Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome.

BACKGROUND: The Björnstad syndrome, an autosomal recessive disorder associated with sensorineural hearing loss and pili torti, is caused by mutation of a previously unidentified gene on chromosome 2q34-36. METHODS: Refined genetic mapping and DNA sequencing of 44 genes between D2S2210 and D2S2244 revealed BCS1L mutations. Functional analyses elucidated how BCS1L mutations cause the Björnstad syndrome. RESULTS: BCS1L encodes a member of the AAA family of ATPases that is necessary for the assembly of complex III in the mitochondria. In addition to the Björnstad syndrome, BCS1L mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. Patients with the Björnstad syndrome have mutations that alter residues involved in protein-protein interactions, whereas mutations in patients with complex III deficiency alter ATP-binding residues, as deduced from the crystal structure of a related AAA-family ATPase. Biochemical studies provided evidence to support this model: complex III deficiency mutations prevented ATP-dependent assembly of BCS1L-associated complexes. All mutant BCS1L proteins disrupted the assembly of complex III, reduced the activity of the mitochondrial electron-transport chain, and increased the production of reactive oxygen species. However, only mutations associated with complex III deficiency increased mitochondrial content, which further increased the production of reactive oxygen species. CONCLUSIONS: BCS1L mutations cause disease phenotypes ranging from highly restricted pili torti and sensorineural hearing loss (the Björnstad syndrome) to profound multisystem organ failure (complex III deficiency and the GRACILE syndrome). All BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit for respiration in human mitochondria), but the clinical expression of the mutations was correlated with the production of reactive oxygen species. Mutations that cause the Björnstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species.

Causes of hearing impairment in the Norwegian paediatric cochlear implant program.

Severe to profound hearing impairment (HI) is estimated to affect around 1/2000 young children. Advances in genetics have made it possible to identify several genes related to HI. This information can cast light upon prognostic factors regarding the outcome in cochlear implantation, and provide information both for scientific and genetic counselling purposes. From 1992 to 2005, 273 children from 254 families (probands) were offered cochlear implants in Norway. An evaluation of the causes of HI, especially regarding the genes GJB2, GJB6, SLC26A4, KCNQ1, KCNE1, and the mutation A1555G in mitochondrial DNA was performed in 85% of the families. The number of probands with unknown cause of HI was thus reduced from 120 to 68 (43% reduction). Ninety-eight (46%) of the probands had an identified genetic etiology of their HI. A relatively high prevalence of Jervell and Lange-Nielsen syndrome was found. The main causes of severe and profound HI were similar to those found in other European countries. GJB2 mutations are a common cause of prelingual HI in Norwegian cochlear implanted children.

The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?

BACKGROUND: Patients with Jervell and Lange-Nielsen syndrome (JLNS) exhibit severe phenotypes that are characterized by congenital deafness, very long QT intervals, and high risk of life-threatening arrhythmias. Current treatment strategies include high doses of beta-blocker medication, left cardiac sympathetic denervation, and ICD placement, which is challenging in young children. OBJECTIVE: The purpose of this study was to evaluate the safety and effect of pacing in addition to beta-blocker treatment in children with JLNS. METHODS: All genetically confirmed patients with JLNS born since 1999 in Norway were included in the study. Data on history of long QT syndrome-related symptoms, QT interval, and beta-blocker and pacemaker treatment were recorded. RESULTS: A total of 9 patients with QT intervals ranging from 510 to 660 ms were identified. Eight patients developed long QT syndrome-related symptoms, and 1 patient died before diagnosis. The survivors received beta-blocker medication. Seven patients also received a pacemaker; 1 had a ventricular lead and 6 had atrial leads. The patient with the ventricular lead died during follow-up. The 6 patients with atrial leads survived without events at a mean follow-up of 6.9 years after pacemaker implantation. Two patients received prophylactic upgrade to a 2-chamber ICD. CONCLUSION: No arrhythmic events occurred in 6 very young JLNS patients who received atrial pacing in combination with increased doses of beta-blockers during 7-year follow-up. If confirmed in additional patients, this treatment strategy may prevent life-threatening arrhythmias in this high-risk patient group and may act as a bridge to insertion of a 2-chamber ICD when left cardiac sympathetic denervation is not available.

Jervell and Lange-Nielsen syndrome in Norwegian children: aspects around cochlear implantation, hearing, and balance.

OBJECTIVES: Jervell and Lange-Nielsen syndrome (JLNS) is a rare cause of autosomal recessive inherited deafness. JLNS patients are candidates for cochlear implantation, and represent a group that needs special attention and precautions. The aim of this article is to draw some guidelines for dealing with these patients, and to emphasize the importance of electrocardiography (ECG) screening of congenitally deaf patients. A probable vestibular dysfunction is also discussed. DESIGN: Eight of 273 implanted children (2.9%) at Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway have been diagnosed with JLNS. All the children were evaluated with ECG, six of them before cochlear implantation. Auditory perception was evaluated with the littlEARS Auditory Questionnaire, or with a test battery developed at Rikshospitalet-Radiumhospitalet Medical Center. DNA sequencing was used to screen for mutations in the genes KCNQ1 and KCNE1. The cases are presented and discussed in a retrospective case review. RESULTS: Two of the children are dead. The corrected QT (QTc) interval in the ECG was markedly prolonged in all the children (median QTc, 0.59 sec; range, 0.53-0.65). Six children have more than 1 yr experience with their cochlear implant. Four of them are performing average or above compared with the other implanted children. All the children have mutations in the KCNQ1 gene. Six of our patients have delayed gross motor development, and the remaining two are markedly delayed compared with their older siblings. CONCLUSIONS: Cochlear implantation can be performed safely and with good results in children with JLNS, but requires knowledge of the diagnosis and necessary precautions have to be taken. ECG should be taken for all children with congenital deafness, preferably before exposure to strong sound stimuli. Vestibular dysfunction seems to be a part of JLNS, but this needs further investigation.