those affected may experience intermittent weakness often occurring at times when blood potassium concentrations are low (hypokalaemic periodic paralysis), and characteristic facial and skeletal abnormalities such as a small lower jaw (micrognathia), low set ears, and fused or abnormally angled fingers and toes (syndactyly and clinodactyly). the condition is inherited in an autosomal-dominant manner and is caused by mutations in the kcnj2 gene which encodes the potassium channel protein kir2.1. timothy syndrome (lqt8) main article: timothy syndrome lqt8, also known as timothy syndrome combines a prolonged qt interval with fused fingers or toes (syndactyly). abnormalities of the structure of the heart are commonly seen including ventricular septal defect, tetralogy of fallot, and hypertrophic cardiomyopathy. the condition presents early in life and the average life expectancy is 2.5 years with death most commonly caused by ventricular arrhythmias. many children with timothy syndrome who survive longer than this have features of autism spectrum disorder. timothy syndrome is caused by variants in the calcium channel cav1.2 encoded by the gene cacna1c. table of associated genes the following is a list of genes associated with long qt syndrome: type omim gene notes lqt1 192500 kcnq1 encodes the α-subunit of the slow delayed rectifier potassium channel kv7.1 carrying the potassium current iks. lqt2 152427 kcnh2 also known as herg. encodes the α-subunit of the rapid delayed rectifier potassium channel kv11.1 carrying the potassium current ikr. lqt3 603830 scn5a encodes the α-subunit of the cardiac sodium channel nav1.5 carrying the sodium current ina. lqt4 600919 ank2 encodes ankyrin b which anchors the ion channels in the cell. disputed whether truly disease causing versus minor qt susceptibility gene. lqt5 176261 kcne1 encodes mink, a potassium channel β-subunit. heterozygous inheritance causes romano–ward, homozygous inheritance causes jervell and lange–nielsen syndrome. lqt6 603796 kcne2 encodes mirp1, a potassium channel β-subunit. disputed whether truly disease causing versus minor qt susceptibility gene. lqt7 170390 kcnj2 encodes inward rectifying potassium current kir2.1 carrying the potassium current ik1. causes andersen–tawil syndrome. lqt8 601005 cacna1c encodes the α-subunit cav1.2 of the calcium channel cav1.2 carrying the calcium current ica(l). causes timothy syndrome. lqt9 611818 cav3 encodes caveolin-3, responsible for forming membrane pouches known as caveolae. mutations in this gene may increase the late sodium current ina. lqt10 611819 scn4b encodes the β4-subunit of the cardiac sodium channel. lqt11 611820 akap9 encodes a-kinase associated protein which interacts with kv7.1. lqt12 601017 snta1 encodes syntrophin-α1. mutations in this gene may increase the late sodium current ina. lqt13 600734 kcnj5 also known as girk4, encodes g protein-sensitive inwardly rectifying potassium channels (kir3.4) which carry the potassium current ik(ach). lqt14 616247 calm1 encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ica(l). lqt15 616249 calm2 encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current ica(l). lqt16 114183 calm3 encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ica(l). acquired main article: drug-induced qt prolongation although long qt syndrome is often a genetic condition, a prolonged qt interval associated with an increased risk of abnormal heart rhythms can also occur in people without a genetic abnormality, commonly due to a side effect of medications. drug-induced qt prolongation is often a result of treatment by antiarrhythmic drugs such as amiodarone and sotalol, antibiotics such as erythromycin, or antihistamines such as terfenadine. other drugs which prolong the qt interval include some antipsychotics such as haloperidol and ziprasidone, and the antidepressant citalopram. lists of medications associated with prolongation of the qt interval such as the crediblemeds database can be found online. other causes of acquired lqts include abnormally low levels of potassium (hypokalaemia) or magnesium (hypomagnesaemia) within the blood. this can be exacerbated following a sudden reduction in the blood supply to the heart (myocardial infarction), low levels of thyroid hormone (hypothyroidism), and a slow heart rate (bradycardia). anorexia nervosa has been associated with sudden death, possibly due to qt prolongation. the malnutrition seen in this condition can sometimes affect the blood concentration of salts such as potassium, potentially leading to acquired long qt syndrome, in turn causing sudden cardiac death. the malnutrition and associated changes in salt balance develop over a prolonged period of time, and rapid refeeding may further disturb the salt imbalances, increasing the risk of arrhythmias. care must therefore be taken to monitor electrolyte levels to avoid the complications of refeeding syndrome. factors which prolong the qt interval are additive, meaning that a combination of factors (such as taking a qt-prolonging drug and having low levels of potassium) can cause a greater degree of qt prolongation than each factor alone. this also applies to some genetic variants which by themselves only minimally prolong the qt interval but can make people more susceptible to significant drug-induced qt prolongation. mechanisms cellular mechanisms leading to arrhythmias in long qt syndrome the various forms of long qt syndrome, both congenital and acquired, produce abnormal heart rhythms (arrhythmias) by influencing the electrical signals used to coordinate individual heart cells. the common theme is a prolongation of the cardiac action potential – the characteristic pattern of voltage changes across the cell membrane that occur with each heart beat. heart cells when relaxed normally have fewer positively charged ions on the inner side of their cell membrane than on the outer side, referred to as the membrane being polarised. when heart cells contract, positively charged ions such as sodium and calcium enter the cell, equalising or reversing this polarity, or depolarising the cell. 