Jervell and Lange-Nielsen syndrome

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Jervell and Lange-Nielsen syndrome
Other namesLong QT interval-deafness syndrome [1]
Jervell and Lange-Nielsen features.jpg
The features of Jervell and Lange-Nielsen syndrome include a prolonged QT interval and sensorineural deafness
Specialty Cardiology
Symptoms Blackouts, seizures, sensorineural deafness
Complications Sudden death
Usual onsetCongenital
CausesGenetic
Differential diagnosis Other forms of Long QT syndrome
Treatment Beta blockers, implantable cardioverter defibrillator

Jervell and Lange-Nielsen syndrome (JLNS) is a rare type of long QT syndrome associated with severe, bilateral sensorineural hearing loss. [2] Those with JLNS are at risk of abnormal heart rhythms called arrhythmias, which can lead to fainting, seizures, or sudden death. JLNS, like other forms of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. It is caused by genetic variants responsible for producing ion channels that carry transport potassium out of cells. The condition is usually diagnosed using an electrocardiogram, but genetic testing can also be used. Treatment includes lifestyle measures, beta blockers, and implantation of a defibrillator in some cases. It was first described by Anton Jervell and Fred Lange-Nielsen in 1957. [3]

Contents

Symptoms and signs

Jervell and Lange-Nielsen syndrome causes severe sensorineural hearing loss from birth, affecting both ears. Those affected have a prolonged QT interval on an electrocardiogram and are at risk of abnormal heart rhythms (arrhythmias), which can cause dizziness, blackouts, or seizures. [2] In general, JLNS affects the heart more severely than other forms of long QT syndrome. 90% of those with JLNS experience arrhythmias, with 50% becoming symptomatic by the age of 3. [4] In some cases these arrhythmias lead to sudden death.[ citation needed ]

Genetics

Jervell and Lange-Nielsen syndrome is inherited in an autosomal recessive manner Autorecessive.svg
Jervell and Lange-Nielsen syndrome is inherited in an autosomal recessive manner

Jervell and Lange-Nielsen syndrome is caused by mutations in the KCNE1 and KCNQ1 genes. The proteins produced by these two genes work together to form a potassium channel that transports positively charged potassium ions out of cells, which is called the slow delayed rectifier potassium current. The movement of potassium ions through these channels is critical for maintaining the normal functions of the inner ear and cardiac muscle. [5] JLNS is an autosomal recessive disorder meaning that two copies of the genetic mutation are required to produce the full syndrome. Mutations in the same genes can produce milder Romano-Ward forms of long QT syndrome if only a single copy of the genetic mutation has been inherited.[ citation needed ]

About 90% of cases of Jervell and Lange-Nielsen syndrome are caused by mutations in the KCNQ1 gene, leading to Jervell and Lange-Nielsen syndrome type 1 (JLNS1). KCNE1 mutations are responsible for the remaining 10% of cases, causing Jervell and Lange-Nielsen syndrome type 2 (JLNS2). Mutations in these genes alter the usual structure and function of potassium channels or prevent the assembly of normal channels. These changes disrupt the flow of potassium ions in the inner ear and in cardiac muscle, leading to the hearing loss and irregular heart rhythm characteristic of Jervell and Lange-Nielsen syndrome. [5]

TypeOMIMGeneNotes
JLNS1 192500 KCNQ1 Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs. [6]
JLNS2 176261 KCNE1 Encodes MinK, a potassium channel β-subunit. [6]

Diagnosis

ECG from a 10-year-old boy with Jervell and Lange-Nielsen syndrome PMC5376485 Adadi 2017 Jervell Lange Nielsen ECG.jpg
ECG from a 10-year-old boy with Jervell and Lange-Nielsen syndrome
Comparison of ECGs from a single family showing unaffected family member (top), Romano-Ward syndrome (middle) and Jervell and Lange-Nielsen syndrome (bottom) PMC2322962 Zhang 2008 Comparison of normal, Romano-Ward and Jervell-Lange-Nielsen ECGs in same family.jpg
Comparison of ECGs from a single family showing unaffected family member (top), Romano-Ward syndrome (middle) and Jervell and Lange-Nielsen syndrome (bottom)

The sensorineural hearing loss in Jervell and Lange-Nielsen syndrome is present from birth and can be diagnosed using audiometry or physiological tests of hearing. [7] The cardiac features of JLNS can be diagnosed by measuring the QT interval corrected for heart rate (QTc) on a 12-lead electrocardiogram (ECG). The QTc is less than 450 ms in 95% of normal males, and less than 460 ms in 95% of normal females. In those with Jervell and Lange-Nielsen syndrome the QTc is typically greater than 500 ms. [8]

