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Jervell and Lange-Nielsen syndrome

This is part of Rare diseases.

Diagnosis: Jervell and Lange-Nielsen syndrome

Synonyms: JLNS, Surdo-cardiac syndrome, Long QT syndrome, LQTS


Publication date: 2012-11-28
Version: 1.0

The disease

Jervell and Lange-Nielsen syndrome (JLNS) is characterised by bilateral congenital hearing loss and a high risk of having abnormal heart rhythm (arrhythmia). This form of arrhythmia can lead to recurrent fainting and sudden death.

The syndrome is named after the two Norwegian physicians, Anton Jervell and Fred Lang-Nielsen, who first described the condition in 1957.

Parents of children with Jervell and Lange-Nielsen syndrome were themselves born with an increased risk of abnormal heart rhythms, but their hearing is not impaired. Their disorder is known as long QT syndrome (LQTS).

Occurrence

It is currently unknown how many people in Sweden have this syndrome, but Norway is one of the countries with the highest occurrence, with an estimated incidence of 1 newborn per 200,000. It is likely that the syndrome is equally common in Sweden, meaning that one child with the syndrome is born approximately every second year.

Cause

Jervell and Lange-Nielsen syndrome is caused by mutations in one of the two genes that regulate the production of (code for) proteins that work together in forming the ion channel that transports potassium across the cell membrane. These genes, known as KCNQ1 and KCNE1, are located on chromosomes 11 (11p15.5) and 21 (21q22.12), respectively. Two mutations, one from each parent, are required to cause potassium channel dysfunction, and in approximately 90 per cent of all cases the underlying mutations are located in KCNQ1. The child will then be diagnosed with Jervell and Lange-Nielsen syndrome. If the child only inherits one mutated gene, the diagnosis will be long QT syndrome. 

Potassium ion channels are found in many cell types, present for example in the inner ear and the heart. The mutations cause structural abnormalities in the potassium channel, impairing or disabling function. When the potassium ion channels do not function properly, deafness results as a consequence of impaired circulation of fluid (endolymph) in the cochlea. Arrhythmia is caused by abnormalities in the outflow of potassium ions in the heart muscle cells, so that it takes longer for them to recharge between beats. This will be visible in an electrocardiogram (ECG) as a prolongation of the QT interval, see figure below.

Figure: Figure: The QT interval in an ECG is measured from the start of the Q wave to the end of the T wave

Figure: The QT interval in an ECG is measured from the start of the Q wave to the end of the T wave.

Heredity

The inheritance pattern of Jervell and Lange-Nielsen syndrome is autosomal recessive, meaning that one mutated gene has been inherited from each parent. The child may either have inherited the same mutation from each parent (homozygous genotype) or two different mutations that interact to affect the function of the potassium channel (compound heterozygous genotype).

In each pregnancy there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent), in which case he or she will have the syndrome. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and, like both parents, will be a carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

Most parents of a child with Jervell and Lange-Nielsen syndrome have one mutated and one normal gene, a condition known as long QT syndrome (LQTS) or Romano-Ward syndrome. Long QT syndrome is associated with a risk of recurrent fainting and sudden death. As people with long QT syndrome may be asymptomatic, parents of children with Jervell and Lange-Nielsen syndrome may not be aware that they are carriers.

If a person with Jervell and Lange-Nielsen syndrome has children with someone who is not a carrier of the mutated gene, all the children will inherit one mutation, meaning that they will have the LQTS genotype. If a person with Jervell and Lange-Nielsen syndrome has a child with a carrier of a single copy of the mutated gene (LQTS genotype), there is a 50 per cent risk that the child will either have Jervell and Lange-Nielsen syndrome or long QT syndrome.

Occasionally, Jervell and Lange-Nielsen syndrome occurs as the result of a new mutation. In these cases one of the mutated genes is present in an individual for the first time and is not inherited from either parent. In most cases, the other mutated gene is inherited. Parents of a child with a new mutation generally do not have an increased risk of having another child with Jervell and Lange-Nielsen syndrome, but there is a risk that they will have a child with long QT syndrome. The new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.

Symptoms

Jervell and Lange-Nielsen syndrome is characterised by congenital hearing loss and a high risk of irregular heartbeats, arrhythmia. Hearing loss is profound, and individuals with the syndrome are usually deaf. The severity of the cardiac symptoms varies among individuals. Severe life-threatening arrhythmia may occur with a risk of cardiac arrest. Left untreated, the syndrome is associated with significantly reduced life expectancy.

