"The affected children usually come to our attention when their baby teeth start to erupt because they start to bite their own tongue, lips and fingers and, in some cases, even bite bits of them off. They are also susceptible to bone fractures, which can go unnoticed for a long time because they cannot feel pain," explains Michaela Auer-Grumbach of the University Department of Orthopaedics at the Medical University of Vienna, lead author of the study together with Ya-Chun Chen of the University of Cambridge. Because they cannot perceive pain, over the course of their lives, sufferers can sustain injuries, burns and bone fractures, which, because there is no pain warning, are often discovered late and do not heal well. Without appropriate medical care these complications can even prove fatal.
The scientists analyzed the whole exome of the patients, that is to say all sections of the genetic material, which encode proteins. In both cases they identified mutations in gene PRDM12. "Identification of mutations in the same gene in two people from different families but with a very similar clinical picture was a strong indication that we had discovered the gene responsible,” says Jan Senderek of the Friedrich Baur Institute at the University of Munich. Definitive proof was then provided by the results of the working group led by Geoffrey Woods at the University of Cambridge: they also identified PRDM12 mutations in patients with congenital analgesia. Together with colleagues at home and abroad, the scientists went on to examine more patients with congenital pain perception disorders and came across further mutations. The results of the study are published in the current issue of "Nature Genetics" magazine.
Disrupted development of the nervous system
"By discovering the cause of the disorder, we are able to provide appropriate genetic diagnosis and counselling for affected patients and their families," says Michaela Auer-Grumbach in summary. Even though no treatment is currently available, we can reduce the risk of serious injury and complications by means of supportive measures, information and training for sufferers and their families. The study authors hope that the publication will make doctors and geneticists more aware of this very rare and little known clinical picture.
In order to understand the mechanism of the disorder, the scientists worked with the developmental biologists Tatsuo Michiue and Shinya Matsukawa from the University of Tokyo to investigate the function of PRDM12 in tadpoles. In these tadpoles the loss of PRDM12 resulted in the defective development of nerve cells or neurons, which are important for pain perception. The PRDM12 gene contains the information for a factor that establishes the activity of other genes and hence the development of cells and tissue. This suggests that the absence of PRDM12 results in a malfunction of as yet unknown target genes, which are necessary for the development of the nervous system and effective pain perception.
The association between the congenital inability to feel pain and the defective development and function of the nervous system had already been demonstrated in earlier studies. These studies showed that mutations affected special sodium channels of pain receptors and signalling pathways for nerve growth factors. The discovery that disruptions to factors, which – like PRDM12 – control the genetic material, can result in insensitivity to pain, is new and provides insights into the development of the nervous system and the functional principle of pain perception. "Further investigations will show what significance the findings regarding PRDM12 have for pain research and the development of new pain medication," says Michaela Auer-Grumbach.