Marsili Syndrome: A mutation in the ZFHX2 gene leaves Italian family painless
Last Updated on December 23, 2017 by Joseph Gut – thasso
December 21, 2017 – No pain on gain. This headline might not at all apply for this Italian family. In a paper just published in the Journal Brain, researchers describe a mysterious genetic mutation that effectively negates the sensation of pain, enabling people with the rare anomaly to persevere effortlessly through extreme physical discomfort. A variant of the ZFHX2 has been identified in an Italian family where members of the family belonging to different generations feel almost no pain even when seriously injured. The authors of the related research paper in Brain have coined this familial phenotypical observation “human pain insensitivity disorder caused by a point mutation in ZFHX2”, better and more memorable, the “Marsili Syndrome”, after the family.
Congenital insensitivity to pain (CIP), also known as congenital analgesia, has been recognised before and represents one or more rare conditions in which a person cannot feel (and has never felt) physical pain. In some cases, the underlying molecular (genetic) factors involved have been identified. For example, the SCN9A gene seems to play an important role in these rare conditions. Thus, SCN9A codes for the voltage-gated sodium-channel type IX α subunit, known as Nav1.7. which is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Nav1.7 dysfunction in different human pain disorders. Nonsense mutations in Nav1.7 result in loss of Nav1.7 function and a condition known as channelopathy-associated insensitivity to pain, where affected individuals are unable to feel physical pain. Quite to the contrary, gain-of-function missense mutations in Nav1.7 have been shown to cause primary erythermalgia (PE) and paroxysmal extreme pain disorder (PEPD).
Generally, physical pain constitutes a protective sensation alerting individuals towards injuries (fractures, etc.), frank organ failures, and emerging diseases, to name only a few. Emotional pain is not even considered in this context here. Thus, while some may find a condition where one does not feel pain as plain cool, finding described for this Italian family here might represent a two-sided sword. A point in case would be the family’s 24-year-old son who plays soccer (football). His incurred sports injuries are masked, because he does not feel when he gets injured; recently X-rays have shown that he carries numerous micro-fractures in both ankles. Similarly, the sons 78-year-old grandmother was suffering from fractures that were only much later diagnosed, meaning they harden naturally but did not heal properly.
At that point in time, it is not yet clear how exactly the identified ZFHX2 mutation interrupts pain signalling. The research team resorted to animal experiments to gain first insights on how the ZFHX2 variant molecularly affects pain processing in mice. Thus, animals bred to not have the gene at all showed reduced pain sensitivity when pressure was applied to their tails, but were still receptive to high heat. When other mice were bred to possess the ZFHX2 mutation, they exhibited the same low sensitivity to high heat as the family member have.
Overall, identifying this mutation and clarifying that it contributes to the family’s pain insensitivity may have opened, we have opened up new routes to drug discovery for pain relief. Understanding exactly how the ZFHX2-mutation impacts pain sensitivity, and to understand what other downstream genes might be involved in pain signalling, ZFHX2 may be novel target for anti-pain drug development. May gene therapeutic approaches involving silencing of ZFHX2 in patients with severe and/or chronic pain disorders might be an future therapy option, apart from the more and more problematic opioid based treatments.