Jervell And Lange-Nielsen Syndrome 1

A number sign (#) is used with this entry because of evidence that this form of Jervell and Lange-Nielsen syndrome (JLNS1) is caused by homozygous or compound heterozygous mutations in the KCNQ1 gene (607542) on chromosome 11p15.

Long QT syndrome-1 (LQT1; 192500), also known as Ward-Romano syndrome, is caused by heterozygous mutation in the KCNQ1 gene.

Description

The Jervell and Lange-Nielsen syndrome is an autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death (Jervell and Lange-Nielsen, 1957).

Genetic Heterogeneity of Jervell and Lange-Nielsen Syndrome

Also see JLNS2 (612347), caused by mutation in the KCNE1 gene (176261) on chromosome 21q22.

Clinical Features

Jervell and Lange-Nielsen (1957) reported a family in which 4 of 6 children, born to unrelated parents, had congenital deafness and prolonged QT interval and died suddenly in childhood. Levine and Woodworth (1958) reported a boy with the same features who died at age 13; no mention was made of parental consanguinity.

Fraser et al. (1964) suggested that heterozygous family members of persons with JLNS may show slight or moderate prolongation of the QT interval.

In studies of the temporal bones of 2 children who died with this condition, Friedmann et al. (1966) found a striking anomaly in the form of PAS-positive hyaline nodules throughout both the cochlear and the vestibular portions of the membranous labyrinth in, or adjacent to, the terminal vessels of the vascular stria. Intracardiac electrophysiologic studies can be done to ascertain more precisely the risk of ventricular fibrillation. In this as in other hereditary forms of the long QT syndrome, as well as in acquired forms of prolonged QT, torsade de pointes (meaning 'turning of the points,' an allusion to the alternating positive and negative major QRS complex) is the usual arrhythmia observed. Secondary torsade de pointes is produced by various drugs and by intracranial disease such as subarachnoid hemorrhage. Stimulation of the left stellate ganglion causes QT abbreviation. These procedures applied to the right stellate ganglion have opposite effects. Left stellate ganglion block or ablation has been used in the treatment of the long QT syndrome.

Till et al. (1988) performed cardiac autotransplantation on an affected 5-year-old son of first-cousin parents. The intention was to achieve complete denervation of the heart. The boy had recurrent loss of consciousness requiring cardiorespiratory resuscitation. The attacks were due to polymorphous ventricular tachycardia (torsade de pointes). Autotransplantation did not relieve the problem, and while awaiting allotransplantation, the patient developed repeated attacks and progressively worsening myocardial failure. Till et al. (1988) interpreted the findings as indicating that the fundamental problem lies in myocardial cells and not in the sympathetic nervous system, although the occurrence of attacks in response to exercise or excitement suggested a triggering role for the nervous system.

Clinical Management

The automatic implantable defibrillator (Mirowski et al., 1980) is useful in patients with frequent ventricular arrhythmia from the long QT syndrome.

Population Genetics

Fraser et al. (1964) estimated that the prevalence of Jervell and Lange-Nielsen syndrome in children aged 4 to 15 years in England, Wales, and Ireland is between 1.6 and 6 per million.

Mapping

Jeffery et al. (1992) found no linkage of the Jervell and Lange-Nielsen syndrome to the HRAS oncogene (190020) on chromosome 11p.

After excluding linkage of the JLNS phenotype to the genes responsible for LQT2 (152427), LQT3 (603830), and LQT4 (600919), Neyroud et al. (1997) studied possible linkage to the LQT1 locus on 11p15.5 and demonstrated linkage to a marker in that region, D11S1318 (lod = 5.24 at theta = 0.0). Homozygosity mapping was used in 4 families in which the parents in each case were first cousins. Recombinants allowed them to map the gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1 (KCNQ1), the potassium channel gene implicated in LQT1, had previously been localized. LQT1 is inherited as an autosomal dominant and is not associated with hearing loss.

Molecular Genetics

In 3 affected children of 2 families with JLNS, Neyroud et al. (1997) detected homozygosity for a deletion-insertion event (1244, -7 +8) in the C-terminal domain of the KCNQ1 gene (607542.0013). By in situ hybridization, they found that KCNQ1 is expressed in the stria vascularis of mouse inner ear. Taken together, the data indicated to them that KCNQ1 is responsible for both recessive JLNS and dominant LQT1 and has a key role not only in ventricular repolarization but also in normal hearing, via control of endolymph homeostasis.

Splawski et al. (1997) hypothesized that JLNS may result from mutations affecting both alleles of the gene that in the heterozygous state causes LQT1. They indeed discovered that a patient with JLNS was homozygous for a frameshift mutation in the KCNQ1 gene (607542.0014) and that other family members had prolongation of the QT interval with an autosomal dominant pattern of inheritance but had normal hearing and were heterozygotes.

Chen et al. (1999) reported a small Amish family consisting of 2 deaf sibs and their hearing parents. Both children had prolonged QTc intervals (0.52s and 0.66s), while their parents had borderline QTc intervals of 0.43s and 0.44s. These findings were consistent with a diagnosis of Jervell and Lange-Nielsen syndrome. Both children were homozygous for a 2-bp deletion in the KCNQ1 gene (607542.0022).

Tyson et al. (2000) studied 10 JLNS families from Great Britain and Norway and identified 9 different mutations in the KCNQ1 gene, 2 of which were novel. Truncation of the protein proximal to the C-terminal assembly domain was expected to preclude assembly of KCNQ1 monomers into tetramers, explaining the recessive inheritance of JLNS.

Schmitt et al. (2000) identified a small domain between residues 589 and 620 in the KCNQ1 C terminus that may function as an assembly domain for KCNQ1 subunits. KCNQ1 C termini do not assemble and KCNQ1 subunits do not express functional potassium channels without this domain. The authors showed that the deletion-insertion mutation at KCNQ1 residue 540 (described by Neyroud et al. (1997)) eliminated important parts of the C-terminal assembly domain. Therefore, JLN mutants may be defective in KCNQ1 subunit assembly. The results provided a molecular basis for the clinical observation that heterozygous JLN carriers show slight cardiac dysfunction and that the severe JLNS phenotype is characterized by the absence of the KCNQ1 channel.

In a study of 252 probands with long QT syndrome, Westenskow et al. (2004) identified 4 individuals with compound heterozygous and 2 with homozygous mutations in KCNQ1, none of whom were deaf. Voltage clamp studies in Xenopus oocytes demonstrated that coexpression of 2 mutant subunits caused a significant but incomplete reduction in I(Ks). Westenskow et al. (2004) concluded that these carriers of biallelic mutations in the KCNQ1 gene had a severe cardiac phenotype but were not deaf because the I(Ks) channel retained some function.

History

Fraser et al. (1964) pointed out an apparent case of this syndrome described by Meissner (1856) in a textbook on 'deaf-mutism.' A young girl was called before the director of her school for a minor offense and fell instantly dead. The parents were not surprised, having lost 2 other 'deaf-mute' children under similar circumstances of fright and rage.