Knowledge on rare diseases and orphan drugs

The disease is very rare. Prevalence is unknown and varies depending on the population studied (1/100,000-1/1,000,000) but is more common in countries in which consanguineous marriage is frequent.

Almost 50% of patients become symptomatic before age of 3 years. The typical presentation of Jervell and Lange-Nielsen syndrome (JLNS) is a congenitally deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. Deafness is congenital, bilateral, profound and sensorineural. The QT interval is usually markedly prolonged (>500 ms) and associated with tachyarrhythmias (including ventricular tachycardia, episodes of Torsades de Pointes (TdP) ventricular tachycardia and ventricular fibrillation) that may cause syncope or sudden death. It is one of the most severe forms of LQTS. Patients become symptomatic much earlier than in any other LQTS form, with the exception of calmodulin-related LQTS. Almost 90% of patients have cardiac events triggered by intense or sudden emotion, competitive sports, fright or jumping into cold water.

The disease is caused by homozygous or compound heterozygous mutations in either the KCNQ1 gene (locus LQT1; 11p15.5) or the KCNE1 gene (locus LQT5; 21q22.1-q22.2) and is inherited in an autosomal recessive manner.

Diagnosis is based on the presence of congenital sensorineural deafness, long QT intervals and disease-causing mutations in either KCNQ1 or KCNE1. Molecular genetic testing is clinically available.

Differential diagnosis for hearing loss includes other forms of syndromic and nonsyndromic congenital and acquired disorders associated with sensorineural hearing loss. Differential diagnosis for cardiac events includes other forms of LQTS, electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia), orthostatic hypotension, vasovagal syncope, and drug-induced LQTS.

Prenatal testing and preimplantation genetic diagnosis may be available for families in which the disease-causing mutation is known.

The pattern of inheritance is autosomal recessive, and genetic counseling is recommended. The risk of offspring inheriting the disease is 25% where both parents are heterozygous carriers of the mutation. Parents may have Romano-Ward syndrome, but typically this is very mild.

Hearing loss in JLNS benefits from cochlear implantation. The main goal in management of JLNS is prevention of syncope, cardiac arrest and sudden death. The therapeutic approach is complicated by the early age at which most of the patients become symptomatic. As the efficacy of beta-blockers in JLNS while good is not complete, an implantable cardioverter defibrillator (ICD) should be seriously considered and, if necessary, left cardiac sympathetic denervation (LCSD). However, even with additional therapies (pacemakers, ICDs, and LCSD), more than 50% of patients experience additional symptoms and are at risk of sudden death. Family members should be trained in cardiopulmonary resuscitation as up to 95% of patients with JLNS have a cardiac event before adulthood.

More than half of untreated children die before 15 years of age.

Last update: September 2020 - Expert reviewer(s): Pr Peter SCHWARTZ