Other factors beyond the QT interval should be taken into account when making a diagnosis, some of which have been incorporated into scoring systems such as the Schwartz score. These factors include a history of characteristic abnormal heart rhythms (Torsades de Pointes), unexplained blackouts (syncope), and a family history of confirmed LQT syndrome. Genetic testing to identify variants in the KCNQ1 or KCNE1 genes can also be used. [8]

Treatment

The risk of arrhythmias can be reduced in several ways. Medications that further prolong the QT interval such as sotalol should be avoided, as should very strenuous or competitive exercise. [2] Blood potassium levels should be kept within the normal range. Potassium supplements may be used at times when potassium is being lost such as when experiencing diarrhoea or vomiting, but medications that encourage the retention of potassium such as spironolactone or amiloride may also be required. [2] [9] Beta blockers such as propranolol or nadolol reduce the risk of arrhythmias. [9]

An implantable defibrillator, a small device that monitors the heart rhythm and can automatically deliver an electric shock to restart the heart, may be used. These devices are recommended for those with JLNS who have experienced a cardiac arrest or a blackout whilst taking beta blockers. [9] Due to the higher risk of arrhythmias associated with JLNS than other forms of long QT syndrome, a defibrillator may be considered even in those without any symptoms. [9]

In those who experience recurrent arrhythmias despite medical therapy, a surgical procedure called sympathetic denervation can be used to interrupt the nerves that stimulate the heart. [2]

Prognosis

The risk of arrhythmias is higher for those with Jervell and Lange-Nielsen syndrome than other forms of long QT syndrome. [10] Although this risk is dependent on the underlying genetic defect and degree of QT prolongation, without treatment more than 50% of those affected will die before the age of 15. [11] However, treatment with beta blockers markedly reduces the risk of death, as does, in selected cases, implantation of a defibrillator. [11]

Epidemiology

Jervell and Lange-Nielsen syndrome affects an estimated one in 166,000 to 625,000 children, and is responsible for less than 10% of all cases of long QT syndrome. It has a markedly higher incidence in Norway and Sweden at up to one per 200,000. [5]

Related Research Articles

<span class="mw-page-title-main">Brugada syndrome</span> Heart conduction disease

Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syncope. The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest. They may be triggered by a fever.

<span class="mw-page-title-main">Long QT syndrome</span> Medical condition

Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death. These episodes can be triggered by exercise or stress. Some rare forms of LQTS are associated with other symptoms and signs including deafness and periods of muscle weakness.

<span class="mw-page-title-main">Short QT syndrome</span> Medical condition

Short QT syndrome (SQT) is a very rare genetic disease of the electrical system of the heart, and is associated with an increased risk of abnormal heart rhythms and sudden cardiac death. The syndrome gets its name from a characteristic feature seen on an electrocardiogram (ECG) – a shortening of the QT interval. It is caused by mutations in genes encoding ion channels that shorten the cardiac action potential, and appears to be inherited in an autosomal dominant pattern. The condition is diagnosed using a 12-lead ECG. Short QT syndrome can be treated using an implantable cardioverter-defibrillator or medications including quinidine. Short QT syndrome was first described in 2000, and the first genetic mutation associated with the condition was identified in 2004.

<span class="mw-page-title-main">Torsades de pointes</span> Type of abnormal heart rhythm

Torsades de pointes, torsade de pointes or torsades des pointes is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). It was described by French physician François Dessertenne in 1966. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm, occurring in between 1% and 10% of patients who receive QT-prolonging antiarrhythmic drugs.

<span class="mw-page-title-main">Ventricular tachycardia</span> Medical condition of the heart

Ventricular tachycardia 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 episodes over a short period of time are referred to as an electrical storm. Short periods may occur without symptoms, or present with lightheadedness, palpitations, or chest pain. Ventricular tachycardia may result in ventricular fibrillation (VF) and turn into cardiac arrest. This conversion of the VT into VF is called the degeneration of the VT. It is found initially in about 7% of people in cardiac arrest.

<span class="mw-page-title-main">QT interval</span> Measurement made on an electrocardiogram

The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken from when the cardiac ventricles start to contract to when they finish relaxing. An abnormally long or abnormally short QT interval is associated with an increased risk of developing abnormal heart rhythms and sudden cardiac death. Abnormalities in the QT interval can be caused by genetic conditions such as long QT syndrome, by certain medications such as sotalol or pitolisant, by disturbances in the concentrations of certain salts within the blood such as hypokalaemia, or by hormonal imbalances such as hypothyroidism.

<span class="mw-page-title-main">Romano–Ward syndrome</span> Medical condition

Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.

<span class="mw-page-title-main">Andersen–Tawil syndrome</span> Rare autosomal dominant genetic disorder

Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram 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.

<span class="mw-page-title-main">KvLQT1</span> Protein-coding gene in the species Homo sapiens

Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the KCNQ1 gene. Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardiac tissue and in inner ear neurons among other tissues. In the cardiac cells, Kv7.1 mediates the IKs (or slow delayed rectifying K+) current that contributes to the repolarization of the cell, terminating the cardiac action potential and thereby the heart's contraction. It is a member of the KCNQ family of potassium channels.

hERG Mammalian protein found in humans

hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating.

