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'''Andersen–Tawil syndrome''' ('''ATS'''), also known as '''Andersen syndrome''' or '''long QT syndrome 7''', is a rare [[genetic disorder]] that affects multiple systems in the body, including the [[cardiovascular system]], [[musculoskeletal system]], and [[nervous system]]. It is characterized by three main features:
* Abnormal [[cardiac conduction]] leading to an extended [[QT interval]] and a predisposition to [[ventricular arrhythmias]].
* Periodic episodes of [[muscle weakness]], known as [[hypokalemic periodic paralysis]].
* Distinctive physical abnormalities affecting the [[face]], [[limbs]], and [[spine]].


'''Andersen–Tawil syndrome''', also called '''Andersen syndrome''' and '''long QT syndrome 7''', is a rare [[genetic disorder]] affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an [[Electrocardiography|electrocardiogram]] (a long [[QT interval]]) and a tendency to [[Heart arrhythmia|abnormal heart rhythms]], physical characteristics including low-set ears and a [[Micrognathism|small lower jaw]], and intermittent periods of muscle weakness known as [[Hypokalemic periodic paralysis|hypokalaemic periodic paralysis]].<ref name="GeneReviews">{{cite book|title=GeneReviews|vauthors=Veerapandiyan A, Statland JM, Tawil R|date=2015|publisher=University of Washington|veditors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A|location=Seattle (WA)|chapter=Andersen-Tawil Syndrome|pmid=20301441|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1264/}}</ref>   
This condition follows an [[autosomal dominant]] pattern of inheritance and is most commonly associated with mutations in the '''[[KCNJ2]]''' gene, which encodes a [[potassium ion channel]] essential for cardiac and muscle function. Management of Andersen–Tawil syndrome primarily focuses on controlling [[arrhythmias]], preventing sudden cardiac death, and managing periodic paralysis episodes.


Andersen–Tawil syndrome is inherited in an [[autosomal dominant]] pattern. It is caused in most cases by a [[mutation]] in the [[Kir2.1|''KCNJ2'']] gene which encodes an [[ion channel]] that transports [[potassium]] out of [[cardiac muscle cell]]s. The arrhythmias seen in the condition can be treated with [[flecainide]] or [[Beta blocker|beta-blockers]], but an [[Implantable cardioverter-defibrillator|implantable defibrillator]] may sometimes be required. Periodic paralysis can be treated with [[carbonic anhydrase inhibitor]]s such as [[acetazolamide]]. The condition is very rare and is estimated to affect one person in every million. The three groups of features seen in this condition were first described in 1971 by [[Ellen Damgaard Andersen|Ellen Andersen]], and significant contributions to its understanding were made by Rabi Tawil.
== Clinical Features ==
Andersen–Tawil syndrome presents with a characteristic triad of:
# '''Cardiac Abnormalities''' – Prolongation of the [[QT interval]], [[ventricular tachycardia]], and increased risk of [[sudden cardiac events]].
# '''Neuromuscular Manifestations''' – Recurrent episodes of [[muscle weakness]], often triggered by [[hypokalemia]].
# '''Dysmorphic Features''' – Distinctive [[craniofacial]], [[skeletal]], and [[limb]] anomalies.