Children

The characteristic ECG abnormalities are present at birth, and most likely also during the foetal period. Apart from long QT intervals on the ECG, it is common to have an abnormally slow heart rate. As a rule the first symptom noted by the parents is fainting. The child is suddenly pale and seems lifeless, and may be rigid or have spasms. After a minute or so the child recovers consciousness, either spontaneously or in response to shaking, and usually feels normal. The condition may be misinterpreted as epilepsy or febrile convulsions. The first fainting episode usually occurs during the first three years of life, but may also come later. It is often triggered by physical or emotional stress, for example lively play, fear, anger, fever or cold baths. As the child grows it is more likely that fainting is associated with sports or stress, and may be preceded by dizziness or heart palpitations. Arrhythmias may also occur without any evident trigger or warning sign.

For unknown reasons some individuals with Jervell and Lange-Nielsen syndrome have frequent or severe arrhythmias, while others have relatively mild cardiac symptoms that are sometimes transient. Studies have found that there is a divergence between girls and boys with the syndrome, as boys who experienced fainting early in life and have long QT intervals also have the greatest risk of severe arrhythmia. It also seems that the risk of arrhythmia increases at certain points in life and that these may also vary in relation to sex: in boys the risk is greater before puberty and in girls after puberty.

Deafness results from damage to the cochlea in the inner ear, and is not principally different from other types of congenital deafness (sensorineural hearing loss).

Adults

The risk of arrhythmias continues into adulthood, especially for women with the syndrome.

Diagnosis

The diagnosis Jervell and Lange-Nielsen syndrome should be suspected if a child who is deaf or has profound hearing loss faints or has a seizure. Apart from family medical history the only diagnostic tool needed is an ECG. The prolongation of the QT interval in a resting ECG is in general considerable enough not to be overlooked. However, the QT interval must be measured manually as the automated ECG interpretation is not reliable for QT diagnostics. In some cases the ECG registration may have to be repeated for the QT prolongation to become fully evident. The long QT interval is often also visible in an exercise ECG test. Having a slow resting heart rate for one’s age strengthens the suspicion of Jervell and Lange-Nielsen syndrome. Early diagnosis is imperative, as untreated symptoms may be life-threatening.

All newborns in Sweden are tested using otoacoustic emission (OAE), and thus hearing loss is usually detected before the age of three months. In families with known long QT syndrome newborn babies should undergo an ECG and hearing tests.

The diagnosis can also be confirmed by DNA analysis. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) are also possible. On considering genetic diagnostics the parents should be offered genetic counselling. When the mutation has been confirmed a genetic counsellor can help decide whether further investigations should be carried out to determine whether other family members also risk having heart symptoms, and need prophylactic treatment.

Treatment/interventions

There is currently no cure for the syndrome and interventions aim to prevent and preclude life-threatening conditions and to compensate as far as possible for hearing loss.
Children and adults with the syndrome should be seen by several medical specialists, and should be regularly monitored by a paediatric cardiologist or a cardiologist. It is important that different types of treatment are coordinated.

The mainstay treatment for Jervell and Lange-Nielsen syndrome is life-long beta-blocker treatment, which prevents high pulse and decreases the risk of arrhythmias. Beta-blocker therapy is well-documented and can be administered from birth. To maintain effectiveness high doses must be administered around the clock. Assistance should be offered in finding strategies that facilitate medication management. A cardiac stimulator (pacemaker), regulating heart rate, is sometimes necessary to prevent the medication from excessive slowing of the heart rhythm. Sometimes even carefully managed medical treatment fails to prevent symptoms. In these cases beta-blocker therapy should be supplemented by an implantable cardioverter defibrillator (ICD). This device monitors heartbeat and can deliver an electric shock to restore normal heart rhythm when necessary. However, there are as yet no ICD devices adapted to the requirements of small children, and in children the existing devices may generate unnecessary, unpleasant electric shocks. If necessary there are also other surgical procedures that can be performed in order to regulate heart stimulation.

The risk of arrhythmia is affected by the potassium concentration in the body, which may become imbalanced by fever or gastroenteritis. As these conditions easily lead to dehydration, and may result in severe salt deficiency, it is important to ensure adequate fluid intake and to seek medical care when needed. Several types of medication may affect potassium concentration and/or prolong the QT interval, including some antibiotics, anti-arrhythmic drugs, anti-depressants, and some dietary supplements. As these medications may be very harmful it is important to be well-informed about them (see under “Information material”). It is also important to inform personnel about the disorder in all forms of contact with the healthcare services.

Children and adults with the syndrome all need to adapt their lifestyle so that activities and situations that may increase the risk of arrhythmia are avoided. Special caution should be taken in all types of exertive physical exercise, and all physically demanding sports at a competitive level are strictly forbidden. Swimming alone is not recommended as fainting in the water poses a risk of drowning. It is also important to keep a close eye on children with Jervell and Lange-Nielsen syndrome when they swim. In general individuals with the syndrome must learn to recognize the body’s warning signs so that they can stop and rest when their pulse rate rises.

