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120-433: Long QT syndrome may be present at birth or develop later in life. The inherited form may occur by itself or as part of larger genetic disorder . Onset later in life may result from certain medications, low blood potassium , low blood calcium , or heart failure . Medications that are implicated include certain antiarrhythmics , antibiotics , and antipsychotics . LQTS can be diagnosed using an electrocardiogram (EKG) if

240-431: A corrected QT interval of greater than 450–500 milliseconds is found, but clinical findings, other EKG features, and genetic testing may confirm the diagnosis with shorter QT intervals. Management may include avoiding strenuous exercise, getting sufficient potassium in the diet, the use of beta blockers , or an implantable cardiac defibrillator . For people with LQTS who survive cardiac arrest and remain untreated,

360-471: A 15% increase in arrhythmic risk. As the QT prolonging effects of both genetic variants and acquired causes of LQTS are additive, those with inherited LQTS are more likely to experience TdP if given QT prolonging drugs or if they experience electrolyte problems such as low blood levels of low potassium ( hypokalaemia ). Similarly, those taking QT prolonging medications are more likely to experience TdP if they have

480-500: A Schwartz score of greater than 3 or if a pathogenic genetic variant associated with LQTS is identified, regardless of QT interval. Those diagnosed with LQTS are usually advised to avoid drugs that can prolong the QT interval further or lower the threshold for TDP, lists of which can be found in public access online databases . In addition to this, two intervention options are known for individuals with LQTS: arrhythmia prevention and arrhythmia termination. Arrhythmia suppression involves

600-463: 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 . 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

720-481: A gene, the new allele may affect the trait that the gene controls, altering the phenotype of the organism. However, while this simple correspondence between an allele and a trait works in some cases, most traits are more complex and are controlled by multiple interacting genes within and among organisms. Developmental biologists suggest that complex interactions in genetic networks and communication among cells can lead to heritable variations that may underlie some of

840-1073: A genetic tendency to a prolonged QT interval, even it this tendency is concealed. Arrhythmias occur more commonly in drug-induced LQTS if the medication in question has been rapidly given intravenously , or if high concentrations of the drug are present in the person's blood. The risk of arrhythmias is also higher if the person receiving the drug has heart failure , is taking digitalis , or has recently been cardioverted from atrial fibrillation . Other risk factors for developing torsades de pointes among those with LQTS include female sex, increasing age, pre-existing cardiovascular disease , and abnormal liver or kidney function . There are several subtypes of long QT syndrome. These can be broadly split into those caused by genetic mutations which those affected are born with, carry throughout their lives, and can pass on to their children (inherited or congenital long QT syndrome), and those caused by other factors which cannot be passed on and are often reversible (acquired long QT syndrome). Inherited, or congenital long QT syndrome,

960-457: 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. 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

1080-460: A mode of inheritance is also achieved primarily through statistical analysis of pedigree data. In case the involved loci are known, methods of molecular genetics can also be employed. An allele is said to be dominant if it is always expressed in the appearance of an organism (phenotype) provided that at least one copy of it is present. For example, in peas the allele for green pods, G , is dominant to that for yellow pods, g . Thus pea plants with

1200-418: 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,

1320-400: A normal QT interval at rest (concealed LQTS). Those with the longest QT intervals are more likely to experience TdP, and a corrected QT interval of greater than 500 ms is thought to represent those at higher risk. Despite this, those with only subtle QT prolongation or concealed LQTS still have some risk of arrhythmias. Overall, every 10 ms increase in the corrected QT interval is associated with

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1440-411: A part of early Lamarckian ideas on evolution. During the 18th century, Dutch microscopist Antonie van Leeuwenhoek (1632–1723) discovered "animalcules" in the sperm of humans and other animals. Some scientists speculated they saw a "little man" ( homunculus ) inside each sperm . These scientists formed a school of thought known as the "spermists". They contended the only contributions of the female to

1560-673: A process called osmosis . When evaluating sodium imbalances, both total body water and total body sodium must be considered. Hypernatremia means that the concentration of sodium in the blood is too high. An individual is considered to be having high sodium at levels above 145 mEq/L of sodium. Hypernatremia is not common in individuals with no other health concerns. Most individuals with this disorder have either experienced loss of water from diarrhea, altered sense of thirst, inability to consume water, inability of kidneys to make concentrated urine, or increased salt intake. There are three types of hypernatremia each with different causes. The first

1680-561: A prolonged QT interval with congenital deafness. Other rare forms include Andersen–Tawil syndrome (LQT7) with features including a prolonged QT interval, periodic paralysis, and abnormalities of the face and skeleton; and Timothy syndrome (LQT8) in which a prolonged QT interval is associated with abnormalities in the structure of the heart and autism spectrum disorder . LQT1 is the most common subtype of Romano–Ward syndrome, responsible for 30 to 35% of all cases. The gene responsible, KCNQ1, has been isolated to chromosome 11p 15.5 and encodes

1800-437: A prolonged QT interval, 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

