NORD gratefully acknowledges Theresa Lai, NORD Editorial Intern from the University of Notre Dame, and Professor Lisbeth Tranebjærg, MD, PhD, Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark, for assistance in the preparation of this report.
Jervell and Lange-Nielsen syndrome (JLNS) is a rare inherited disorder characterized by deafness present at birth (congenital) occurring in association with abnormalities affecting the electrical system of the heart. The severity of cardiac symptoms associated with JLNS varies from person to person. Some individuals may have no apparent symptoms (asymptomatic); others may develop abnormally increased heartbeats (tachyarrhythmias) resulting in episodes of unconsciousness (syncope), cardiac arrest, and potentially sudden death. Physical activity, excitement, fright, or stress may trigger the onset of these symptoms. Fainting during the aforementioned activities is also a classic sign of JLNS. JLNS is usually detected during early childhood and is inherited as an autosomal recessive genetic disorder. More than half of the untreated cases of JLNS result in death before the age of 15.
Anton Jervell and Fred Lange-Nielsen provided the first complete description of the electrical conduction problem in the heart called long QT syndrome (LQTS) in 1957. LQTS refers to the QT-interval measured on the electrocardiogram that indicates that the heart muscle is taking longer than usual to recharge between beats. It predisposes those affected to tachyarrhythmias called torsade de pointes (TdP) which leads to syncope and may cause sudden cardiac death.
Symptoms of JLNS are usually apparent during early childhood. Hearing loss is detected at birth or during early childhood. Hearing loss associated with JLNS is caused by the inability of the auditory nerves to transmit sensory information to the brain (sensorineural hearing loss) and affects both ears (bilateral). In JLNS hearing loss is usually profound, but it tends to affect the hearing of high frequencies more than low frequencies. Low levels of iron and increased levels of gastrin are often present in patients with JLNS, possibly leading to iron deficient anemia.
The most common cardiac symptom associated with JLNS is partial or total loss of consciousness (syncope or fainting) accompanied by abnormally fast heart rhythms known as torsade de pointes (TdPs). TdPs may progress to a more serious condition known as ventricular fibrillation in which the heart’s normal electrical activity becomes disordered resulting uncoordinated heartbeats and malfunction of the main pumping chambers of the heart (ventricles). Consequently, little or no blood is pumped from the heart. Ventricular fibrillation potentially results in cardiac arrest or sudden death.
Symptoms of JLNS such as syncope tend to occur without warning and to recur unexpectedly. Overexertion, excitement or stress may trigger these recurrent symptoms, although they often begin without any particular cause too. In some cases, episodes may be triggered by “startle” events such as an alarm clock going off or the phone ringing in the middle of the night. The severity and frequency of attacks vary. Some people may have mild chest pain with no loss of consciousness; others may lose consciousness completely or have grand mal seizures followed by a period of disorientation. In some cases seizures may be the first presenting cardiac symptom of JLNS. The severity and frequency of episodes often decrease during middle age. The seizures are frequently misdiagnosed as epilepsy and treated accordingly for several years before the correct diagnosis is made.
Researchers have determined that most cases of JLNS are caused by disruptions or changes (mutations) of one of two different genes (KCNQ1 or KCNE1). Most of these mutations result in the truncation, or premature shortening of the protein length. This results in a dysfunctional protein. More than 90 percent of cases of JLNS are caused by mutations of the KCNQ1 gene. These two genes produce (encode) proteins essential to the function of the ion channels of the heart and the snail-like tube that forms part of the inner ear (cochlea). Ion channels regulate the movement of electrically charged particles (e.g., potassium and sodium ions) in certain structures of the ear and heart. These ions carry electrical impulses necessary for hearing and the normal function of the heart. Mutations of these genes result in abnormal function of the ion channels and, in turn, affect hearing and the proper function of the heart’s electrical system
JLNS is inherited as an autosomal recessive genetic disorder, caused by mutations in both copies of a gene, one received from the father and one from the mother.