== Signs and symptoms ==
=== Cardiac Abnormalities ===
Andersen–Tawil Syndrome classically comprises three groups of features: abnormal electrical function of the heart, [[hypokalemic periodic paralysis]], and characteristic physical features, although some of those affected will not exhibit all aspects of the condition.<ref name="Electrical Disease of the Heart Chapter 32">{{cite book | vauthors = Tristani-Firouzi M, Etheridge SP |chapter=Chapter 32 – Andersen-Tawil and Timothy Syndromes | veditors = Gussak I, Antzelevitch C |title=Electrical diseases of the heart. Volume 1, Basic foundations and primary electrical diseases | date=2013 |location=London |publisher=Springer |isbn=978-1-4471-4881-4 |edition= 2nd |oclc=841465583 }}</ref>
The [[electrocardiogram]] (ECG) of an individual with Andersen–Tawil syndrome typically shows:
[[File:PMC6177042 Nguyen 2018 Bidirectional ventricular tachycardia in Andersen-Tawil syndrome.jpg|left|thumb|[[Electrocardiography|Electrocardiogram]] showing bidirectional [[Ventricular tachycardia|Ventricular Tachycardia]] in a 9-year-old female with Andersen–Tawil syndrome]]
* '''Prolonged QT interval''', increasing the risk of [[ventricular arrhythmias]].
Andersen–Tawil syndrome affects the heart by prolonging the [[QT interval]], a measure of how long it takes the heart to relax after each heart beat. This, as in other forms of long QT syndrome, can lead to [[Heart arrhythmia|abnormal heart rhythms]] such as [[Premature ventricular contraction|ventricular ectopy]] or [[ventricular tachycardia]] causing [[palpitations]].<ref name="Electrical Disease of the Heart Chapter 32" /> The ventricular tachycardia seen in Andersen–Tawil syndrome often takes a form known as bidirectional ventricular tachycardia. The arrhythmias seen in association with the condition can cause sudden cardiac death, but the risk of this is lower than in other forms of long QT syndrome.<ref name="GeneReviews" />
* '''Frequent premature ventricular contractions (PVCs)''', which may progress to [[ventricular tachycardia]].
[[File:Sampleclinodactyly.jpg|left|thumb|213x213px|[[Clinodactyly]] – abnormal curvature of 5th finger towards 4th finger]]
* '''Bidirectional ventricular tachycardia''', a characteristic arrhythmia associated with ATS.
The physical abnormalities associated with Andersen–Tawil syndrome typically affect the head, face, limbs and spine. Abnormalities of the head and face include an unusually small lower jaw ([[micrognathia]]), low-set ears, widely spaced eyes ([[hypertelorism]]), a broad forehead and nasal root, a high arched or [[Cleft lip and cleft palate|cleft palate]], and a long narrow head ([[scaphocephaly]]).<ref name="Nguyen 2013" /> Abnormalities of the limbs and spine include an abnormal curvature of the fingers, particularly the fifth finger ([[clinodactyly]]), fused fingers or toes ([[syndactyly]]), short stature, and a curved spine ([[scoliosis]]).<ref name="Nguyen 2013" />
* '''Palpitations, dizziness, and syncope''', especially during [[exercise]] or [[emotional stress]].


The third key feature of Andersen–Tawil syndrome is intermittent muscle weakness. This can last from seconds to minutes, but in some cases may last for days at a time. Weakness often occurs at times when the levels of potassium in the blood are lower than normal ([[Hypokalemia|hypokalaemia]]), and is referred to as hypokalaemic periodic paralysis. This weakness can however occur at times when potassium levels are normal, triggered by other factors including exercise, cold, or even menstruation.<ref name="Nguyen 2013" />
While ATS is associated with [[long QT syndrome]], the risk of sudden cardiac death is lower compared to other forms of [[congenital long QT syndromes]].


==Cause==
=== Neuromuscular Manifestations ===
Andersen–Tawil syndrome is a genetic disorder which in the majority of cases is caused by [[mutations]] in the ''[[KCNJ2]]'' gene. The condition is often inherited from a parent in an [[Dominance (genetics)|autosomal dominant]] manner, but may occur due to a new genetic mutation in the affected person.<ref name="Nguyen 2013" />
* Recurrent episodes of [[muscle weakness]], lasting from minutes to hours.
* Weakness is typically '''triggered by low potassium levels''' ([[hypokalemia]]).
* Episodes may be provoked by '''exercise, stress, fasting, or certain medications'''.
* Some patients experience '''persistent muscle weakness''' between episodes.


Two types of Andersen–Tawil syndrome have been described, distinguished by the genetic abnormality that is detected. Type 1 Andersen–Tawil, accounting for about 60% of cases, is caused by mutations in the ''KCNJ2'' gene.<ref name="Donaldson 2004">{{cite journal | vauthors = Donaldson MR, Yoon G, Fu YH, Ptacek LJ | title = Andersen-Tawil syndrome: a model of clinical variability, pleiotropy, and genetic heterogeneity | journal = Annals of Medicine | volume = 36 | issue = Suppl 1 | pages = 92–7 | date = 2004 | pmid = 15176430 | doi = 10.1080/17431380410032490 }}</ref> In type 2 Andersen–Tawil, accounting for about 40% of cases, a ''KCNJ2'' mutation is not identified. Mutations in a related gene encoding a similar potassium ion channel, ''[[KCNJ5]]'', have been identified in some of those with type 2 Andersen–Tawil, but in many cases a genetic mutation is not found.<ref name="GeneReviews" />
=== Physical Abnormalities ===
The '''skeletal and craniofacial abnormalities''' seen in Andersen–Tawil syndrome include:
* '''Low-set ears''' and '''widely spaced eyes''' ([[hypertelorism]]).
* '''Micrognathia''' – A small lower jaw.
* '''Clinodactyly''' – Abnormal curvature of the '''fifth finger'''.
* '''Syndactyly''' – Fusion of two or more fingers or toes.
* '''Scoliosis''' – Abnormal curvature of the '''spine'''.
* '''Short stature''' and '''high-arched palate'''.