1920-410: 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

2040-533: A role. Calcium, magnesium, potassium, and sodium ions are cations (+), while chloride, and phosphate ions are anions (−). Chronic laxative abuse or severe diarrhea or vomiting can lead to dehydration and electrolyte imbalance. People with malnutrition are at especially high risk for an electrolyte imbalance. Severe electrolyte imbalances must be treated carefully as there are risks with overcorrecting too quickly, which can result in arrhythmias , brain herniation , or refeeding syndrome depending on

2160-499: A small sustained 'late' sodium current. This continued inward current prolongs the action potential and thereby the QT interval. While some variants in SCN5A cause LQT3, other variants can cause quite different conditions. Variants causing a reduction in the early peak current can cause Brugada syndrome and cardiac conduction disease, while other variants have been associated with dilated cardiomyopathy . Some variants which affect both

2280-533: 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

2400-403: A variety of ideas about heredity: Theophrastus proposed that male flowers caused female flowers to ripen; Hippocrates speculated that "seeds" were produced by various body parts and transmitted to offspring at the time of conception; and Aristotle thought that male and female fluids mixed at conception. Aeschylus , in 458 BC, proposed the male as the parent, with the female as a "nurse for

2520-427: Is genetics . In humans, eye color is an example of an inherited characteristic: an individual might inherit the "brown-eye trait" from one of the parents. Inherited traits are controlled by genes and the complete set of genes within an organism's genome is called its genotype . The complete set of observable traits of the structure and behavior of an organism is called its phenotype . These traits arise from

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2640-428: 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

2760-549: Is also associated with certain types of long QT syndrome. The arrhythmias that lead to faints and sudden death are more likely to occur in specific circumstances, in part determined by which genetic variant is present. While arrhythmias can occur at any time, in some forms of LQTS arrhythmias are more commonly seen in response to exercise or mental stress (LQT1), in other forms following a sudden loud noise (LQT2), and in some forms during sleep or immediately upon waking (LQT3). Some rare forms of long QT syndrome affect other parts of

2880-421: Is caused by genetic abnormalities. LQTS can arise from variants in several genes, leading in some cases to quite different features. The common thread linking these variants is that they affect one or more ion currents leading to prolongation of the ventricular action potential , thus lengthening the QT interval. Classification systems have been proposed to distinguish between subtypes of the condition based on

3000-525: Is caused by inheriting two copies of certain variant in the KCNE1 or KCNQ1 genes. The same genetic variants lead to the LQT5 and LQT1 forms of Romano-Ward syndrome if only a single copy of the variant is inherited. JLNS is generally associated with a higher risk of arrhythmias than most other forms of LQTS. LQT7, also known as Andersen–Tawil syndrome , is characterised by a triad of features – in addition to

3120-465: Is caused by mutations in the KCNJ2 gene which encodes the potassium channel protein K ir 2.1. 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

3240-529: Is dehydration along with low total body sodium. This is most commonly caused by heatstroke, burns, extreme sweating, vomiting, and diarrhea. The second is low total body water with normal body sodium. This can be caused by diabetes insipidus , renal disease, hypothalamic dysfunction , sickle cell disease , and certain drugs. The third is increased total body sodium which is caused by increased ingestion, Conn's syndrome , or Cushing's syndrome . Symptoms of hypernatremia may vary depending on type and how quickly

3360-530: Is determining whether the deficiency is caused by a gastrointestinal or kidney problem. People with no or minimal symptoms are given oral magnesium; however, many people experience diarrhea and other gastrointestinal discomfort. Those who cannot tolerate or receive magnesium, or those with severe symptoms can receive intravenous magnesium. Hypomagnesemia may prevent the normalization of other electrolyte deficiencies. If other electrolyte deficiencies are associated, normalizing magnesium levels may be necessary to treat

3480-457: Is from kidney losses from diuretics, alcohol use, hypercalcemia, and genetic disorders. Low dietary intake can also contribute to magnesium deficiency. Hypomagnesemia is typically associated with other electrolyte abnormalities, such as hypokalemia and hypocalcemia. For this reason, there may be overlap in symptoms seen in these other electrolyte deficiencies. Severe symptoms include arrhythmias, seizures, and tetany . The first step in treatment

3600-404: Is growing evidence that there is transgenerational inheritance of epigenetic changes in humans and other animals. The description of a mode of biological inheritance consists of three main categories: These three categories are part of every exact description of a mode of inheritance in the above order. In addition, more specifications may be added as follows: Determination and description of

3720-781: Is lab error due to potassium released as blood cells from the sample break down. Other common causes are kidney disease, cell death , acidosis , and drugs that affect kidney function. Part of the danger of hyperkalemia is that it is often asymptomatic, and only detected during normal lab work done by primary care physicians. As potassium levels get higher, individuals may begin to experience nausea, vomiting, and diarrhea. Patients with severe hyperkalemia, defined by levels above 7 mEq/L, may experience muscle cramps, numbness, tingling, absence of reflexes, and paralysis. Patients may experience arrhythmias that can result in death. There are three mainstays of treatment of hyperkalemia. These are stabilization of cardiac cells , shift of potassium into