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. in long qt syndrome it takes longer for this repolarisation to occur, shown in individual cells as a longer action potential while being marked on the surface ecg as a long qt interval. the prolonged action potentials can lead to arrhythmias through several mechanisms. the arrhythmia characteristic of long qt syndrome, torsades de pointes, starts when an initial action potential triggers further abnormal action potentials in the form of afterdepolarisations. early afterdepolarisations, occurring before the cell has fully repolarised, are particularly likely to be seen when action potentials are prolonged, and arise due to reactivation of calcium and sodium channels that would normally switch off until the next heartbeat is due. under the right conditions, reactivation of these currents, facilitated by the sodium-calcium exchanger, can cause further depolarisation of the cell. the early afterdepolarisations triggering arrhythmias in long qt syndrome tend to arise from the purkinje fibres of the cardiac conduction system. early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell. some research suggests that delayed afterdepolarisations, occurring after repolarisation has completed, may also play a role in long qt syndrome. this form of afterdepolarisation originates from the spontaneous release of calcium from the intracellular calcium store known as the sarcoplasmic reticulum, forcing calcium out of cell through the sodium calcium exchanger in exchange for sodium, generating a net inward current. while there is strong evidence that the trigger for torsades de pointes comes from afterdepolarisations, it is less certain what sustains this arrhythmia. some lines of evidence suggest that repeated afterdepolarisations from many sources contribute to the continuing arrhythmia. however, some suggest that the arrhythmia sustains through a mechanism known as re-entry. according to this model, the action potential prolongation occurs to a variable extent in different layers of the heart muscle with longer action potentials in some layers than others. in response to a triggering impulse, the waves of depolarisation will spread through regions with shorter action potentials but block in regions with longer action potentials. this allows the depolarising wavefront to bend around areas of block, potentially forming a complete loop and self-perpetuating. the twisting pattern on the ecg can be explained by movement of the core of the re-entrant circuit in the form of a meandering spiral wave. diagnosis measurement of the qt interval with normal and prolonged qt intervals range of qt intervals expected in healthy males, healthy females, and those with long qt syndrome. diagnosing long qt syndrome is challenging. whilst the hallmark of lqts is prolongation of the qt interval, the qt interval is highly variable among both those who are healthy and those who have lqts. this leads to overlap between the qt intervals of those with and without lqts. 2.5% of those with genetically proven lqts have a qt interval within the normal range. conversely, given the normal distribution of qt intervals, a proportion of healthy people will have a longer qt interval than any arbitrary cutoff. other factors beyond the qt interval should therefore be taken into account when making a diagnosis, some of which have been incorporated into scoring systems. electrocardiogram characteristic ecg patterns associated with the three major subtypes of inherited long qt syndrome long qt syndrome is principally diagnosed by measuring the qt interval corrected for heart rate (qtc) on a 12-lead electrocardiogram (ecg). long qt syndrome is associated with a prolonged qtc, although in some genetically proven cases of lqts this prolongation can be hidden, known as concealed lqts. the qtc is less than 450 ms in 95% of normal males, and less than 460 ms in 95% of normal females. lqts is suggested if the qtc is longer than these cutoffs. however, as 5% of normal people also fall into this category, some suggest cutoffs of 470 and 480 ms for males and females respectively, corresponding with the 99th centiles of normal values. the major subtypes of inherited lqts are associated with specific ecg features. lqt1 is typically associated with broad-based t-waves, whereas the t-waves in lqt2 are notched and of lower amplitude, whilst in lqt3 the t-waves are often late onset, being preceded by a long isoelectric segment. schwartz score t-wave alternans in an individual with long qt syndrome the schwartz score has been proposed as a method of combining clinical and ecg factors to assess how likely an individual is to have an inherited form of lqts. the table below lists the criteria used to calculate the score. schwartz score to aid diagnosis of inherited long qt syndrome. corrected qt interval (qtc) ≥ 480 ms 3 points qtc defined according to bazett's correction 460–470 ms 2 points 450 ms and male gender 1 point torsades de pointes 2 points t-wave alternans 1 point notched t-waves in at least 3 leads 1 point low heart rate for age (children) 0.5 points syncope with stress 2 points cannot receive points both for syncope and torsades without stress 1 point congenital deafness 0.5 points family history other family member with confirmed lqts 1 point same family member cannot be counted for lqts and sudden death sudden cardiac death in immediate family member aged <30 0.5 point score: 0–1 : low probability of lqts; 2–3 : intermediate probability of lqts; ≥ 4 : high probability of lqts other investigations in cases of diagnostic uncertainty, other investigations may be helpful to unmask a prolonged qt. in addition to prolonging the resting qt interval, lqts may affect how the qt changes in response to exercise and stimulation by catecholamines such as adrenaline. provocation tests, in the form of exercise tolerance tests or direct infusion of adrenaline, can be used to detect these abnormal responses. these investigations are most useful for identifying those with concealed congenital type 1 lqts 1 (lqt1) who have a normal qt interval at rest. while in healthy persons the qt interval shortens during exercise, in those with concealed lqt1 exercise or adrenaline infusion may lead to paradoxical prolongation of the qt interval, revealing the underlying condition. guideline cutoffs international consensus guidelines differ on the degree of qt prolongation required to diagnose lqts. the european society of cardiology recommends that, with or without symptoms or other investigations, lqts can be diagnosed if the corrected qt interval is longer than 480ms. they recommend that a diagnosis can be considered in the presence of a qtc of greater than 460 ms if unexplained syncope has occurred. the heart rhythm society guidelines are more stringent, recommending qtc cutoff of greater than 500 ms in the absence of other factors that prolong the qt, or greater than 480 ms with syncope. both sets of guidelines agree that lqts can