The protein made by the ''KCNJ2'' gene forms an [[ion channel]] that transports potassium ions into [[muscle]] [[Cell (biology)|cells]]. This specific channel (the inward rectifier potassium channel [[Kir2.1]]) carries a potassium current known as ''I''<sub>K1</sub> which is responsible for setting the [[Resting potential|resting membrane potential]] of muscle cells and is therefore critical for maintaining the normal functions of skeletal and [[cardiac muscle]].<ref name="Nguyen 2013" /> Pathogenic mutations in the ''KCNJ2'' gene alter the usual structure and function of potassium channels or prevent the channels from being inserted correctly into the cell membrane. Many mutations prevent a molecule called PIP2 from binding to the channels and effectively regulating their activity. These changes disrupt the flow of potassium ions, leading to the periodic paralysis and abnormal heart rhythms characteristic of Andersen–Tawil syndrome.<ref name="Donaldson 2004" />
== Genetics and Pathophysiology ==
Andersen–Tawil syndrome is caused by mutations in the '''[[KCNJ2]]''' gene, which encodes the '''Kir2.1 potassium channel'''. This ion channel plays a crucial role in regulating:
* '''Cardiac repolarization''', ensuring proper electrical conduction in the heart.
* '''Muscle membrane potential''', preventing abnormal muscle contractions and weakness.


{| class="wikitable"
=== Genetic Inheritance ===
|'''Type'''
* ATS follows an '''autosomal dominant''' inheritance pattern.
|'''OMIM'''
* Some cases result from '''de novo mutations''', meaning they occur spontaneously without a family history.
|'''Gene'''
* '''Type 1 ATS''' (60% of cases) results from mutations in '''KCNJ2'''.
|'''Notes'''
* '''Type 2 ATS''' (40% of cases) is genetically undefined but may involve mutations in '''[[KCNJ5]]'''.
|-


|-
=== Mechanisms of Disease ===
|Type 1 Andersen–Tawil syndrome
* '''Reduced Kir2.1 channel function''' results in abnormal '''potassium ion transport'''.
|{{OMIM|170390||none}}
* '''Increased cardiac excitability''' leads to '''prolonged repolarization''' and susceptibility to arrhythmias.
|''[[KCNJ2]]''
* '''Muscle hyperexcitability and depolarization''' cause episodes of periodic paralysis.
|Encodes inward rectifying potassium current K<sub>ir</sub>2.1 carrying the potassium current ''I''<sub>K1</sub>.<ref name="GeneReviews" />
|-
|Type 2 Andersen–Tawil syndrome
|{{OMIM|600734||none}}
|''[[KCNJ5]]''
|Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (K<sub>ir</sub>3.4) which carry the potassium current ''I''<sub>K(ACh)</sub>.<ref name="GeneReviews" />


|}
== Diagnosis ==
A diagnosis of Andersen–Tawil syndrome is based on a combination of:
* '''Clinical criteria''' (triad of cardiac, neuromuscular, and skeletal features).
* '''Electrocardiogram (ECG)''' findings (QT prolongation, bidirectional VT).
* '''Genetic testing''' to identify mutations in '''KCNJ2''' or related genes.


== Mechanisms ==
=== Diagnostic Criteria ===
Andersen–Tawil syndrome increases the risk of abnormal heart rhythms by disturbing the electrical signals that are used to coordinate individual [[Cardiac muscle cell|heart cells]]. The genetic mutation disturbs an ion channel responsible for the flow of potassium, reducing the /<sub>K1</sub> current. This prolongs of the [[cardiac action potential]] – the characteristic pattern of voltage changes across the cell membrane that occur with each heart beat, and depolarises the resting membrane potential of cardiac and [[Skeletal muscle|skeletal muscle cells]].<ref name="Nguyen 2013" />
A diagnosis is likely if two of the following are present:
1. '''Periodic paralysis''' with episodes of muscle weakness.
2. '''Prolonged QT interval''' and ventricular arrhythmias.
3. '''Distinctive physical features''' such as '''clinodactyly, low-set ears, and scoliosis'''.
4. '''A family history of Andersen–Tawil syndrome'''.