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3840-616: Is low. Chloride, after sodium, is the second most abundant electrolyte in the blood and most abundant in the extracellular fluid . Most of the chloride in the body is from salt (NaCl) in the diet. Chloride is part of gastric acid (HCl), which plays a role in absorption of electrolytes, activating enzymes, and killing bacteria. The levels of chloride in the blood can help determine if there are underlying metabolic disorders. Generally, chloride has an inverse relationship with bicarbonate, an electrolyte that indicates acid-base status. Overall, treatment of chloride imbalances involve addressing

3960-524: Is normal, stopping the source of magnesium intake is sufficient. Diuretics can help increase magnesium excretion in the urine. Severe symptoms may be treated with dialysis to directly remove magnesium from the blood. Hypomagnesemia, or low magnesium levels in the blood, can occur in up to 12% of hospitalized patients. Symptoms or effects of hypomagnesemia can occur after relatively small deficits. Major causes of hypomagnesemia are from gastrointestinal losses such as vomiting and diarrhea. Another major cause

4080-444: 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

4200-447: Is often asymptomatic, and symptoms may not appear until potassium concentration is <2.5 mEq/L. Typical symptoms consist of muscle weakness and cramping. Low potassium can also cause cardiac arrhythmias. Hypokalemia is treated by replacing the body's potassium. This can occur either orally or intravenously. Because low potassium is usually accompanied by low magnesium, patients are often given magnesium alongside potassium. Sodium

4320-428: Is people with the inherited trait of albinism , who do not tan at all and are very sensitive to sunburn . Heritable traits are known to be passed from one generation to the next via DNA , a molecule that encodes genetic information. DNA is a long polymer that incorporates four types of bases , which are interchangeable. The Nucleic acid sequence (the sequence of bases along a particular DNA molecule) specifies

4440-418: Is placement of an implantable cardioverter-defibrillator (ICD). Also, external defibrillation can be used to restore sinus rhythm. ICDs are commonly used in patients with fainting episodes despite beta blocker therapy, and in patients having experienced a cardiac arrest. As mentioned earlier, ICDs may be used also in patients considered at high risk of life-threatening arrhythmic events. With better knowledge of

4560-452: 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

4680-808: Is responsible for maintaining the magnesium levels in this narrow range. Hypermagnesemia, or abnormally high levels of magnesium in the blood, is relatively rare in individuals with normal kidney function. This is defined by a magnesium concentration >2.5 mg/dL. Hypermagnesemia typically occurs in individuals with abnormal kidney function. This imbalance can also occur with use of antacids or laxatives that contain magnesium. Iatrogenic cases of hypermagnesemia can be prevented by avoiding magnesium-containing medications. Mild symptoms include nausea, flushing, tiredness. Neurologic symptoms are seen most commonly including decreased deep tendon reflexes. Severe symptoms include paralysis, respiratory failure, and bradycardia progressing to cardiac arrest. If kidney function

4800-483: Is responsible for sensing changes in calcium concentration and regulating the electrolyte with parathyroid hormone . Hypercalcemia describes when the concentration of calcium in the blood is too high. This occurs above 10.5 mg/dL. The most common causes of hypercalcemia are certain types of cancer, hyperparathyroidism , hyperthyroidism , pheochromocytoma , excessive ingestion of vitamin D, sarcoidosis , and tuberculosis . Hyperparathyroidism and malignancy are

4920-410: Is that developmental biology (' evo-devo ') played little part in the synthesis, but an account of Gavin de Beer 's work by Stephen Jay Gould suggests he may be an exception. Almost all aspects of the synthesis have been challenged at times, with varying degrees of success. There is no doubt, however, that the synthesis was a great landmark in evolutionary biology. It cleared up many confusions, and

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5040-470: Is the most abundant electrolyte in the blood. It is a common saying in human physiology that "cells are bags of Potassium floating in a sea of Sodium " Sodium and its homeostasis in the human body is highly dependent on fluids. The human body is approximately 60% water, a percentage which is also known as total body water . The total body water can be divided into two compartments called extracellular fluid (ECF) and intracellular fluid (ICF). The majority of

5160-468: Is the most plentiful electrolyte in the body, a large percentage of it is used to form the bones. It is mainly absorbed and excreted through the GI system. The majority of calcium resides extracellularly, and it is crucial for the function of neurons , muscle cells , function of enzymes , and coagulation . The normal range for calcium concentration in the body is 8.5 - 10.5 mg/dL. The parathyroid gland

5280-451: Is the second-most common form of Romano–Ward syndrome, responsible for 25 to 30% of all cases. It is caused by variants in the KCNH2 gene (also known as hERG ) on chromosome 7 which encodes the potassium channel that carries the rapid inward rectifier current I Kr . This current contributes to the terminal repolarisation phase of the cardiac action potential, and therefore the length of