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy. It is defined as the sudden and unexpected, non-traumatic and non-drowning death of a person with epilepsy, without a toxicological or anatomical cause of death detected during the post-mortem examination.

SCN5A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.

<span class="mw-page-title-main">KCNE1</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.

<span class="mw-page-title-main">Catecholaminergic polymorphic ventricular tachycardia</span> Medical condition

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 during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.

<span class="mw-page-title-main">KCNE2</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. MiRP1 is a voltage-gated potassium channel accessory subunit associated with Long QT syndrome. It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.

<span class="mw-page-title-main">KCNE3</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, Isk-related family, member 3 (KCNE3), also known as MinK-related peptide 2(MiRP2) is a protein that in humans is encoded by the KCNE3 gene.

<span class="mw-page-title-main">KCNE5</span> Protein-coding gene in the species Homo sapiens

KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.

QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an ECG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation.

<span class="mw-page-title-main">Fred Lange-Nielsen</span>

Fred Lange-Nielsen was a Norwegian doctor and jazz musician, known in the early Oslo environments, and from several recordings.

References

  1. ↑ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Jervell and Lange Nielsen syndrome". www.orpha.net. Retrieved 28 May 2019.{{cite web}}: CS1 maint: numeric names: authors list (link)
  2. 1 2 3 4 5 Tester DJ, Schwartz PJ, Ackerman MJ (2013). "Congenital Long QT Syndrome". In Gussak I, Antzelevitch C (eds.). Electrical Diseases of the Heart. London: Springer. pp. 439–469. doi:10.1007/978-1-4471-4881-4_27. ISBN   978-1-4471-4881-4.
  3. ↑ Jervell, A.; Lange-Nielsen, F. (1957). "Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval, and sudden death". American Heart Journal. 54 (1): 59–68. doi:10.1016/0002-8703(57)90079-0. PMID   13435203.
  4. ↑ Crotti, Lia; Celano, Giuseppe; Dagradi, Federica; Schwartz, Peter J. (2008-07-07). "Congenital long QT syndrome". Orphanet Journal of Rare Diseases. 3: 18. doi: 10.1186/1750-1172-3-18 . ISSN   1750-1172. PMC   2474834 . PMID   18606002.
  5. 1 2 3 Tranebjaerg, L.; Samson, R.A.; Green, G.E. (1993). "Jervell and Lange-Nielsen Syndrome". GeneReviews . University of Washington, Seattle. PMID   20301579 . Retrieved 29 November 2013.
  6. 1 2 Giudicessi, John R.; Wilde, Arthur A. M.; Ackerman, Michael J. (October 2018). "The genetic architecture of long QT syndrome: A critical reappraisal". Trends in Cardiovascular Medicine. 28 (7): 453–464. doi:10.1016/j.tcm.2018.03.003. ISSN   1873-2615. PMC   6590899 . PMID   29661707.
  7. ↑ Shearer, A. Eliot; Hildebrand, Michael S.; Smith, Richard JH (1993). "Genetic Hearing Loss Overview". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.). Hereditary Hearing Loss and Deafness Overview. University of Washington, Seattle. PMID   20301607 . Retrieved 2020-05-03.{{cite book}}: |work= ignored (help)
  8. 1 2 Tranebjærg, Lisbeth; Samson, Ricardo A.; Green, Glenn Edward (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Jervell and Lange-Nielsen Syndrome", GeneReviews®, University of Washington, Seattle, PMID   20301579 , retrieved 2020-05-03
  9. 1 2 3 4 Priori, Silvia G.; Blomström-Lundqvist, Carina; Mazzanti, Andrea; Blom, Nico; Borggrefe, Martin; Camm, John; Elliott, Perry Mark; Fitzsimons, Donna; Hatala, Robert; Hindricks, Gerhard; Kirchhof, Paulus (2015-11-01). "2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)". European Heart Journal. 36 (41): 2793–2867. doi: 10.1093/eurheartj/ehv316 . hdl: 11380/1140282 . ISSN   0195-668X. PMID   26320108.
  10. ↑ Giudicessi, John R.; Ackerman, Michael J. (October 2013). "Genotype- and phenotype-guided management of congenital long QT syndrome". Current Problems in Cardiology. 38 (10): 417–455. doi:10.1016/j.cpcardiol.2013.08.001. ISSN   1535-6280. PMC   3940076 . PMID   24093767.
  11. 1 2 Pabba, Krishna; Chakraborty, Rebanta K. (2019), "Jervell and Lange Nielsen Syndrome", StatPearls, StatPearls Publishing, PMID   30725985 , retrieved 2019-06-17

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