Cardiac and skeletal muscle cells, when relaxed, have fewer positively charged [[Ion trap|ions]] on the inner side of their [[cell membrane]] than on the outer side, referred to as their membranes being polarised.<ref name="Santana 2010">{{Cite journal|last=Santana|first=Luis F.|last2=Cheng|first2=Edward P.|last3=Lederer|first3=W. Jonathan|date=December 2010|title=How does the shape of the cardiac action potential control calcium signaling and contraction in the heart?|journal=Journal of Molecular and Cellular Cardiology|volume=49|issue=6|pages=901–903|doi=10.1016/j.yjmcc.2010.09.005|issn=1095-8584|pmc=3623268|pmid=20850450}}</ref> The main ion current responsible for maintaining this polarity is /<sub>K1</sub>, and a decrease in this current leads to less polarity at rest, or a depolarised resting membrane potential. When these cells [[Muscle contraction|contract]], positively charged ions such as sodium and calcium enter the cell through ion channels, depolarising or reversing this polarity. After a contraction has taken place, the cell restores its polarity (or repolarises) by allowing positively charged ions such as potassium to leave the cell, restoring the membrane to its relaxed, polarised state.<ref name="Santana 2010" /> The genetic mutation found in those with Andersen–Tawil decreases the flow of potassium, slowing the rate of repolarisation which can be seen in individual cardiac muscle cells as a longer action potential and on the surface ECG as a prolonged QT interval.<ref name="Nguyen 2013" />
=== Differential Diagnosis ===
[[File:Mechanisms of arrhythmia.jpg|thumb|Mechanisms underlying early afterdepolarisations (EADs) and delayed afterdepolarisations (DADs) responsible for the arrhythmias seen in Andersen–Tawil syndrome]]
Conditions that may mimic Andersen–Tawil syndrome include:
The prolonged action potentials can lead to arrhythmias through several potential mechanisms. The frequent ventricular ectopy and bidirectional VT typical of Andersen–Tawil syndrome are initiated by a triggering beat in the form of an [[Afterdepolarization|afterdepolarisation]]. Early afterdepolarisations, occurring before the cell has fully repolarised, arise due to reactivation of calcium and sodium channels that would normally be inactivated until the next heartbeat is due.<ref name="Wit 2019">{{Cite journal|last=Wit|first=Andrew L.|date=2018-06-19|title=Afterdepolarizations and triggered activity as a mechanism for clinical arrhythmias|journal=Pacing and Clinical Electrophysiology: PACE|volume=41|issue=8|pages=883–896|doi=10.1111/pace.13419|issn=1540-8159|pmid=29920724}}</ref> Under the right conditions, reactivation of these currents can cause further depolarisation of the cell, facilitated by the [[sodium-calcium exchanger]].<ref name="Wit 2019" /> Early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell.<ref name="Wit 2019" /> Delayed afterdepolarisations, occurring after repolarisation has completed, arise from the spontaneous release of calcium from the intracellular calcium store known as the [[sarcoplasmic reticulum]]. This calcium release then leaves the cell through the sodium calcium exchanger in exchange for sodium, generating a net inward current and depolarising the cell membrane.<ref name="Wit 2019" /> If this transient inward current is large enough, a premature action potential is triggered.
* '''[[Long QT syndrome]] (types 1–6)''' – Prolonged QT interval without skeletal abnormalities.
* '''[[Catecholaminergic polymorphic ventricular tachycardia]] (CPVT)''' – Exercise-induced ventricular arrhythmias.
* '''[[Familial periodic paralysis]] (hyperkalemic or hypokalemic forms)''' – Muscle weakness without cardiac abnormalities.


The muscle weakness seen in those with Andersen–Tawil syndrome arises from the depolarisation of the resting membrane potential caused by a decrease in /<sub>K1</sub>.<ref name="Nguyen 2013" /> The depolarised resting membrane potential means that sodium channels which are responsible for initiating action potentials are unable to fully recover from inactivation, leading to a less excitable membrane and less forceful muscle contraction.<ref name="Nguyen 2013" />
== Treatment and Management ==
As a '''genetic disorder''', Andersen–Tawil syndrome has no cure. However, treatment focuses on:
* '''Preventing life-threatening arrhythmias'''.
* '''Managing periodic paralysis episodes'''.
* '''Monitoring and treating skeletal abnormalities'''.


The mechanisms underlying the skeletal abnormalities seen in Andersen–Tawil syndrome have not been fully explained. Possibilities include impaired function of [[Osteoclast|osteoclasts]], cells which regulate bone growth, or disruption of the [[bone morphogenetic protein]] signalling cascade.<ref name="Nguyen 2013" />
=== Cardiac Management ===
* '''Beta-blockers''' (e.g., '''propranolol''') help prevent arrhythmias by reducing heart excitability.
* '''Flecainide and verapamil''' may be used for arrhythmia suppression.
* '''Implantable cardioverter-defibrillators (ICDs)''' are considered for high-risk patients who have experienced life-threatening arrhythmias.