5400-484: The KCNE2 gene responsible for the potassium channel beta subunit MiRP1 which generates the potassium current I Kr . Variants that decrease this current have been associated with prolongation of the QT interval. However, subsequent evidence such as the relatively common finding of variants in the gene in those without long QT syndrome, and the general need for a second stressor such as hypokalaemia to be present to reveal

5520-514: The Moravian monk Gregor Mendel who published his work on pea plants in 1865. However, his work was not widely known and was rediscovered in 1901. It was initially assumed that Mendelian inheritance only accounted for large (qualitative) differences, such as those seen by Mendel in his pea plants – and the idea of additive effect of (quantitative) genes was not realised until R.A. Fisher 's (1918) paper, " The Correlation Between Relatives on

5640-518: The LQT1 subtype of Romano–Ward syndrome when a single copy of the variant is inherited (heterozygous, autosomal dominant inheritance). Inheriting two copies of the variant (homozygous, autosomal recessive inheritance) leads to the more severe Jervell and Lange–Nielsen syndrome. Conversely, variants in KCNQ1 that increase I Ks lead to more rapid repolarisation and the short QT syndrome . The LQT2 subtype

5760-574: The Origin of Species and his later biological works. Darwin's primary approach to heredity was to outline how it appeared to work (noticing that traits that were not expressed explicitly in the parent at the time of reproduction could be inherited, that certain traits could be sex-linked , etc.) rather than suggesting mechanisms. Darwin's initial model of heredity was adopted by, and then heavily modified by, his cousin Francis Galton , who laid

5880-489: 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

6000-428: 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. 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

6120-552: The QT interval. The LQT3 subtype of Romano–Ward syndrome is caused by variants in the SCN5A gene located on chromosome 3p22–24. SCN5A encodes the alpha subunit of the cardiac sodium channel, Na V 1.5, responsible for the sodium current I Na which depolarises cardiac cells at the start of the action potential. Cardiac sodium channels normally inactivate rapidly, but the mutations involved in LQT3 slow their inactivation leading to

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6240-463: 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. Long QT syndrome

6360-460: The QT prolongation, has suggested that this gene instead represents a modifier to susceptibility to QT prolongation. Some therefore dispute whether variants in KCNE2 are sufficient to cause Romano-Ward syndrome by themselves. LQT9 is caused by variants in the membrane structural protein, caveolin -3. Caveolins form specific membrane domains called caveolae in which voltage-gated sodium channels sit. Similar to LQT3, these caveolin variants increase

6480-605: 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

6600-501: The Supposition of Mendelian Inheritance " Mendel's overall contribution gave scientists a useful overview that traits were inheritable. His pea plant demonstration became the foundation of the study of Mendelian Traits. These traits can be traced on a single locus. In the 1930s, work by Fisher and others resulted in a combination of Mendelian and biometric schools into the modern evolutionary synthesis . The modern synthesis bridged

6720-432: The T-waves are often late onset, being preceded by a long isoelectric segment. 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. In cases of diagnostic uncertainty, other investigations may be helpful to unmask a prolonged QT. In addition to prolonging

6840-472: The United States it results in about 3,500 deaths a year. The condition was first clearly described in 1957. Many people with long QT syndrome have no signs or symptoms. When symptoms occur, they are generally caused by abnormal heart rhythms (arrhythmias), most commonly a form of ventricular tachycardia called Torsades de pointes (TdP). If the arrhythmia reverts to a normal rhythm spontaneously

6960-546: The abnormal repolarization in animals were published. Ankyrin : Long QT syndrome 4 Heredity Heredity , also called inheritance or biological inheritance , is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction , the offspring cells or organisms acquire the genetic information of their parents. Through heredity, variations between individuals can accumulate and cause species to evolve by natural selection . The study of heredity in biology

7080-427: 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

7200-416: The affected person may experience lightheadedness (known as presyncope ) or faint which may be preceded by a fluttering sensation in the chest. If the arrhythmia continues, the affected person may experience a cardiac arrest , which if untreated may lead to sudden death. Those with LQTS may also experience non-epileptic seizures as a result of reduced blood flow to the brain during an arrhythmia. Epilepsy

7320-857: The alleles in an organism. Electrolyte imbalance Electrolyte imbalance , or water-electrolyte imbalance , is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, fluid balance , oxygen delivery , acid–base balance and much more. Electrolyte imbalances can develop by consuming too little or too much electrolyte as well as excreting too little or too much electrolyte. Examples of electrolytes include calcium, chloride, magnesium, phosphate, potassium, and sodium. Electrolyte disturbances are involved in many disease processes and are an important part of patient management in medicine. The causes, severity, treatment, and outcomes of these disturbances can differ greatly depending on

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7440-535: The alpha subunit of the KvLQT1 potassium channel. This subunit interacts with other proteins (in particular, the minK beta subunit) to create the channel, which carries the delayed potassium rectifier current I Ks responsible for the repolarisation phase of the cardiac action potential . Variants in KCNQ1 that decrease I Ks (loss of function variants) slow the repolarisation of the action potential. This causes

