Jervell and Lange-Nielsen syndrome

Jervell and Lange-Nielsen syndrome
ICD-9	426.82
OMIM	220400
DiseasesDB	7249
MeSH	D029593

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.

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.