Jervell and Lange-Nielsen syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: 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 with 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.

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:

Type	Chromosome Locus	Gene Mutation	Protein Involved
Jervell and Lange-Nielsen syndrome 1	11p15​.5-p15.4	KCNQ1	Potassium voltage-gated channel subfamily KQT member 1
Jervell and Lange-Nielsen syndrome 2	21q22​.12	KCNE1	Potassium voltage-gated channel subfamily E member 1

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

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

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

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

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.

Hearing Loss Severity	Hearing Threshold
Mild hearing loss	26-40 Decibels
Moderate hearing loss	41-55 Decibels
Moderately severe hearing loss	56-70 Decibels
Severe hearing loss	71-90 Decibels
Profound hearing loss	90 Decibels

Heart

Representative electrocardiograms (ECG) from members of a family with LQTS. Top, ECG from a normal family member (I-1); Middle, ECG from a heterozygous mutation carrier; Bottom, ECG from a homozygous mutation carrier.

• 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

ECG in Jervell and Lange-Nielsen syndrome shows markedly prolonged corrected QT interval (QTc). Case courtesy by Jae Suk Baek et al

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

Imaging Findings

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

Treatment

Medical Therapy

• Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
• Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
• Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
• 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).

Disease Name

• 1 Stage 1 - Name of stage
  • 1.1 Specific Organ system involved 1
    • 1.1.1 Adult
      • Preferred regimen (1): drug name 100 mg PO q12h for 10-21 days (Contraindications/specific instructions)
      • Preferred regimen (2): drug name 500 mg PO q8h for 14-21 days
      • Preferred regimen (3): drug name 500 mg q12h for 14-21 days
      • Alternative regimen (1): drug name 500 mg PO q6h for 7–10 days
      • Alternative regimen (2): drug name 500 mg PO q12h for 14–21 days
      • Alternative regimen (3): drug name 500 mg PO q6h for 14–21 days
    • 1.1.2 Pediatric
      • 1.1.2.1 (Specific population e.g. children < 8 years of age)
        • Preferred regimen (1): drug name 50 mg/kg PO per day q8h (maximum, 500 mg per dose)
        • Preferred regimen (2): drug name 30 mg/kg PO per day in 2 divided doses (maximum, 500 mg per dose)
        • Alternative regimen (1): drug name10 mg/kg PO q6h (maximum, 500 mg per day)
        • Alternative regimen (2): drug name 7.5 mg/kg PO q12h (maximum, 500 mg per dose)
        • Alternative regimen (3): drug name 12.5 mg/kg PO q6h (maximum, 500 mg per dose)
      • 1.1.2.2 (Specific population e.g. 'children < 8 years of age')
        • Preferred regimen (1): drug name 4 mg/kg/day PO q12h（maximum, 100 mg per dose）
        • Alternative regimen (1): drug name 10 mg/kg PO q6h (maximum, 500 mg per day)
        • Alternative regimen (2): drug name 7.5 mg/kg PO q12h (maximum, 500 mg per dose)
        • Alternative regimen (3): drug name 12.5 mg/kg PO q6h (maximum, 500 mg per dose)
  • 1.2 Specific Organ system involved 2
    • 1.2.1 Adult
      • Preferred regimen (1): drug name 500 mg PO q8h
    • 1.2.2 Pediatric
      • Preferred regimen (1): drug name 50 mg/kg/day PO q8h (maximum, 500 mg per dose)

• 2 Stage 2 - Name of stage
  • 2.1 Specific Organ system involved 1

    Note (1):

    Note (2):

    Note (3):

    • 2.1.1 Adult
      • Parenteral regimen
        • Preferred regimen (1): drug name 2 g IV q24h for 14 (14–21) days
        • Alternative regimen (1): drug name 2 g IV q8h for 14 (14–21) days
        • Alternative regimen (2): drug name 18–24 MU/day IV q4h for 14 (14–21) days
      • Oral regimen
        • Preferred regimen (1): drug name 500 mg PO q8h for 14 (14–21) days
        • Preferred regimen (2): drug name 100 mg PO q12h for 14 (14–21) days
        • Preferred regimen (3): drug name 500 mg PO q12h for 14 (14–21) days
        • Alternative regimen (1): drug name 500 mg PO q6h for 7–10 days
        • Alternative regimen (2): drug name 500 mg PO q12h for 14–21 days
        • Alternative regimen (3):drug name 500 mg PO q6h for 14–21 days