Jervell and Lange-Nielsen syndrome
Synonyms and keywords: Autosomal recessive long QT syndrome (LQTS), cardioauditory syndrome, cardioauditory syndrome of Jervell and Lange-Nielsen, deafness, congenital, and functional heart disease, Jervell and Lange-Nielsen (JLNS), surdocardiac syndrome

# Overview
Jervell and Lange-Nielsen syndrome is a rare autosomal recessive condition that leads to sensorineural deafness, abnormal ventricular myocardial repolarization which results in long QT syndrome (LQTS) and other cardiac events. Jervell and Lange-Nielsen syndrome is due to KCNQ1 or KCNE1 gene mutations. The range of symptoms and severity of symptoms in Jervell and Lange-Nielsen syndrome differs from patient to patient. In The United States of America in order to categorise a condition as a rare disease it should affect fewer than 200,000 people. Rare diseases also called as orphan diseases. Orphan Drug Act was passed on 1983 by congress for the rare diseases. Today an average of 25-30 million americans have been reported with rare diseases. The number of people with individual rare disease may be less but overall the number of people with rare diseases are large in number.

# Historical Perspective
- Jervell and Lange-Nielsen syndrome (JLNS) was first discovered by Anton Jervell a Norwegian physician and Fred Lange-Nielsen a Norwegian doctor and jazz musician, in 1957.

# Classification
- Jervell and Lange-Nielsen syndrome (JLNS) may be classified according into two subtypes:

# Pathophysiology

## Physiology
The normal physiology of KCNQ1 and KCNE1 genes can be understood as follows:
- Both KCNQ1 and KCNE1 genes encodes for the slow potassium channel currents of the cochlea and the heart.
- Normally the slow potassium channel currents were stimulated by the sound, when stimulated the potassium from the scala media passes the action potential through the apex of the hair cells.
- The potassium action potential then depolarises the hair cells.
- Once depolarised there is a release calcium-channel-induced release of neurotransmitter.
- The neurotransmitter then passes along with the auditory nerve and then depolarizes and the currents are sent centrally where they are received as sound.

## Pathogenesis
- It is understood that Jervell and Lange-Nielsen syndrome (JLNS) is the result of mutations in the gene KCNQ1 and KCNE1.
KCNQ1
- KCNQ1 gene normally consists of 16 exons and have a general spanning of 400 kb.
- The normal gene product of KCNQ1 gene is potassium voltage-gated channel subfamily KQT member 1.
- When KCNQ1 gene undergoes frameshift mutation it results in yielding truncated protein.
- Then the truncated protein either delete or duplicate the exons of the KCNQ1 gene and results in abnormal gene product which is known to result in long QT syndrome.
KCNE1
- KCNE1 gene normally consists of 3 exons and have a general spanning of 40 kb.
- The normal gene product of KCNE1 gene is potassium voltage-gated channel subfamily E member 1.
- Potassium voltage-gated channel subfamily E member 1 is also called as minK potassium channel protein beta subunit.
- When KCNE1 gene undergoes missense mutation it results in yielding truncated protein.
- Then the truncated protein results in impairing potassium channel function, which is known to result in long QT syndrome.

# Genetics
- Jervell and Lange-Nielsen syndrome (JLNS) is transmitted in a autosomal recessive pattern.
- Jervell and Lange-Nielsen syndrome appear to have low penetrance.
- Genes involved in the pathogenesis of Jervell and Lange-Nielsen syndrome (JLNS) include:
KCNQ1
KCNE1
- KCNQ1
- KCNE1

# Causes

## Genetic Causes
- Jervell and Lange-Nielsen syndrome (JLNS) is caused by a mutation in the KCNQ1 and KCNE1 genes.

# Differentiating Jervell and Lange-Nielsen syndrome from other Diseases
- Jervell and Lange-Nielsen syndrome (JLNS)  must be differentiated from Romano-Ward syndrome, Timothy syndrome, Andersen-Tawil syndrome, Brugada syndrome, and Sudden infant death syndrome (SIDS).