== Diagnosis==
=== Managing Periodic Paralysis ===
[[File:Syndactyly.jpg|thumb|160x160px|Foot with partial [[syndactyly]] – fusion of two toes]]
* '''Potassium supplementation''' during episodes can help '''restore muscle function'''.
Andersen–Tawil syndrome is generally diagnosed based on symptoms, the findings on examination, and the results of an [[Electrocardiography|electrocardiogram]].<ref name="Nguyen 2013" /> Clinical diagnostic criteria have been proposed which suggest that a diagnosis can be made if two of the following four criteria are met: (1) periodic paralysis; (2) ventricular arrhythmias (frequent ventricular ectopic beats or ventricular tachycardia), a prolonged QT interval when corrected for rate, and/or a prominent U wave; (3) at least two of the following dysmorphic features: low-set ears, wide-set eyes, a small mandible, fifth-digit clinodactyly, and syndactyly; and (4) a family member with confirmed Andersen–Tawil syndrome.<ref name="Nguyen 2013" />
* '''Acetazolamide (a carbonic anhydrase inhibitor)''' may reduce the frequency of attacks.
* '''Avoiding triggers''' such as fasting, stress, and excessive exercise is recommended.


Genetic testing can be used to identify the specific mutation in an affected person, which if found can assist with screening family members.<ref name="Nguyen 2013" /> Other investigations that may be helpful in making a diagnosis include [[Holter monitor|ambulatory ECG monitoring]] to assess for arrhythmias, measurement of blood potassium levels at baseline and during periods of weakness, and measurement of [[Thyroid function tests|thyroid function]].<ref name="Statland 2018" />
=== Lifestyle Considerations ===
* '''Avoid medications that prolong the QT interval''', such as '''amiodarone''' and '''sotalol'''.
* '''Mild to moderate exercise''' is encouraged, but '''competitive sports''' should be avoided due to arrhythmia risks.
* '''Regular monitoring with ECG and Holter monitoring''' is essential to track arrhythmia burden.


=== Differential diagnosis ===
== Prognosis ==
The differential diagnosis for a prolonged QT interval includes other forms of long QT syndrome such as [[Romano–Ward syndrome]] in which only the electrical activity of the heart is affected without involving any other organs; [[Jervell and Lange-Nielsen syndrome]] in which a prolonged QT interval is combined with congenital [[Hearing loss|deafness]]; and [[Timothy syndrome]] in which a prolonged QT interval is combined with abnormalities in the structure of the heart, in addition to [[Autism spectrum|autism-spectrum disorder]].<ref name="ESC Guidelines on VA/SCD">{{cite journal | vauthors = Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ | display-authors = 6 | title = 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC) | journal = Europace | volume = 17 | issue = 11 | pages = 1601–87 | date = November 2015 | pmid = 26318695 | doi = 10.1093/europace/euv319 }}</ref> The frequent ventricular ectopy and bidirectional ventricular tachycardia seen in Andersen–Tawil syndrome can also occur in [[catecholaminergic polymorphic ventricular tachycardia]].<ref name="Electrical Disease of the Heart Chapter 32" />
The '''prognosis of Andersen–Tawil syndrome''' varies depending on the severity of symptoms:
 
* '''Most individuals lead normal lives''' with appropriate treatment.
The intermittent weakness seen in Andersen–Tawil syndrome also occurs in other forms of periodic paralysis – hypokalaemic periodic paralysis, [[Hyperkalemic periodic paralysis|hyperkalaemic periodic paralysis]], and [[paramyotonia congenita]].<ref name="Statland 2018">{{cite journal | vauthors = Statland JM, Fontaine B, Hanna MG, Johnson NE, Kissel JT, Sansone VA, Shieh PB, Tawil RN, Trivedi J, Cannon SC, Griggs RC | display-authors = 6 | title = Review of the Diagnosis and Treatment of Periodic Paralysis | journal = Muscle & Nerve | volume = 57 | issue = 4 | pages = 522–530 | date = April 2018 | pmid = 29125635 | pmc = 5867231 | doi = 10.1002/mus.26009 }}</ref>
* '''Severe arrhythmias may increase the risk of sudden cardiac events''', requiring close monitoring.
 