7560-409: 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 . The following is a list of genes associated with Long QT syndrome: Although long QT syndrome

7680-460: The blood is too high. This occurs when the concentration of potassium is >5 mEq/L. It can lead to cardiac arrhythmias and even death. As such it is considered to be the most dangerous electrolyte disturbance. Hyperkalemia is typically caused by decreased excretion by the kidneys, shift of potassium to the extracellular space, or increased consumption of potassium rich foods in patients with kidney failure. The most common cause of hyperkalemia

7800-513: The blood stream causing the sodium concentration to be lower. Diagnosis of the cause of hyponatremia relies on three factors: volume status, plasma osmolality , urine sodium levels and urine osmolality . Many individuals with mild hyponatremia will not experience symptoms. Severity of symptoms is directly correlated with severity of hyponatremia and rapidness of onset. General symptoms include loss of appetite, nausea, vomiting, confusion, agitation, and weakness. More concerning symptoms involve

7920-555: The body, leading to deafness in the Jervell and Lange-Nielsen form of the condition, and periodic paralysis in the Andersen–Tawil (LQT7) form. While those with long QT syndrome have an increased risk of developing abnormal heart rhythms, the absolute risk of arrhythmias is very variable. The strongest predictor of whether someone will develop TdP is whether they have experienced this arrhythmia or another form of cardiac arrest in

8040-489: The cause of imbalance. Electrolytes are important because they are what cells (especially nerve , heart and muscle cells) use to maintain voltages across their cell membranes . Electrolytes have different functions, and an important one is to carry electrical impulses between cells. Kidneys work to keep the electrolyte concentrations in blood constant despite changes in the body. For example, during heavy exercise, electrolytes are lost in sweat , particularly in

8160-439: 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

8280-419: 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

8400-453: The cells, and removal of potassium from the body. Stabilization of cardiac muscle cells is done by administering calcium intravenously. Shift of potassium into the cells is done using both insulin and albuterol inhalers. Excretion of potassium from the body is done using either hemodialysis , loop diuretics , or a resin that causes potassium to be excreted in the fecal matter. The most common electrolyte disturbance, hypokalemia means that

8520-473: The clinical features (and named after those who first described the condition) and subdivided by the underlying genetic variant. The most common of these, accounting for 99% of cases, is Romano–Ward syndrome (genetically LQT1-6 and LQT9-16), an autosomal dominant form in which the electrical activity of the heart is affected without involving other organs. A less commonly seen form is Jervell and Lange-Nielsen syndrome, an autosomal recessive form of LQTS combining

8640-546: The concentration of potassium is <3.5 mEq/L. It often occurs concurrently with low magnesium levels. Low potassium is caused by increased excretion of potassium, decreased consumption of potassium rich foods, movement of potassium into the cells, or certain endocrine diseases . Excretion is the most common cause of hypokalemia and can be caused by diuretic use, metabolic acidosis , diabetic ketoacidosis , hyperaldosteronism , and renal tubular acidosis . Potassium can also be lost through vomiting and diarrhea. Hypokalemia

8760-463: 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 also be diagnosed if an individual has

8880-436: The direct control of genes include the inheritance of cultural traits , group heritability , and symbiogenesis . These examples of heritability that operate above the gene are covered broadly under the title of multilevel or hierarchical selection , which has been a subject of intense debate in the history of evolutionary science. When Charles Darwin proposed his theory of evolution in 1859, one of its major problems

9000-508: The early and late sodium current can cause overlap syndromes which combine aspects of both LQT3 and Brugada syndrome. LQT5 is caused by variants in the KCNE1 gene responsible for the potassium channel beta subunit MinK. This subunit, in conjunction with the alpha subunit encoded by KCNQ1, is responsible for the potassium current I Ks which is decreased in LQTS. LQT6 is caused by variants in

9120-528: The electrolyte disturbance developed. Common symptoms are dehydration, nausea, vomiting, fatigue, weakness, increased thirst, and excess urination. Patients may be on medications that caused the imbalance such as diuretics or nonsteroidal anti-inflammatory drugs . Some patients may have no obvious symptoms at all. It is crucial to first assess the stability of the patient. If there are any signs of shock such as tachycardia or hypotension , these must be treated immediately with IV saline infusion.  Once

9240-465: The form of homologous chromosomes , containing a unique combination of DNA sequences that code for genes. The specific location of a DNA sequence within a chromosome is known as a locus . If the DNA sequence at a particular locus varies between individuals, the different forms of this sequence are called alleles . DNA sequences can change through mutations , producing new alleles. If a mutation occurs within

9360-516: The form of sodium and potassium. The kidneys can also generate dilute urine to balance sodium levels. These electrolytes must be replaced to keep the electrolyte concentrations of the body fluids constant. Hyponatremia, or low sodium, is the most commonly seen type of electrolyte imbalance. Treatment of electrolyte imbalance depends on the specific electrolyte involved and whether the levels are too high or too low. The level of aggressiveness of treatment and choice of treatment may change depending on