# Epidemiology and Demographics

## Incidence
- The incidence of Jervell and Lange-Nielsen syndrome (JLNS) is approximately 1 per 100,000 individuals in Norway.
- The incidence of Jervell and Lange-Nielsen syndrome (JLNS) is approximately 1 per 100,000 individuals in Sweden.
- It is estimated that Jervell and Lange-Nielsen syndrome (JLNS) affects 166,000 to 625,000 children worldwide.

## Prevalence
- The prevalence of Jervell and Lange-Nielsen syndrome (JLNS) is approximately 1:200,000 individuals in Norway.

## Age
- The incidence of Jervell and Lange-Nielsen syndrome (JLNS)  increases with age; the median age at diagnosis is 6.8 years.
- The exact time of presentation in Jervell and Lange-Nielsen syndrome (JLNS)  is highly variable.

## Gender
- Jervell and Lange-Nielsen syndrome (JLNS) affects men and women equally. But the severity of cardiac events is much more common in men.

# Risk Factors
- The most potent risk factor in the development of Jervell and Lange-Nielsen syndrome (JLNS) is KCNQ1 and KCNE1 genes mutation.
- Other common risk factors in the development of Jervell and Lange-Nielsen syndrome (JLNS) symptoms include sudden sleep arousal, exercise and intense or sudden emotion which include the following:
Competitive sports
Amusement park rides
Frightening movies
Jumping into cold water
- Competitive sports
- Amusement park rides
- Frightening movies
- Jumping into cold water

# Screening
- According to the American College of Medical Genetics, screening for Jervell and Lange-Nielsen syndrome (JLNS) by hearing evaluation which is standard and electrocardiograms is recommended among patients with a family history.

# Natural History, Complications and Prognosis

## Natural History
- The symptoms of Jervell and Lange-Nielsen syndrome (JLNS) usually develop in the first or second of life, and start with symptoms such as hearing loss and syncope.

## Complications
- Common complications of Jervell and Lange-Nielsen syndrome (JLNS) include:
Cardiac arrhythmias
Seizures
Sudden cardiac death
- Cardiac arrhythmias
- Seizures
- Sudden cardiac death

## Prognosis
- Depending on the severity of the genetic mutation at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as poor as most of the untreated patients die around the age of 15 years.
- The prognosis varies with the gender, gene mutation and baseline QTc interval.

# Diagnosis

### Diagnostic Study of Choice
- Molecular genetic testing is the gold standard test for the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS) which includes single-gene testing, use of a multigene testing panel, and more comprehensive genomic testing.
- The following result of molecular genetic testing is confirmatory of Jervell and Lange-Nielsen syndrome (JLNS):
KCNQ1 or KCNE1 pathogenic gene mutation variants identification
- KCNQ1 or KCNE1 pathogenic gene mutation variants identification

# History and Symptoms

## Common Symptoms
Common symptoms of Jervell and Lange-Nielsen syndrome (JLNS) include:
- Congenital Deafness: Usually identified at the time of birth, most commonly sensorineural hearing loss and is due to disruption of endolymph homeostasis in the cochlea and vestibular system
- Syncope: Due to abnormal heart rhythm and is typically precipitous and without warning
- Seizures: Most commonly grand mal seizures
- Palpitations
- Mild to moderate chest pain
- Ventricular fibrillation
- Sudden cardiac death

# Physical Examination

## HEENT
- All patients with Jervell and Lange-Nielsen syndrome (JLNS) are positive for profound bilateral congenital sensorineural deafness.

## Heart
- Cardiovascular examination of patients with Jervell and Lange-Nielsen syndrome (JLNS) shows Long QTc.
- Patients with Jervell and Lange-Nielsen syndrome (JLNS) shows QTc interval more than 500 mse.
- Palpitations

# Laboratory Findings
Laboratory findings consistent with the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS) include:
- Anemia: patients with Jervell and Lange-Nielsen syndrome (JLNS) are more prone to develop anemia especially iron deficiency anemia
- Hypergastrinemia is due to the potassium channels defect
- Increased gastrin levels due to gastric hyperplasia

