Dr Hanno Bolz reveals common cause of deafness and cardiac arrhythmia

At the first glance, hearing and heart rhythm seem to be entirely unrelated processes. Now a recent study shows that there is a close functional link between the two.
The study, which has been the work of an international collaboration of researchers from Germany, Pakistan, Austria and France, was published online in the renowned Nature Neuroscience journal on December 5, 2010.

The research group of clinical geneticist Dr Hanno J. Bolz at the Institute of Human Genetics of the University Hospital of Cologne (and now deputy medical head of the Bioscientia Center for Human Genetics, Ingelheim) investigated Pakistani families with congenital deafness and identified a mutation in the CACNA1D gene, which encodes a voltage-gated calcium channel (Cav1.3). „It has been known that in mice, loss of Cav1.3 function results not only in deafness but also in cardiac arrhythmia. We therefore recorded ECGs in patients carrying the CACNA1D mutation and indeed found that they had cardiac arrhythmia with a markedly decreased heart rate at rest” says Dr. Bolz. In some patients, the heart rate was only slightly above 30 beats per minute. However, since there was no indication of any cardiac complications in these families, this disturbance of the heart rhythm is apparently well compatible with life. The researchers termed the new syndrome „SANDD” (sinoatrial node dysfunction and deafness).

In collaboration with the research group of Prof. Jörg Striessnig, Director of the Institute of Pharmacology and Toxicology of the University of Innsbruck, the researchers were able to demonstrate that the CACNA1D mutation leads to a loss of function of the Cav1.3 calcium channel. Specifically, the mutation interrupts the molecular switch in the channel protein that is responsible for opening its pore upon excitation of the cell. In the inner ear, Cav1.3 plays an essential role in transforming sound waves into electrical signals. In patients with defective Cav1.3, the transport of the auditory impression to the brain is interrupted. In the sinoatrial node, the major pacemaker of the heart, Cav1.3 controls the heart rate. This had been demonstrated by Striessnig's research group in mice and has now for the first time been confirmed in humans.

„At this time, we do not know how frequent the SANDD syndrome is among many deaf individuals” says Dr Bolz. Since the cardiac arrhythmia had not been noticed by any of the patients, it is feasible that some patients diagnosed with isolated deafness might in fact have SANDD syndrome. Even though this type of cardiac arrhythmia is apparently not harmful, the new findings should warrant cardiological examinations in all individuals affected by congenital deafness of unknown cause. Resting pulse rate may serve as a first indicator. „If the pulse is abnormally low or irregular, the next step should be recording a long-term ECG. Subsequently, mutation analysis in CACNA1D can be performed to confirm the diagnosis of SANDD syndrome”.

Congenital deafness is genetically extremely heterogeneous. Since it is assumed that causative mutations exist in more than 100 genes, establishing a genetic diagnosis is only successful in few cases. As Dr. Bolz says, „The enormous advances in the field of new high-throughput sequencing technologies have opened the door to solving these problems. This will allow simultaneous testing of all known deafness genes and we may thus soon identify SANDD patients by applying such a genotype-first approach.”

Contact

PD Dr. med. Hanno Jörn Bolz
- or -
Phone: +49-6132-781206 (Zentrum für Humangenetik, Bioscientia, Ingelheim)

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