Marsili Syndrome: A mutation in the ZFHX2 gene leaves Italian family painless

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 Na_v1.7. which is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Na_v1.7 dysfunction in different human pain disorders. Nonsense mutations in Na_v1.7 result in loss of Na_v1.7 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 Na_v1.7 have been shown to cause primary erythermalgia (PE) and paroxysmal extreme pain disorder (PEPD).