Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
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
electrocardiogram (a long
QT interval
The QT interval is a measurement made on an Electrocardiography, electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the QRS complex, Q wave to the end of the T wave, an ...
) and a tendency to
abnormal heart rhythms, physical characteristics including low-set ears and a
small lower jaw, and intermittent periods of muscle weakness known as
hypokalaemic periodic paralysis.
Andersen–Tawil syndrome is inherited in an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
pattern. It is caused in most cases by a
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
in the
''KCNJ2'' gene which encodes an
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
that transports
potassium
Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
out of
cardiac muscle cell
Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the Heart#Wa ...
s. The arrhythmias seen in the condition can be treated with
flecainide or
beta-blockers, but an
implantable defibrillator may sometimes be required. Periodic paralysis can be treated with
carbonic anhydrase inhibitor
Carbonic anhydrase inhibitors are a class of pharmaceuticals that suppress the activity of carbonic anhydrase. Their clinical use has been established as anti-glaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, g ...
s such as
acetazolamide
Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, acute mountain sickness, periodic paralysis, idiopathic intracranial hypertension (raised brain pressure of unclear cause), heart f ...
. 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 Andersen, and significant contributions to its understanding were made by Rabi Tawil.
Signs and symptoms
Andersen–Tawil Syndrome classically comprises three groups of features: abnormal electrical function of the heart,
hypokalemic periodic paralysis
Hypokalemic periodic paralysis (hypoKPP), also known as familial hypokalemic periodic paralysis (FHPP), is a rare, autosomal dominant channelopathy characterized by muscle weakness or paralysis when there is a fall in potassium levels in the bl ...
, and characteristic physical features, although some of those affected will not exhibit all aspects of the condition.

Andersen–Tawil syndrome affects the heart by prolonging the
QT interval
The QT interval is a measurement made on an Electrocardiography, electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the QRS complex, Q wave to the end of the T wave, an ...
, 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
abnormal heart rhythms such as
ventricular ectopy or
ventricular tachycardia
Ventricular tachycardia (V-tach or VT) is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple ...
causing
palpitations
Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest.
Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
.
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.

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
Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition, the distance between the inner eye corners, a ...
), a broad forehead and nasal root, a high arched or
cleft palate
A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
, and a long narrow head (
scaphocephaly).
Abnormalities of the limbs and spine include an abnormal curvature of the fingers, particularly the fifth finger (
clinodactyly
Clinodactyly is a medical term describing the curvature of a digit (a finger or toe) in the plane of the palm, most commonly the fifth finger (the "little finger") towards the adjacent fourth finger (the "ring finger").
It is a fairly common i ...
), fused fingers or toes (
syndactyly
Syndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, but is an unusual condition in humans. The term is .
Classification
Syndactyly can be simple or complex.
* In simple syndactyly, adja ...
), short stature, and a curved spine (
scoliosis
Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...
).
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 (
hypokalaemia
Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an ...
), 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.
Cause
Andersen–Tawil syndrome is a genetic disorder which in the majority of cases is caused by
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
in the ''
KCNJ2'' gene. The condition is often inherited from a parent in an
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
manner, but may occur due to a new genetic mutation in the affected person.
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.
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
G protein-activated inward rectifier potassium channel 4 (GIRK-4) is a protein that in humans is encoded by the ''KCNJ5'' gene and is a type of G protein-gated ion channel.
Function
Potassium channels are present in most mammalian cells, wher ...
'', have been identified in some of those with type 2 Andersen–Tawil, but in many cases a genetic mutation is not found.
The protein made by the ''KCNJ2'' gene forms an
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
that transports potassium ions into
muscle
Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
cells. This specific channel (the inward rectifier potassium channel
Kir2.1) carries a potassium current known as ''I''
K1 which is responsible for setting the
resting membrane potential
The relatively static membrane potential of quiescent cells is called the resting membrane potential (or resting voltage), as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential. The re ...
of muscle cells and is therefore critical for maintaining the normal functions of skeletal and
cardiac muscle
Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
.
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.
Mechanisms
Andersen–Tawil syndrome increases the risk of abnormal heart rhythms by disturbing the electrical signals that are used to coordinate individual
heart cells. The genetic mutation disturbs an ion channel responsible for the flow of potassium, reducing the /
K1 current. This prolongs of the
cardiac action potential
Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generati ...
– 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 cells.
Cardiac and skeletal muscle cells, when relaxed, have fewer positively charged
ions
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
on the inner side of their
cell membrane
The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
than on the outer side, referred to as their membranes being polarised.
The main ion current responsible for maintaining this polarity is /
K1, and a decrease in this current leads to less polarity at rest, or a depolarised resting membrane potential. When these cells
contract
A contract is an agreement that specifies certain legally enforceable rights and obligations pertaining to two or more parties. A contract typically involves consent to transfer of goods, services, money, or promise to transfer any of thos ...
, 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.
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.