9480-467: The framework for the biometric school of heredity. Galton found no evidence to support the aspects of Darwin's pangenesis model, which relied on acquired traits. The inheritance of acquired traits was shown to have little basis in the 1880s when August Weismann cut the tails off many generations of mice and found that their offspring continued to develop tails. Scientists in Antiquity had

9600-403: The fundamental unit of life is the cell, and not some preformed parts of an organism. Various hereditary mechanisms, including blending inheritance were also envisaged without being properly tested or quantified, and were later disputed. Nevertheless, people were able to develop domestic breeds of animals as well as crops through artificial selection. The inheritance of acquired traits also formed

9720-463: The gap between experimental geneticists and naturalists; and between both and palaeontologists, stating that: The idea that speciation occurs after populations are reproductively isolated has been much debated. In plants, polyploidy must be included in any view of speciation. Formulations such as 'evolution consists primarily of changes in the frequencies of alleles between one generation and another' were proposed rather later. The traditional view

9840-516: The genetic information: this is comparable to a sequence of letters spelling out a passage of text. Before a cell divides through mitosis , the DNA is copied, so that each of the resulting two cells will inherit the DNA sequence. A portion of a DNA molecule that specifies a single functional unit is called a gene ; different genes have different sequences of bases. Within cells , the long strands of DNA form condensed structures called chromosomes . Organisms inherit genetic material from their parents in

9960-540: The genetics underlying LQTS, more precise treatments hopefully will become available. Genotype and QTc interval duration are the strongest predictors of outcome for patients with LQTS. 2022 European Society of Cardiology clinical practice guidelines have endorsed the use of independently validated risk score calculator, called 1-2-3-LQTS-Risk Calculator, which allows to calculate individual 5-year risk of life-threatening arrhythmic events. For people who experience cardiac arrest or fainting caused by LQTS and who are untreated,

10080-545: The girl's parents reported that her older brother, also deaf, had previously died after a terrible fright. This was several decades before the ECG was invented, but is likely the first described case of Jervell and Lange-Nielsen syndrome. In 1957, the first case documented by ECG was described by Anton Jervell and Fred Lange-Nielsen , working in Tønsberg , Norway . Italian pediatrician Cesarino Romano, in 1963, and Irish pediatrician Owen Conor Ward, in 1964, separately described

10200-485: The heart. Clinically, the patients are characterized by only modest QT prolongation, but an increased propensity for atrial arrhythmias. LQT14, LQT15 and LQT16 are caused by variants in the genes responsible for calmodulin ( CALM1, CALM2, and CALM3 respectively). Calmodulin interacts with several ion channels and its roles include modulation of the L-type calcium current in response to calcium concentrations, and trafficking

10320-555: The hypercalcemia is severe and/or associated with cancer, it may be treated with bisphosphonates. For very severe cases, hemodialysis may be considered for rapid removal of calcium from the blood. Hypocalcemia describes when calcium levels are too low in the blood, usually less than 8.5 mg/dL. Hypoparathyroidism and vitamin D deficiency are common causes of hypocalcemia . It can also be caused by malnutrition , blood transfusion, ethylene glycol intoxication, and pancreatitis . Neurological and cardiovascular symptoms are

10440-423: The implicated electrolyte. The most serious electrolyte disturbances involve abnormalities in the levels of sodium , potassium or calcium . Other electrolyte imbalances are less common and often occur in conjunction with major electrolyte changes. The kidney is the most important organ in maintaining appropriate fluid and electrolyte balance, but other factors such as hormonal changes and physiological stress play

10560-403: The interaction of the organism's genotype with the environment . As a result, many aspects of an organism's phenotype are not inherited. For example, suntanned skin derives from the interaction between a person's genotype and sunlight; thus, suntans are not passed on to people's children. However, some people tan more easily than others, due to differences in their genotype: a striking example

10680-513: The late sustained sodium current, which impairs cellular repolarization . LQT10 is an extremely rare subtype, caused by variants in the SCN4B gene. The product of this gene is an auxiliary beta-subunit (Na V β4) forming cardiac sodium channels, variants in which increase the late sustained sodium current. LQT13 is caused by variants in GIRK4, a protein involved in the parasympathetic modulation of

10800-434: The laws of heredity through compiling data on family phenotypes (nose size, ear shape, etc.) and expression of pathological conditions and abnormal characteristics, particularly with respect to the age of appearance. One of the projects aims was to tabulate data to better understand why certain traits are consistently expressed while others are highly irregular. The idea of particulate inheritance of genes can be attributed to

10920-493: The mechanics in developmental plasticity and canalization . Recent findings have confirmed important examples of heritable changes that cannot be explained by direct agency of the DNA molecule. These phenomena are classed as epigenetic inheritance systems that are causally or independently evolving over genes. Research into modes and mechanisms of epigenetic inheritance is still in its scientific infancy, but this area of research has attracted much recent activity as it broadens