All family members and other people who come in close contact with the child, such as school and preschool personnel, must learn what to do if the child has an attack and faints. They must both be informed about the disorder and learn CPR (cardiopulmonary resuscitation). People with Jervell and Lange-Nielsen syndrome should carry medical alert identification that provides information about the diagnosis and the risk of cardiac arrest.
Having a life-threatening heart disease that affects the possibility of participating fully in activities related to preschool, school, work and leisure may feel limiting for both children and adults. It is important to compensate with suitable activities.

A great deal can be done to support and compensate for hearing loss/deafness. Early diagnosis is important, not least to ensure that the child has access to appropriate habilitation and to decrease the social isolation that may arise as a consequence of hearing loss. As the child’s hearing loss is congenital, parents need support from an audiologist and the hearing habilitation services to make decisions on potential hearing appliances, such as a cochlear implant, and to be introduced to sign language. Hearing loss restricts the possibility of communication. Therefore it is necessary to assist these children by facilitating their participation in social activities. Parents of children with Jervell and Lange-Nielsen syndrome usually have normal hearing, and must therefore be given the opportunity to learn sign language at an early stage, regardless of which hearing devices will be used. These children will eventually communicate, either by speaking, if they have a cochlear implant, or using sign language. It is important that children with cochlear implants are also given the possibility to use alternative means of communication, such as sign language.

Today most children with Jervell and Lange-Nielsen syndrome have cochlear implants, and can hear. A cochlear implant consists of a speech processor (a small computer) that is worn behind the ear and an electrode array implanted under the skin, also behind the ear. The implant converts sound into coded electrical impulses that are transferred via the electrode array to the auditory nerve, enabling the brain to interpret them as sound. Before the cochlear implant is used the speech processor is individually programmed. Infants born deaf are now commonly fitted with a cochlear implant when they are approximately one year old. The results are good, especially when the operation is performed at an early age.

In Sweden, adults with Jervell and Lange-Nielsen syndrome commonly use sign language as their first language and therefore often depend on an interpreter when communicating, whereas children with the syndrome are capable to a great extent of hearing via a cochlear implant and primarily communicate using speech, supported by sign language.

The habilitation team, with special knowledge on hearing loss and its consequences, provides psychological and educational support, as well as technical support in the form of hearing aids and other hearing assistive technology at home and at school. Treatment and support are planned according to individual needs and are carried out in close cooperation with people in the child’s/young person’s social network. There is close collaboration with the local authority, which can offer different forms of support to facilitate daily life activities.

Young people with Jervell and Lange-Nielsen syndrome should be offered career counselling. Career guidance and occupational assessment are provided by the Swedish Public Employment Service. They also assist in finding suitable workplaces.

The parents should be offered psychological support, both at the time of diagnosis and later. Children and young people with the syndrome should also be offered psychological support, adapted to the needs of the individual.

Practical advice

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National and regional resources in Sweden

Tests for DNA analysis are sent to clinical genetics laboratories at university hospitals.

Cardiologists and paediatric cardiologists at university hospitals have knowledge of long QT syndrome.

The Family Clinic for Long QT Syndrome (LQTS) at the Centre for Cardiovascular Genetics (CKG), Norrland University Hospital in Umeå, has experience of evaluation and follow-up of individuals with Jervell and Lange-Nielsen syndrome. Contact the centre via a nurse, tel: +46 90 785 13 19, email: ckg@vll.se. For further information see: www.vll.se (select “Hjärtcentrum” and then “CKG”).

Resource personnel

Håkan Eliasson, Assistant Senior Consultant, Paediatric Cardiology Unit, The Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Eva Karltorp, Senior Consultant, Ear, Nose and Throat Clinic, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Annika Rydberg, Senior Consultant, Paediatric Cardiology Unit, Norrland University Hospital, SE-901 85 Umeå, Sweden. Tel: +46 90 785 00 00, email: annika.rydberg@vll.se.

Annika Winbo, Medical Doctor, Paediatric Cardiology Clinic, Norrland University Hospital, SE-901 85 Umeå, Sweden. Tel: +46 90 785 00 00, email: annika.winbo@pediatri.umu.se.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations etc.

There is currently no specific association for families with long QT syndrome or Jervell and Lange-Nielsen syndrome.

The Swedish Heart-Children’s Association, Kammakaregatan 47, SE-111 24 Stockholm, Sweden. Tel: +46 8 442 46 50, email: kansliet@hjartebarn.org, www.hjartebarn.org.