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
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.
Under the right conditions, reactivation of these currents can cause further depolarisation of the cell, facilitated by the
sodium-calcium exchanger
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by ...
.
Early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell.
Delayed afterdepolarisations, occurring after repolarisation has completed, arise from the spontaneous release of calcium from the intracellular calcium store known as the
sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kep ...
. 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.
If this transient inward current is large enough, a premature action potential is triggered.
The muscle weakness seen in those with Andersen–Tawil syndrome arises from the depolarisation of the resting membrane potential caused by a decrease in /
K1.
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.
The mechanisms underlying the skeletal abnormalities seen in Andersen–Tawil syndrome have not been fully explained. Possibilities include impaired function of
osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
s, cells which regulate bone growth, or disruption of the
bone morphogenetic protein
Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Professor Marshall Urist and Professor Hari Reddi discovered their ability to induce the formation of bone and cartilage, BMPs are now ...
signalling cascade.
Diagnosis
Andersen–Tawil syndrome is generally diagnosed based on symptoms, the findings on examination, and the results of an
electrocardiogram.
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.
Genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
can be used to identify the specific mutation in an affected person, which if found can assist with screening family members.
Other investigations that may be helpful in making a diagnosis include
ambulatory ECG monitoring to assess for arrhythmias, measurement of blood potassium levels at baseline and during periods of weakness, and measurement of
thyroid function.
Differential diagnosis
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
deafness
Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is writte ...
; and
Timothy syndrome
Timothy syndrome is a rare autosomal dominant, autosomal-dominant disorder characterized by physical malformations, as well as neurological and developmental defects, including heart LQTS, QT-prolongation, heart arrhythmias, structural heart defec ...
in which a prolonged QT interval is combined with abnormalities in the structure of the heart, in addition to
autism-spectrum disorder
Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...
.
The frequent ventricular ectopy and bidirectional ventricular tachycardia seen in Andersen–Tawil syndrome can also occur in
catecholaminergic polymorphic ventricular tachycardia
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur du ...
.
The intermittent weakness seen in Andersen–Tawil syndrome also occurs in other forms of periodic paralysis – hypokalaemic periodic paralysis,
hyperkalaemic periodic paralysis, and
paramyotonia congenita
''Paramyotonia congenita'' (PC) is a rare congenital autosomal dominant neuromuscular disorder characterized by "paradoxical" myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical my ...
.
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
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
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
adequately powered clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s.
General measures
Medications should be avoided that further prolong the QT interval such as
sotalol
Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into ...
and
amiodarone
Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxys ...
as these drugs can promote abnormal heart rhythms.
Lists of medications associated with prolongation of the QT interval can be found
online
In computer technology and telecommunications, online indicates a state of connectivity, and offline indicates a disconnected state. In modern terminology, this usually refers to an Internet connection, but (especially when expressed as "on lin ...
. Drugs which reduce blood levels of potassium such as
diuretic
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics ...
s like
furosemide
Furosemide, sold under the brand name Lasix among others, is a loop diuretic medication used to treat edema due to heart failure, liver scarring, or kidney disease. Furosemide may also be used for the treatment of high blood pressure. It can ...
and
bendroflumethiazide
Bendroflumethiazide, formerly bendrofluazide, trade name Aprinox, is a thiazide diuretic used to treat hypertension.
Bendroflumethiazide is a thiazide diuretic which works by inhibiting sodium reabsorption at the beginning of the distal convolut ...
should also be avoided as these can worsen the tendency to periodic paralysis and arrhythmias.
Conversely, potassium-containing supplements to increase blood potassium levels may be helpful.
Very strenuous or competitive sport should be discouraged as these may increase the risk of arrhythmias, although gentle exercise should be encouraged.
Arrhythmias

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
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...
s such as
propranolol
Propranolol is a medication of the beta blocker class. It is used to treat hypertension, high blood pressure, some types of cardiac dysrhythmia, irregular heart rate, thyrotoxicosis, capillary hemangiomas, akathisia, performance anxiety, and ...
that block the effects of
adrenaline
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
on the heart.
Other
antiarrhythmic drugs such as
flecainide and
verapamil
Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be use ...
may also be helpful.
Those at highest risk of recurrent arrhythmias such as those who have already had a
cardiac arrest
Cardiac arrest (also known as sudden cardiac arrest CA is when the heart suddenly and unexpectedly stops beating. When the heart stops beating, blood cannot properly Circulatory system, circulate around the body and the blood flow to the ...
may benefit from an
implantable cardioverter defibrillator
An implantable cardioverter-defibrillator (ICD) or automated implantable cardioverter defibrillator (AICD) is a device implant (medicine), implantable inside the body, able to perform defibrillation, and depending on the type, cardioversion a ...
– a small device implanted under the skin which can detect dangerous arrhythmias and automatically treat them with a small
electric shock
An electrical injury (electric injury) or electrical shock (electric shock) is damage sustained to the skin or internal organs on direct contact with an electric current.
The injury depends on the Current density, density of the current, tissu ...
.
Periodic paralysis
Periodic paralysis may be improved by taking
carbonic anhydrase inhibitor
Carbonic anhydrase inhibitors are a class of pharmaceuticals that suppress the activity of carbonic anhydrase. Their clinical use has been established as anti-glaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, g ...
s such as
acetazolamide
Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, acute mountain sickness, periodic paralysis, idiopathic intracranial hypertension (raised brain pressure of unclear cause), heart f ...
.
Epidemiology
Andersen–Tawil syndrome is very rare, and as of 2013 approximately 200 cases had been described in the medical literature.
The condition is estimated to affect one person in every 1,000,000.
History
Although a description of the condition had probably been made by Klein in 1963,
Andersen–Tawil syndrome is named after
Ellen Andersen who described the triad of symptoms in 1971, and Rabi Tawil who made significant contributions to the understanding of the condition in 1994.
References
* ''This article incorporates public domain text fro
The U.S. National Library of Medicine'
External links
{{DEFAULTSORT:Andersen-Tawil syndrome
Cardiac arrhythmia
Channelopathies
Rare syndromes
Syndromes affecting the heart
Cardiogenetic disorders