11040-560: The more common variant of LQTS with normal hearing, later called Romano-Ward syndrome. The establishment of the International Long-QT Syndrome Registry in 1979 allowed numerous pedigrees to be evaluated in a comprehensive manner. This helped in detecting many of the numerous genes involved. Transgenic animal models of the LQTS helped define the roles of various genes and hormones involved, and recently experimental pharmacological therapies to normalize

11160-492: The most common manifestations of hypocalcemia. Patients may experience muscle cramping or twitching, and numbness around the mouth and fingers. They may also have shortness of breath, low blood pressure, and cardiac arrhythmias. Patients with hypocalcemia may be treated with either oral or IV calcium. Typically, IV calcium is reserved for patients with severe hypocalcemia. It is also important to check magnesium levels in patients with hypocalcemia and to replace magnesium if it

11280-490: The next generation were the womb in which the homunculus grew, and prenatal influences of the womb. An opposing school of thought, the ovists, believed that the future human was in the egg, and that sperm merely stimulated the growth of the egg. Ovists thought women carried eggs containing boy and girl children, and that the gender of the offspring was determined well before conception. An early research initiative emerged in 1878 when Alpheus Hyatt led an investigation to study

11400-504: 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

11520-406: The other deficiencies. Potassium resides mainly inside the cells of the body, so its concentration in the blood can range anywhere from 3.5 mEq/L to 5 mEq/L. The kidneys are responsible for excreting the majority of potassium from the body. This means their function is crucial for maintaining a proper balance of potassium in the blood stream. Hyperkalemia means the concentration of potassium in

11640-400: The pair of alleles either GG (homozygote) or Gg (heterozygote) will have green pods. The allele for yellow pods is recessive. The effects of this allele are only seen when it is present in both chromosomes, gg (homozygote). This derives from Zygosity , the degree to which both copies of a chromosome or gene have the same genetic sequence, in other words, the degree of similarity of

11760-420: The past. Those with LQTS who have experienced syncope without an ECG having been recorded at the time are also at higher risk, as syncope in these cases is frequently due to an undocumented self-terminating arrhythmia. In addition to a history of arrhythmias, the extent to which the QT is prolonged predicts risk. While some have QT intervals that are very prolonged, others have only slight QT prolongation, or even

11880-399: The patient is stable, it is important to identify the underlying cause of hypernatremia as that may affect the treatment plan. The final step in treatment is to calculate the patients free water deficit, and to replace it at a steady rate using a combination of oral or IV fluids.  The rate of replacement of fluids varies depending on how long the patient has been hypernatremic. Lowering

12000-485: The postoperative state, and in the setting of accidental water intoxication as can be seen with intense exercise. Common causes in pediatric patients may be diarrheal illness, frequent feedings with dilute formula, water intoxication via excessive consumption, and enemas . Pseudohyponatremia is a false low sodium reading that can be caused by high levels of fats or proteins in the blood. Dilutional hyponatremia can happen in diabetics as high glucose levels pull water into

12120-495: The predominant causes. It can also be caused by muscle cell breakdown, prolonged immobilization, dehydration. The predominant symptoms of hypercalcemia are abdominal pain, constipation, extreme thirst, excessive urination, kidney stones, nausea and vomiting. In severe cases where the calcium concentration is >14 mg/dL, individuals may experience confusion, altered mental status, coma, and seizure. Primary treatment of hypercalcemia consists of administering IV fluids. If

12240-411: The process of niche construction is defined by the regular and repeated activities of organisms in their environment. This generates a legacy of effect that modifies and feeds back into the selection regime of subsequent generations. Descendants inherit genes plus environmental characteristics generated by the ecological actions of ancestors. Other examples of heritability in evolution that are not under

12360-441: The proteins produced by KCNQ1 and thereby influencing potassium currents. The precise mechanisms by which means these genetic variants prolong the QT interval remain uncertain. Jervell and Lange–Nielsen syndrome (JLNS) is a rare form of LQTS inherited in an autosomal recessive manner. In addition to severe prolongation of the QT interval, those affected are born with severe sensorineural deafness affecting both ears. The syndrome

12480-450: 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

12600-516: The risk of death within 15 years is around 50%. With careful treatment this decreases to less than 1% over 20 years. Those who exhibit symptoms before the age of 18 are more likely to experience a cardiac arrest. Inherited LQTS is estimated to affect between one in 2,500 and 7,000 people. The first documented case of LQTS was described in Leipzig by Meissner in 1856, when a deaf girl died after her teacher yelled at her. Soon after being notified,

12720-436: The risk of death within 15 years is greater than 50%. With proper treatment this decreases to less than 1% over 20 years. Long QT syndrome is estimated to affect 1 in 7,000 people. Females are affected more often than males. Most people with the condition develop symptoms before they are 40 years old. It is a relatively common cause of sudden death along with Brugada syndrome and arrhythmogenic right ventricular dysplasia . In

