fontaine B. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol. 2004;56:650–61. [PubMed: 15389891]
  19. Fox DJ, Klein GJ, Hahn A, Skanes AC, Gula LJ, Yee RK, Subbiah RN, Krahn AD. Reduction of complex ventricular ectopy and improvement in exercise capacity with flecainide therapy in Andersen-Tawil syndrome. Europace. 2008;10:1006–8. [PubMed: 18621769]
  20. Haruna Y, Kobori A, Makiyama T, Yoshida H, Akao M, Doi T, Tsuji K, Ono S, Nishio Y, Shimizu W, Inoue T, Murakami T, Tsuboi N, Yamanouchi H, Ushinohama H, Nakamura Y, Yoshinaga M, Horigome H, Aizawa Y, Kita T, Horie M. Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome. Hum Mutat. 2007;28:208. [PubMed: 17221872]
  21. Hasegawa K, Ohno S, Kimura H, Itoh H, Makiyama T, Yoshida Y, Horie M. Mosaic KCNJ2 mutation in Andersen-Tawil syndrome: targeted deep sequencing is useful for the detection of mosaicism. Clin Genet. 2015;87:279–83. [PubMed: 24635491]
  22. Hosaka Y, Hanawa H, Washizuka T, Chinushi M, Yamashita F, Yoshida T, Komura S, Watanabe H, Aizawa Y. Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen's syndrome. J Mol Cell Cardiol. 2003;35:409–15. [PubMed: 12689820]
  23. Katz JS, Wolfe GI, Iannaccone S, Bryan WW, Barohn RJ. The exercise test in Andersen syndrome. Arch Neurol. 1999;56:352–6. [PubMed: 10190827]
  24. Kimura H, Zhou J, Kawamura M, Itoh H, Mizusawa Y, Ding WG, Wu J, Ohno S, Makiyama T, Miyamoto A, Naiki N, Wang Q, Xie Y, Suzuki T, Tateno S, Nakamura Y, Zang WJ, Ito M, Matsuura H, Horie M. Phenotype variability in patients carrying KCNJ2 mutations. Circ Cardiovasc Genet. 2012;5:344–53. [PubMed: 22589293]
  25. Kokunai Y, Nakata T, Furuta M, Sakata S, Kimura H, Aiba T, Yoshinaga M, Osaki Y, Nakamori M, Itoh H, Sato T, Kubota T, Kadota K, Shindo K, Mochizuki H, Shimizu W, Horie M, Okamura Y, Ohno K, Takahashi MP. A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. Neurology. 2014;82:1058–64. [PubMed: 24574546]
  26. Kuntzer T, Flocard F, Vial C, Kohler A, Magistris M, Labarre-Vila A, Gonnaud PM, Ochsner F, Soichot P, Chan V, Monnier G. Exercise test in muscle channelopathies and other muscle disorders. Muscle Nerve. 2000;23:1089–94. [PubMed: 10883004]
  27. Lange PS, Er F, Gassanov N, Hoppe UC. Andersen mutations of KCNJ2 suppress the native inward rectifier current IK1 in a dominant-negative fashion. Cardiovasc Res. 2003;59:321–7. [PubMed: 12909315]
  28. Lestner JM, Ellis R, Canham N. Delineating the 17q24.2-q24.3 microdeletion syndrome phenotype. Eur J Med Genet. 2012;55:700–4. [PubMed: 22982078]
  29. Limberg MM, Zumhagen S, Netter MF, Coffey AJ, Grace A, Rogers J, Böckelmann D, Rinné S, Stallmeyer B, Decher N, Schulze-Bahr E. Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype. Basic Res Cardiol. 2013;108:353. [PubMed: 23644778]
  30. Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron. 2002;34:933–44. [PubMed: 12086641]
  31. Marquis-Nicholson R, Prosser DO, Love JM, Zhang L, Hayes I, George AM, Crawford JR, Skinner JR, Love DR. Array comparative genomic hybridization identifies a heterozygous deletion of the entire KCNJ2 gene as a cause of sudden cardiac death. Circ Cardiovasc Genet. 2014;7:17–22. [PubMed: 24395924]
  32. Marrus SB, Cuculich PS, Wang W, Nerbonne JM. Characterization of a novel, dominant negative KCNJ2 mutation associated with Andersen-Tawil syndrome. Channels (Austin) 2011;5:500–9. [PMC free article: PMC3265798] [PubMed: 22186697]
  33. Miyamoto K, Aiba T, Kimura H, Hayashi H, Ohno S, Yasuoka C, Tanioka Y, Tsuchiya T, Yoshida Y, Hayashi H, Tsuboi I, Nakajima I, Ishibashi K, Okamura H, Noda T, Ishihara M, Anzai T, Yasuda S, Miyamoto Y, Kamakura S, Kusano K, Ogawa H, Horie M, Shimizu W. Efficacy and safety of flecainide for ventricular arrhythmias in patients with Andersen-Tawil syndrome with KCNJ2 mutations. Heart Rhythm. 2015;12:596–603. [PubMed: 25496985]
  34. Pellizzón OA, Kalaizich L, Ptácek LJ, Tristani-Firouzi M, Gonzalez MD. Flecainide suppresses bidirectional ventricular tachycardia and reverses tachycardia-induced cardiomyopathy in Andersen-Tawil syndrome. J Cardiovasc Electrophysiol. 2008;19:95–7. [PubMed: 17655675]
  35. Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptácek LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell. 2001;105:511–9. [PubMed: 11371347]