* '''Skeletal abnormalities''' can impact mobility and may require orthopedic interventions.
== Treatment ==
As a genetic condition, Andersen–Tawil syndrome cannot be cured. However, many of symptoms of Andersen–Tawil such as blackouts due to abnormal heart rhythms or periodic paralysis can be successfully treated with [[medication]] or implantable devices. The rarity of the condition means that many of these treatments are based on consensus opinion as there are too few patients to conduct [[Power (statistics)|adequately powered]] [[clinical trial]]s.<ref name="Nguyen 2013" />
 
=== General measures ===
Medications should be avoided that further prolong the QT interval such as [[sotalol]] and [[amiodarone]] as these drugs can promote abnormal heart rhythms.<ref name="Nguyen 2013" /> Lists of medications associated with prolongation of the QT interval can be found [[CredibleMeds|online]].<ref>{{Cite journal|last=Woosley|first=Raymond L.|last2=Black|first2=Kristin|last3=Heise|first3=C. William|last4=Romero|first4=Klaus|date=February 2018|title=CredibleMeds.org: What does it offer?|journal=Trends in Cardiovascular Medicine|volume=28|issue=2|pages=94–99|doi=10.1016/j.tcm.2017.07.010|issn=1873-2615|pmid=28801207|hdl=10150/627826|url=https://repository.arizona.edu/bitstream/10150/627826/1/CM_What_does_it_offer.pdf}}</ref> Drugs which reduce blood levels of potassium such as [[diuretic]]s like [[furosemide]] and [[bendroflumethiazide]] should also be avoided as these can worsen the tendency to periodic paralysis and arrhythmias.<ref name="Nguyen 2013" /> Conversely, potassium-containing supplements to increase blood potassium levels may be helpful.<ref name="Nguyen 2013" /> Very strenuous or competitive sport should be discouraged as these may increase the risk of arrhythmias, although gentle exercise should be encouraged.<ref name="ESC Guidelines on VA/SCD" />
 
=== Arrhythmias ===
[[File:Labelled DDD ICD.jpg|thumb|Labelled chest X-ray showing an implantable cardioverter defibrillator.]]
As in other forms of long QT syndrome which predispose those affected to dangerous heart rhythm disturbances, the risk of arrhythmias can be reduced by taking [[beta blocker]]s such as [[propranolol]] that block the effects of [[adrenaline]] on the heart.<ref name="Nguyen 2013" /> Other [[Antiarrhythmic agent|antiarrhythmic drugs]] such as [[flecainide]] and [[verapamil]] may also be helpful.<ref name="Nguyen 2013" /> Those at highest risk of recurrent arrhythmias such as those who have already suffered a [[cardiac arrest]] may benefit from an [[Implantable cardioverter-defibrillator|implantable cardioverter defibrillator]] – a small device implanted under the skin which can detect dangerous arrhythmias and automatically treat them with a small [[Cardioversion|electric shock]].<ref name="Nguyen 2013" />
 
=== Periodic paralysis ===
Periodic paralysis may be improved by taking [[carbonic anhydrase inhibitor]]s such as [[acetazolamide]].<ref name="Nguyen 2013" />


== Epidemiology ==
== Epidemiology ==
Andersen–Tawil syndrome is very rare, and as of 2013 approximately 200 cases had been described in the medical literature.<ref name="Nguyen 2013">{{cite journal | vauthors = Nguyen HL, Pieper GH, Wilders R | title = Andersen-Tawil syndrome: clinical and molecular aspects | journal = International Journal of Cardiology | volume = 170 | issue = 1 | pages = 1–16 | date = December 2013 | pmid = 24383070 | doi = 10.1016/j.ijcard.2013.10.010 }}</ref> The condition is estimated to affect one person in every 1,000,000.<ref name="Nguyen 2013" />
Andersen–Tawil syndrome is an '''extremely rare condition''', affecting '''approximately 1 in 1,000,000 individuals worldwide'''. Due to its rarity, many cases remain '''undiagnosed or misdiagnosed'''.


== History ==
== History ==
Although a description of the condition had probably been made by Klein in 1963,<ref name="Nguyen 2013" /> Andersen–Tawil syndrome is named after [[Ellen Damgaard Andersen|Ellen Andersen]] who described the triad of symptoms in 1971,<ref>{{cite journal | vauthors = Andersen ED, Krasilnikoff PA, Overvad H | title = Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? | journal = Acta Paediatrica Scandinavica | volume = 60 | issue = 5 | pages = 559–64 | date = September 1971 | pmid = 4106724 | doi = 10.1111/j.1651-2227.1971.tb06990.x }}</ref> and Rabi Tawil who made significant contributions to the understanding of the condition in 1994.<ref name="pmid8080508">{{cite journal | vauthors = Tawil R, Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir C, Griggs RC | title = Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features | journal = Annals of Neurology | volume = 35 | issue = 3 | pages = 326–30 | date = March 1994 | pmid = 8080508 | doi = 10.1002/ana.410350313 }}</ref><ref>{{Cite web|url=http://www.whonamedit.com/synd.cfm/3410.html|title=Andersen's syndrome (Ellen Damgaard Andersen)|website=www.whonamedit.com|access-date=2019-09-16}}</ref>
The condition was first described in '''1971''' by '''Dr. Ellen Damgaard Andersen''', who documented the triad of symptoms. Further contributions were made by '''Dr. Rabi Tawil''' in 1994, leading to the modern understanding of the disorder.
 