HRF, The Swedish Association of Hard of Hearing People, Gävlegatan 16, Box 6605, SE-113 84 Stockholm, Sweden. Tel: +46 8 457 55 00, text tel: +46 8 457 55 01, fax: +46 8 457 55 03, email: hrf@hrf.se, www.hrf.se. SDR, The Swedish National Association of the Deaf. Tel: +46 247 641 00, text tel: +46 247 641 01, email: sdr@sdrf.se, www.sdr.org.

SDU, The Swedish Deaf Youth Association, Förmansvägen 2, SE-117 43 Stockholm, Sweden. Email: sdu@sdrf.se, www.sduf.se.

DHB, The Swedish National Association for Deaf, Hearing-Impaired and Language-Impaired Children, Klostergatan 15, SE-703 61 Örebro, Sweden. Tel: +46 19 17 08 30, text tel: dial +46 19 19 68 90 and give the number 019122146*, videophone: see website, email: kansliet@dhb.se, www.dhb.se.

“Barnplantorna”- The National Association for Children with Cochlear Implants and Children with Hearing Aids, Lilla Bommen 1, SE-411 04 Göteborg, Sweden. Tel: +46 31 29 34 72, fax: +46 31 69 45 73, email: info@barnplantorna.se, ww.barnplantorna.se. “Barnplantorna” represents families of children with hearing loss, using any type of hearing device.

Courses, exchanges of experience for personnel

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Research and development

Research is ongoing at Norrland University Hospital with the aim of increasing knowledge about Jervell and Lange-Nielsen syndrome. The study maps the number of individuals with the syndrome in Sweden, and compiles symptoms that may be associated with the syndrome. The study also includes interviews with all Swedish families with Jervell and Lange-Nielsen syndrome.

Information material

An information leaflet on Jervell and Lange-Nielsen syndrome summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2012-4-5). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Information (in Swedish) about long QT syndrome is available in PDF form at: www.vll.se/default.aspx?id=49409&refid=49410&parid=30449.

Information (in Swedish) on Jervell and Lange-Nielsen syndrome, written by senior physician Anders Freijd, CI Unit, Karolinska University Hospital, Huddinge: www.barnplantorna.se/UserFiles/file/artiklar/Jervell_Lange_bp06_1.pdf.

A website with an updated list on drugs that lengthen the QT time, www.qtdrugs.org/ (in English).

Information in English on Jervell and Lange-Nielsen syndrome is available at: www.healthline.com/galecontent/jervell-and-lange-nielsen-syndrome, and www.madisonsfoundation.org/index.php?option=com_mpower&task=disease&diseaseID=555.

Literature

Crotti L, Celano G, Dagradi F, Schwartz PJ. Congenital long QT syndrome. Orphanet J Rare Dis 2008; 3:18.

Fraser GR, Froggatt P, Murphy T. Genetical aspects of the cardio-auditory syndrome of Jervell and Lange-Nielsen (congenital deafness and electrocardiographic abnormalities). Ann Hum Genet 1964; 28: 133-157.

Goldenberg I, Moss AJ, Zareba W, McNitt S, Robinson JL, Qi M et al. Clinical course and risk stratification of patients affected with the Jervell and Lange-Nielsen syndrome. J Cardiovasc Electrophysiol 2006; 17: 1161-1168.

Kang SL, Jackson C, Kelsall W. Electrocardiogram screening of deaf children for long QT syndrome: are we following UK national guidelines? J Laryngol Otol 2011; 125: 354-356.

Langslet A, Sorland SJ. Surdocardiac syndrome of Jervell and Lange-Nielsen, with prolonged QT interval present at birth, and severe anaemia and syncopal attacks in childhood. Br Heart J 1975; 37: 830-832.

Schwartz PJ, Spazzolini C, Crotti L, Bathen J, Amlie JP, Timothy K et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 2006; 113: 783-790.

Siem G, Früh A, Leren TP, Heimdal K, Teig E, Harris S. Jervell and Lange-Nielsen syndrome in Norwegian children: aspects around cochlear implantation, hearing, and balance. Ear Hear 2008; 29: 261-269.

Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M. Jervell and Lange-Nielsen syndrome: a Norwegian perspective. Am J Med Genet 1999; 89: 137-146.

Yanmei F, Yaqin W, Haibo S, Huiqun Z, Zhengnong C, Dongzhen Y et al. Cochlear implantation in patients with Jervell and Lange-Nielsen syndrome, and a review of literature. Int J Pediatr Otorhinolaryngol 2008; 72: 1723-1729.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: Jervell and Lange-Nielsen syndrome

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: Jervell and Lange-Nielsen syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical experts who wrote the draft of this information material are Annika Winbo, MD, and Associate Professor Annika Rydsberg, Norrland University Hospital in Umeå.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2012-11-28
Version: 1.0
Publication date of the Swedish version: 2012-06-26

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: + 46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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