# Electrocardiogram
An ECG may be helpful in the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS). Findings on an ECG diagnostic of Jervell and Lange-Nielsen syndrome (JLNS) include the following:
- Prolongation of the QTc interval greater than 500 msec
- Tachyarrhythmias: due to abnormal cardiac depolarization and cardiac repolarization
- Ventricular tachycardia
- Torsade de pointes ventricular tachycardia
- Ventricular fibrillation
Stress ECG or a treadmill ECG Testing also may be helpful in the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS)

# Imaging Findings
There are no other imaging findings associated with Jervell and Lange-Nielsen syndrome (JLNS).

# Treatment

## Medical Therapy
- Patients with Jervell and Lange-Nielsen syndrome (JLNS) are treated with beta-adrenergic blockers as the first line in the management of the disease.
- In patients with Jervell and Lange-Nielsen syndrome (JLNS) despite treated with the beta-blockers risk of cardiac events still persists.
- Propranolol and nadolol are the beta-blockers of choice when treating a patient with Jervell and Lange-Nielsen syndrome (JLNS). Of the two nadolol is the preference of choice due to less favorable pharmacokinetic profile of propranolol.
 Preferred regimen (1): Nadolol  11.5 mg/kg/day administered once a day in patients 12 years of age, divided twice daily in infants and children
- Preferred regimen (1): Nadolol  11.5 mg/kg/day administered once a day in patients 12 years of age, divided twice daily in infants and children
Acute Management of Torsades de pointes
- The treatment of choice for hemodynamically unstable patients acute management of Torsades de pointes in Jervell and Lange-Nielsen syndrome (JLNS) patients are with the following:
Electrical cardioversion or defibrillation
If ventricular tachycardia is suspected or diagnosed treat the patient with cardiopulmonary resuscitation and the advanced cardiac life support (ACLS) protocol has to be initiated.
- Electrical cardioversion or defibrillation
- If ventricular tachycardia is suspected or diagnosed treat the patient with cardiopulmonary resuscitation and the advanced cardiac life support (ACLS) protocol has to be initiated.
- If the patient is hemodynamically stable or cardioversion fails then treat the patient with following:
Preferred regimen (1): Magnesium sulfate 2050 mg/kg intravenously initially up to 2 grams max.
- Preferred regimen (1): Magnesium sulfate 2050 mg/kg intravenously initially up to 2 grams max.

# Interventions
- The feasibility of interventions depends on the severity of Jervell and Lange-Nielsen syndrome (JLNS) patients at the time of diagnosis which include:
Implantable cardioverter-defibrillators (ICDs)
ICDs are reserved for the patients who undergone cardiac arrest resuscitation
ICDs are good alternative choice of treatment for the patients who are resistant to beta blockers
Left cardiac sympathetic denervation (LCSD)
LCSDs are reserved for the patients who are not compatible with beta blocker or Implantable cardioverter-defibrillators (ICDs)
- Implantable cardioverter-defibrillators (ICDs)
ICDs are reserved for the patients who undergone cardiac arrest resuscitation
ICDs are good alternative choice of treatment for the patients who are resistant to beta blockers
- ICDs are reserved for the patients who undergone cardiac arrest resuscitation
- ICDs are good alternative choice of treatment for the patients who are resistant to beta blockers
- Left cardiac sympathetic denervation (LCSD)
LCSDs are reserved for the patients who are not compatible with beta blocker or Implantable cardioverter-defibrillators (ICDs)
- LCSDs are reserved for the patients who are not compatible with beta blocker or Implantable cardioverter-defibrillators (ICDs)

# Surgery
- Surgical intervention is not the first line for the management of Jervell and Lange-Nielsen syndrome (JLNS). But it is recommended for the patients who are having hearing problem which includes the following:
Cochlear implantation: Which is safe and improves the quality of life
- Cochlear implantation: Which is safe and improves the quality of life

# Primary Prevention
- There are no established measures for the primary prevention of Jervell and Lange-Nielsen syndrome (JLNS).

# Secondary Prevention
- Effective measures for the secondary prevention of Jervell and Lange-Nielsen syndrome (JLNS) include:
Taking special care while giving the anesthesia due to the risk of cardiac arrhythmias
Avoiding intense or sudden emotions which are trigger for syncope
- Taking special care while giving the anesthesia due to the risk of cardiac arrhythmias
- Avoiding intense or sudden emotions which are trigger for syncope