  36. Ryan DP, da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AW, Jongjaroenprasert W, Liang MC, Khoo DH, Cheah JS, Ho SC, Bernstein HS, Maciel RM, Brown RH Jr, Ptácek LJ. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell. 2010;140:88–98. [PMC free article: PMC2885139] [PubMed: 20074522]
  37. Sansone V, Griggs RC, Meola G, Ptácek LJ, Barohn R, Iannaccone S, Bryan W, Baker N, Janas SJ, Scott W, Ririe D, Tawil R. Andersen's syndrome: a distinct periodic paralysis. Ann Neurol. 1997;42:305–12. [PubMed: 9307251]
  38. Schoonderwoerd BA, Wiesfeld AC, Wilde AA, van den Heuvel F, Van Tintelen JP, van den Berg MP, Van Veldhuisen DJ, Van Gelder IC. A family with Andersen-Tawil syndrome and dilated cardiomyopathy. Heart Rhythm. 2006;3:1346–50. [PubMed: 17074642]
  39. Subbiah RN, Gula LJ, Skanes AC, Krahn AD. Andersen-Tawil syndrome: management challenges during pregnancy, labor, and delivery. J Cardiovasc Electrophysiol. 2008;19:987–9. [PubMed: 18554214]
  40. Tan SV, Matthews E, Barber M, Burge JA, Rajakulendran S, Fialho D, Sud R, Haworth A, Koltzenburg M, Hanna MG. Refined exercise testing can aid DNA-based diagnosis in muscle channelopathies. Ann Neurol. 2011;69:328–40. [PMC free article: PMC3051421] [PubMed: 21387378]
  41. Tawil R, Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir C, Griggs RC. Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol. 1994;35:326–30. [PubMed: 8080508]
  42. Tristani-Firouzi M, Chen J, Mitcheson JS, Sanguinetti MC. Molecular biology of K(+) channels and their role in cardiac arrhythmias. Am J Med. 2001;110:50–9. [PubMed: 11152866]
  43. Tristani-Firouzi M, Etheridge SP. Kir 2.1 channelopathies: the Andersen-Tawil syndrome. Pflugers Arch. 2010;460:289–94. [PubMed: 20306271]
  44. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest. 2002;110:381–8. [PMC free article: PMC151085] [PubMed: 12163457]
  45. Tristani-Firouzi M. Andersen-Tawil syndrome: an ever-expanding phenotype? Heart Rhythm. 2006;3:1351–2. [PubMed: 17074643]
  46. Vergult S, Dauber A, Delle Chiaie B, Van Oudenhove E, Simon M, Rihani A, Loeys B, Hirschhorn J, Pfotenhauer J, Phillips JA 3rd, Mohammed S, Ogilvie C, Crolla J, Mortier G, Menten B. 17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations. Eur J Hum Genet. 2012;20:534–9. [PMC free article: PMC3330218] [PubMed: 22166941]
  47. Yoon G, Oberoi S, Tristani-Firouzi M, Etheridge SP, Quitania L, Kramer JH, Miller BL, Fu YH, Ptácek LJ. Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype. Am J Med Genet A. 2006a;140:312–21. [PubMed: 16419128]
  48. Yoon G, Quitania L, Kramer JH, Fu YH, Miller BL, Ptácek LJ. Andersen-Tawil syndrome: definition of a neurocognitive phenotype. Neurology. 2006b;66:1703–10. [PubMed: 16769944]
  49. Zaritsky JJ, Eckman DM, Wellman GC, Nelson MT, Schwarz TL. Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation. Circ Res. 2000;87:160–6. [PubMed: 10904001]
  50. Zhang L, Benson DW, Tristani-Firouzi M, Ptacek LJ, Tawil R, Schwartz PJ, George AL, Horie M, Andelfinger G, Snow GL, Fu YH, Ackerman MJ, Vincent GM. Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation. 2005;111:2720–6. [PubMed: 15911703]

Suggested Reading

  1. Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, Tristani-Firouzi M, Tawil R, Griggs RC., CINCH investigators. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain. 2006;129:8–17. [PubMed: 16195244]

Chapter Notes

Acknowledgments

The authors are funded in part by the Consortium for Clinical Investigation of Neurological Channelopathies (CINCH) supported by NIH 8 U54 NS59065 (NINDS/ORD).

Revision History

  • 3 September 2015 (rt) Revision: Treatment of Manifestations
  • 6 August 2015 (me) Comprehensive update posted live
  • 3 January 2013 (me) Comprehensive update posted live
  • 13 May 2010 (me) Comprehensive update posted live
  • 19 March 2007 (me) Comprehensive update posted to live Web site
  • 27 April 2005 (cd) Revision: prenatal diagnosis available
  • 22 November 2004 (me) Review posted to live Web site
  • 1 June 2004 (rt) Original submission
Copyright © 1993-2016, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1264PMID: 20301441

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...