Information on the following diseases can be found in the Related Disorders section of this report:

• Romano-Ward Syndrome
• Epilepsy

Symptoms of Jervell and Lange-Nielsen syndrome are usually apparent during early childhood. Hearing loss is detected at birth (congenital) or during early childhood. Hearing loss associated with Jervell and Lange-Nielsen syndrome is caused by an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) and affects both ears (bilateral). In Jervell and Lange-Nielsen syndome hearing loss is usually profound.

The most common cardiac symptom associated with Jervell and Lange-Nielsen syndrome is partial or total loss of consciousness (syncope) accompanied by abnormally fast heart rhythms known as torsade de pointes (TdPs). TdPs may progress to 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 Jervell and Lange-Nielsen syndrome 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 precipitating factors. 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 Jervell and Lange-Nielsen syndrome. The severity and frequency of episodes often decrease during middle age.
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Jervell and Lange-Nielsen syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

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 a carrier for the disease, but usually will not show symptoms. 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%.

Some cases of Jervell and Lange-Nielsen syndrome have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) 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.

Researchers have determined that most cases of Jervell and Lange-Nielsen syndrome are caused by disruptions or changes (mutations) of one of two different genes (KCNQ1 or KCNE1). More than 90 percent of cases of Jervell and Lange-Nielsen syndrome 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.

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).
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Jervell and Lange-Nielsen syndrome affects males and females in equal numbers. The prevalence of the disorder is 1-6 in 1,000,000 live births. The disorder has a higher prevalence in Norway (1 in 200,000).
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Symptoms of the following disorders can be similar to those of Jervell and Lange-Nielsen syndrome. Comparisons may be useful for a differential diagnosis:

Romano-Ward syndrome is a rare genetic heart disorder characterized by abnormalities affecting the electrical system of the heart. The severity of Romano-Ward syndrome varies greatly from case to case. 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. Romano-Ward syndrome is inherited as an autosomal dominant trait.
(For more information on this disorder, choose "Romano-Ward" as your search term in the Rare Disease Database.)

Brugada syndrome is a rare inherited heart disorder characterized by abnormalities of the heart's electrical system. The symptoms vary greatly from case to case. Some affected individuals will experience no apparent symptoms (asymptomatic); others may develop irregular heartbeats leading to episodes of unconsciousness (syncopes), cardiac arrest, and, potentially, sudden death often during sleep. Brugada syndrome is inherited as an autosomal dominant trait.

Acquired long QT syndrome is a rare heart disorder characterized by heart rhythm abnormalities potentially resulting in loss of consciousness, cardiac arrest, and sudden death. The disorder most often occurs secondary to the administration of certain medications. Some researchers believe affected individuals may be genetically susceptibility to the development of acquired long QT syndrome. Neurological disorders, strokes, and electrolyte imbalances have also been indicated as potential causes of acquired long QT syndrome.

Epilepsy is a group of disorders of the central nervous system characterized by repeated convulsive electrical (paroxysomal) disturbances of the brain. Major symptoms may include loss of consciousness, convulsive seizures, spasms, sensory confusion, and disturbances in the nerves that control involuntary body functions (autonomic nervous system dysfunction). Episodes may be preceded by an aura, described as a feeling of uneasiness or sensory discomfort that comes before a seizure. The most common causes of recurring epilepsy in infants and children include genetic inborn errors of metabolism, developmental brain defects, injuries or trauma to the head before or after birth, and other metabolic or brain-related disorders. (For more information on this group of disorders, choose "Epilepsy" as your search term in the Rare Disease Database.)
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Diagnosis
A diagnosis of Jervell and Lange-Nielsen syndrome 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 Jervell and Lange-Nielsen syndrome. An electrocardiogram records the heart's electrical impulses, may reveal abnormal electrical patterns such as a prolonged QT interval characteristic of individuals with Jervell and Lange-Nielsen syndrome. A diagnosis can be confirmed through tests to detect disease-specific mutations in the KCNQ1 gene or the KCNE1 gene.

Treatment
The treatment of individuals with Jervell and Lange-Nielsen syndrome is aimed at treating hearing loss and preventing characteristic symptoms such as loss of consciousness or cardiac arrest. Specific medications, avoidance of triggering events, and certain medical devices may all be used to treat individuals with Jervell and Lange-Nielsen syndrome.

Hearing loss in individuals with Jervell and Lange-Nielsen syndrome 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 Jervell and Lange-Nielsen syndrome 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 antiarrythmic drug therapy.

Some individuals with Jervell and Lange-Nielsen syndrome are encouraged to avoid potential triggering events such as jumping into cold water, amusement park rides or competitive sports. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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An implantable device, the QT-sensitive cybernetic pacemaker, is also being tested for individuals with high-risk Jervell and Lange-Nielsen syndrome. 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 Jervell and Lange-Nielsen syndrome 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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:220400; Last Update:2/10/03.

TEXTBOOKS
Towbin JA. Romano-Ward Long QT Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:54.

Towbin JA. Jervell and Lange-Nielsen Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:51-52.

Buyse ML, ed. Birth Defects Encyclopedia. Blackwell Scientific Publications, 1990:281-82.

Braunwald E, ed. Heart Disease. A Textbook of Cardiovascular Medicine. 3rd ed. Philadelphia, PA: W. B. Saunders Company; 1988:749, 1635.

JOURNAL ARTICLES
Chorbachi R, et al. Cochlear implantation in Jervell and Lange-Nielsen syndrome. Int J Pediatr Otorhinolaryngol. 2002;66:213-21.

Monning G, et al. Clinical aspects and molecular genetics of the Jervell- and Lange-Nielsen syndrome. Z Kardiol. 2002;91:380-88.

Wang Z, et al. Compound heterozygous mutations in KvLQT1 case Jervell and Lange-Nielsen syndrome. Mol Genet Metab. 2002;75:308-16.

Towbin JA, Vatta M, Molecular biology and prolonged QT syndromes. Am J Med. 2001;110:385-98.

Tyson J, et al. Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen. Hum Genet. 2000;107:499-503. Erratum in: Hum Genet. 2001;108:75.

Mannens M, et al. KVLQT1, the rhythm of imprinting. Nature Genetics. 1997;15:113-17.

Neyroud N, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Genetics. 1997;15:186-89.

Weintraub RG, et al. The congenital long QT syndrome. J Am Coll Cardiol. 1990;16:674-80.

Gospe SM, et al. Hereditary long Q-T syndrome presenting as epilepsy: electroenceph laboratory diagnosis. Ann Neurol. 1989;25:514-16.

Kossmann CE The long Q-T interval and syndromes. Adv Intern Med. 1987;32:87-110.

FROM THE INTERNET
Zareba W, Rosero S. Long QT Syndrome. eMedicine Journal. 2002;3:11pp. Available at http://www.emedicine.com.

Daley SM, Tranebjaerg L, Samson RA, Green GE. Updated:1/13/2003. Jervell and Lange-Nielsen Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.