Investigators have determined that the KCNQ1 gene is located on the short arm (p) of chromosome 11 (11p15.5). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p15.5” refers to band 15 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The KCNE1 gene is located on the long arm (q) of chromosome 21 (21q22.1-q22.2).
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be heterozygous and a carrier for the disease, but usually will not show symptoms. Some carriers of a KCNQ1 or KCNE1 gene mutation have disruption of the normal cardiac rhythm, but their hearing is usually normal. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. Among unaffected sibs in a sibship with a recessive disorder, the risk of being a carrier is 2/3, or 67%.
Some cases of JLNS have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
JLNS affects males and females in equal numbers, but females seem to have a lower number of life-threatening events. JLNS is generally present in early childhood with a 90% chance of symptomatic problems by the age of 18. The prevalence of the disorder is 1 to 6 people per 1,000,000 live births. The disorder has a higher prevalence in Norway as well as Sweden (both are 1 in 200,000).
A diagnosis of JLNS is made based upon a thorough clinical evaluation, a detailed patient history and a specialized test called an electrocardiogram (ECG or EKG). Children with congenital sensorineural hearing loss, particularly those with an unexplained history of fainting, syncope or sudden cardiac arrest, should be evaluated for JLNS. An electrocardiogram records the heart’s electrical impulses, may reveal abnormal electrical patterns such as a prolonged QT interval characteristic of individuals with JLNS. A diagnosis can be confirmed through molecular genetic tests that detect disease-specific mutations in the KCNQ1 gene or the KCNE1 gene. Gene sequencing of the KCNQ1 gene is usually performed as a first step since most affected individuals have mutations in this gene. The diagnosis is crucial to make before anesthesia and surgery, i.e. for insertion of a cochlear implant in congenitally deaf children because of the risk of cardiac severe complications in the case of JLNS.
The treatment of individuals with JLNS is aimed at treating hearing loss and preventing characteristic symptoms such as loss of consciousness or cardiac arrest. Specific medications, avoidance of triggering events such as competitive sports, triggers that elicit intense emotions (Tranebjaerg L et al, GeneReviews), and certain medical devices may all be used to treat individuals with JLNS.
Hearing loss in individuals with JLNS may be treated with a small device known as a cochlear implant. Unlike hearing aids, which increase and clarify sound, a cochlear implant improves hearing by stimulating nerve fibers within the inner ear.
The treatment of choice for cardiac abnormalities in most individuals with JLNS is drug therapy with beta-adrenergic agents (beta blockers). Beta blockers, which include propranolol, atenolol, and nadolol, reduce the workload of the heart by decreasing the electrical stimulation of the heart.
Individuals for whom beta blockers are unsuccessful may be treated by a surgical procedure in which certain nerves going to the heart are removed (left cardiac sympathetic denervation or sympathectomy). However, recently treatment with an implantable automatic cardioverter-defibrillator (ICD) has replaced sympathectomy as the treatment of choice in these individuals. This device detects the abnormal heartbeat automatically and selectively delivers an electrical impulse to the heart. ICDs are used in conjunction with antiarrhythmic drug therapy.
Some individuals with JLNS are encouraged to avoid potential triggering events such as jumping into cold water, amusement park rides or competitive sports. Individuals with JLNS and professionals treating these patients for various diseases including those unrelated to JLNS, are strongly encouraged to be familiar with all the types of medication which may provoke serious cardiac attacks (https://www.crediblemeds.org/)
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
An implantable device, the QT-sensitive cybernetic pacemaker, is also being tested for individuals with high-risk JLNS. This unit may be able to monitor heart rhythm and detect development of severe heart beat irregularities. Effectiveness and side effects of these implanted devices have not been fully documented and more extensive research is being pursued before their therapeutic value for JLNS can be evaluated.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Contact for additional information about Jervell and Lange-Nielsen syndrome:
Professor Lisbeth Tranebjærg, MD, PhD
Department of Audiology
DK-2400 Copenhagen NV, Denmark
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