12840-467: The risk of stress-induced arrhythmias. Nadolol , a powerful non-selective beta blocker , has been shown to reduce the arrhythmic risk in all three main genotypes (LQT1, LQT2, and LQT3). Genotype and QT interval duration are independent predictors of recurrence of life-threatening events. Arrhythmia termination involves stopping a life-threatening arrhythmia once it has already occurred. One effective form of arrhythmia termination in individuals with LQTS

12960-439: The scope of heritability and evolutionary biology in general. DNA methylation marking chromatin , self-sustaining metabolic loops , gene silencing by RNA interference , and the three dimensional conformation of proteins (such as prions ) are areas where epigenetic inheritance systems have been discovered at the organismic level. Heritability may also occur at even larger scales. For example, ecological inheritance through

13080-444: The severity of the disturbance. If the levels of an electrolyte are too low, a common response to electrolyte imbalance may be to prescribe supplementation. However, if the electrolyte involved is sodium, the issue is often water excess rather than sodium deficiency. Supplementation for these people may correct the electrolyte imbalance but at the expense of volume overload. For newborn children, this has serious risks. Though calcium

13200-564: The sodium in the body stays in the extracellular fluid compartment. This compartment consists of the fluid surrounding the cells and the fluid inside the blood vessels. ECF has a sodium concentration of approximately 140 mEq/L. Because cell membranes are permeable to water but not sodium, the movement of water across membranes affects the concentration of sodium in the blood. Sodium acts as a force that pulls water across membranes, and water moves from places with lower sodium concentration to places with higher sodium concentration. This happens through

13320-799: The sodium level too quickly can cause cerebral edema. Hyponatremia means that the concentration of sodium in the blood is too low. It is generally defined as a concentration lower than 135 mEq/L. This relatively common electrolyte disorder can indicate the presence of a disease process, but in the hospital setting is more often due to administration of Hypotonic fluids. The majority of hospitalized patients only experience mild hyponatremia, with levels above 130 mEq/L. Only 1-4% of patients experience levels lower than 130 mEq/L. Hyponatremia has many causes including heart failure , chronic kidney disease , liver disease , treatment with thiazide diuretics, psychogenic polydipsia , and syndrome of inappropriate antidiuretic hormone secretion . It can also be found in

13440-571: 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

13560-414: The underlying cause of this electrolyte imbalance. Treat the underlying cause, which commonly includes increasing fluid intake. Magnesium is mostly found in the bones and within cells. Approximately 1% of total magnesium in the body is found in the blood. Magnesium is important in control of metabolism and is involved in numerous enzyme reactions. A normal range is 0.70 - 1.10 mmol/L. The kidney

13680-439: The underlying cause rather than supplementing or avoiding chloride. Hyperchloremia, or high chloride levels, is usually associated with excess chloride intake (e.g., saltwater drowning), fluid loss (e.g., diarrhea, sweating), and metabolic acidosis. Patients are usually asymptomatic with mild hyperchloremia. Symptoms associated with hyperchloremia are usually caused by the underlying cause of this electrolyte imbalance. Treat

13800-426: The underlying cause, which commonly includes increasing fluid intake. Hypochloremia, or low chloride levels, are commonly associated with gastrointestinal (e.g., vomiting) and kidney (e.g., diuretics) losses. Greater water or sodium intake relative to chloride also can contribute to hypochloremia. Patients are usually asymptomatic with mild hypochloremia. Symptoms associated with hypochloremia are usually caused by

13920-410: The use of medications or surgical procedures that attack the underlying cause of the arrhythmias associated with LQTS. Since the cause of arrhythmias in LQTS is early afterdepolarizations (EADs), and they are increased in states of adrenergic stimulation, steps can be taken to blunt adrenergic stimulation in these individuals. These include administration of beta receptor blocking agents , which decreases

14040-525: The young life sown within her". Ancient understandings of heredity transitioned to two debated doctrines in the 18th century. The Doctrine of Epigenesis and the Doctrine of Preformation were two distinct views of the understanding of heredity. The Doctrine of Epigenesis, originated by Aristotle , claimed that an embryo continually develops. The modifications of the parent's traits are passed off to an embryo during its lifetime. The foundation of this doctrine

14160-413: Was based on the theory of inheritance of acquired traits . In direct opposition, the Doctrine of Preformation claimed that "like generates like" where the germ would evolve to yield offspring similar to the parents. The Preformationist view believed procreation was an act of revealing what had been created long before. However, this was disputed by the creation of the cell theory in the 19th century, where

14280-515: Was directly responsible for stimulating a great deal of research in the post- World War II era. Trofim Lysenko however caused a backlash of what is now called Lysenkoism in the Soviet Union when he emphasised Lamarckian ideas on the inheritance of acquired traits . This movement affected agricultural research and led to food shortages in the 1960s and seriously affected the USSR. There

14400-418: Was the lack of an underlying mechanism for heredity. Darwin believed in a mix of blending inheritance and the inheritance of acquired traits ( pangenesis ). Blending inheritance would lead to uniformity across populations in only a few generations and then would remove variation from a population on which natural selection could act. This led to Darwin adopting some Lamarckian ideas in later editions of On

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