== References ==
{{Reflist}}


* ''This article incorporates public domain text from [http://ghr.nlm.nih.gov The U.S. National Library of Medicine]''
== See Also ==
* '''[[Long QT syndrome]]'''
* '''[[Periodic paralysis]]'''
* '''[[Arrhythmogenic disorders]]'''
* '''[[Ion channel disorders]]'''


== External links ==
== External Links ==
{{Medical resources
{{Medical resources
| DiseasesDB     = 700
| DiseasesDB = 700
| ICD10           = {{ICD10|I|45|8|i|45}}  
| ICD10 = {{ICD10|I|45|8|i|45}}
| ICD9           = {{ICD9|426.82}}, {{ICD9|794.31}}
| ICD9 = {{ICD9|426.82}}, {{ICD9|794.31}}
| ICDO            = 
| OMIM = 170390
|  OMIM           = 170390
| MedlinePlus =
| MedlinePlus     = 
| GeneReviewsNBK = NBK1264
|  eMedicineSubj  = 
| GeneReviewsName = Andersen-Tawil syndrome
|  eMedicineTopic  = 
| Orphanet = 37553
|  MeshID          = D050030 
| GeneReviewsNBK   = NBK1264  
| GeneReviewsName = Andersen-Tawil syndrome  
| Orphanet       = 37553
}}
}}
 
{{syndromes}}
{{Heart diseases}}
[[Category:Cardiac arrhythmias]]
{{Channelopathy}}
 
{{DEFAULTSORT:Andersen-Tawil syndrome}}
[[Category:Cardiac arrhythmia]]
[[Category:Channelopathies]]
[[Category:Channelopathies]]
[[Category:Rare syndromes]]
[[Category:Rare diseases]]
[[Category:Syndromes affecting the heart]]
[[Category:Neuromuscular disorders]]
[[Category:Cardiogenetic disorders]]
[[Category:Genetic syndromes]]
{{dictionary-stub1}}
[[Category:Skeletal disorders]]
[[Category:Long QT syndrome]]

Latest revision as of 05:05, 19 March 2025

Rare autosomal dominant genetic disorder



Andersen–Tawil syndrome
Synonyms Cardiodysrhythmic potassium-sensitive periodic paralysis, long QT syndrome type 7
Pronounce
Field Cardiology
Symptoms Abnormal heart rhythms, periodic paralysis, characteristic physical features
Complications Sudden death
Onset Birth
Duration Lifelong
Types Type 1 (KCNQ2 mutation positive), Type 2 (genetic mutation not identified)
Causes Genetic
Risks
Diagnosis Clinical, genetic testing
Differential diagnosis Romano-Ward syndrome, Jervell and Lange-Nielsen syndrome, Timothy syndrome
Prevention
Treatment Medication, implantable cardioverter-defibrillator
Medication Flecainide, beta-blockers, acetazolamide
Prognosis
Frequency 1:1,000,000
Deaths


Andersen–Tawil syndrome (ATS), also known as Andersen syndrome or long QT syndrome 7, is a rare genetic disorder that affects multiple systems in the body, including the cardiovascular system, musculoskeletal system, and nervous system. It is characterized by three main features:

This condition follows an autosomal dominant pattern of inheritance and is most commonly associated with mutations in the KCNJ2 gene, which encodes a potassium ion channel essential for cardiac and muscle function. Management of Andersen–Tawil syndrome primarily focuses on controlling arrhythmias, preventing sudden cardiac death, and managing periodic paralysis episodes.

Clinical Features[edit]

Andersen–Tawil syndrome presents with a characteristic triad of:

  1. Cardiac Abnormalities – Prolongation of the QT interval, ventricular tachycardia, and increased risk of sudden cardiac events.
  2. Neuromuscular Manifestations – Recurrent episodes of muscle weakness, often triggered by hypokalemia.
  3. Dysmorphic Features – Distinctive craniofacial, skeletal, and limb anomalies.

Cardiac Abnormalities[edit]

The electrocardiogram (ECG) of an individual with Andersen–Tawil syndrome typically shows:

While ATS is associated with long QT syndrome, the risk of sudden cardiac death is lower compared to other forms of congenital long QT syndromes.

Neuromuscular Manifestations[edit]

  • Recurrent episodes of muscle weakness, lasting from minutes to hours.
  • Weakness is typically triggered by low potassium levels (hypokalemia).
  • Episodes may be provoked by exercise, stress, fasting, or certain medications.
  • Some patients experience persistent muscle weakness between episodes.

Physical Abnormalities[edit]

The skeletal and craniofacial abnormalities seen in Andersen–Tawil syndrome include:

  • Low-set ears and widely spaced eyes (hypertelorism).
  • Micrognathia – A small lower jaw.
  • Clinodactyly – Abnormal curvature of the fifth finger.
  • Syndactyly – Fusion of two or more fingers or toes.
  • Scoliosis – Abnormal curvature of the spine.
  • Short stature and high-arched palate.

Genetics and Pathophysiology[edit]

Andersen–Tawil syndrome is caused by mutations in the KCNJ2 gene, which encodes the Kir2.1 potassium channel. This ion channel plays a crucial role in regulating:

  • Cardiac repolarization, ensuring proper electrical conduction in the heart.
  • Muscle membrane potential, preventing abnormal muscle contractions and weakness.

Genetic Inheritance[edit]

  • ATS follows an autosomal dominant inheritance pattern.
  • Some cases result from de novo mutations, meaning they occur spontaneously without a family history.
  • Type 1 ATS (60% of cases) results from mutations in KCNJ2.
  • Type 2 ATS (40% of cases) is genetically undefined but may involve mutations in KCNJ5.

Mechanisms of Disease[edit]

  • Reduced Kir2.1 channel function results in abnormal potassium ion transport.
  • Increased cardiac excitability leads to prolonged repolarization and susceptibility to arrhythmias.
  • Muscle hyperexcitability and depolarization cause episodes of periodic paralysis.

Diagnosis[edit]

A diagnosis of Andersen–Tawil syndrome is based on a combination of:

  • Clinical criteria (triad of cardiac, neuromuscular, and skeletal features).
  • Electrocardiogram (ECG) findings (QT prolongation, bidirectional VT).
  • Genetic testing to identify mutations in KCNJ2 or related genes.

Diagnostic Criteria[edit]

A diagnosis is likely if two of the following are present: 1. Periodic paralysis with episodes of muscle weakness. 2. Prolonged QT interval and ventricular arrhythmias. 3. Distinctive physical features such as clinodactyly, low-set ears, and scoliosis. 4. A family history of Andersen–Tawil syndrome.

Differential Diagnosis[edit]

Conditions that may mimic Andersen–Tawil syndrome include:

Treatment and Management[edit]

As a genetic disorder, Andersen–Tawil syndrome has no cure. However, treatment focuses on:

  • Preventing life-threatening arrhythmias.
  • Managing periodic paralysis episodes.
  • Monitoring and treating skeletal abnormalities.

Cardiac Management[edit]

  • Beta-blockers (e.g., propranolol) help prevent arrhythmias by reducing heart excitability.
  • Flecainide and verapamil may be used for arrhythmia suppression.
  • Implantable cardioverter-defibrillators (ICDs) are considered for high-risk patients who have experienced life-threatening arrhythmias.

Managing Periodic Paralysis[edit]

  • Potassium supplementation during episodes can help restore muscle function.
  • Acetazolamide (a carbonic anhydrase inhibitor) may reduce the frequency of attacks.
  • Avoiding triggers such as fasting, stress, and excessive exercise is recommended.

Lifestyle Considerations[edit]

  • Avoid medications that prolong the QT interval, such as amiodarone and sotalol.
  • Mild to moderate exercise is encouraged, but competitive sports should be avoided due to arrhythmia risks.
  • Regular monitoring with ECG and Holter monitoring is essential to track arrhythmia burden.

Prognosis[edit]

The prognosis of Andersen–Tawil syndrome varies depending on the severity of symptoms:

  • Most individuals lead normal lives with appropriate treatment.
  • Severe arrhythmias may increase the risk of sudden cardiac events, requiring close monitoring.
  • Skeletal abnormalities can impact mobility and may require orthopedic interventions.

Epidemiology[edit]

Andersen–Tawil syndrome is an extremely rare condition, affecting approximately 1 in 1,000,000 individuals worldwide. Due to its rarity, many cases remain undiagnosed or misdiagnosed.

History[edit]

The condition was first described in 1971 by Dr. Ellen Damgaard Andersen, who documented the triad of symptoms. Further contributions were made by Dr. Rabi Tawil in 1994, leading to the modern understanding of the disorder.

See Also[edit]

External Links[edit]

Syndromes
General Syndromes
Metabolic Syndromes
Neurological Syndromes
Psychiatric Syndromes
Other Syndromes
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