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Complex Regional Pain Syndrome Could Have Genetic Basis

Some people may be genetically predisposed to develop the rare, disabling disorder complex regional pain syndrome type 1 (CRPS-1), according to a new study led by the University of Cambridge. The condition is poorly understood, and its exact cause remains unclear.

The researchers noted that 95% of cases were triggered by injury, with the skin of the affected body part thereafter hypersensitive to the slightest touch or temperature change. However, it was not known why some people developed CRPS-1, yet others didn’t, following a similar injury.

The phenomenon usually occurs within a month of injury and most often involves the hand and wrist; foot and ankle, or knee, although sometimes the whole limb can be affected. It is usually confined to one limb but can sometimes spread to other parts of the body. Rarely, it can occur following a stroke or multiple operations on a limb, and in some cases develops without any obvious trigger. The condition can remit with time, but some people experience intense pain for many years, and CRPS-1 is often resistant to treatment.

Multiple Systems May Be Involved

The researchers behind the new study suggested that CRPS-1 may involve sensory, motor, and autonomic nervous systems, as well as trophic and bone changes in some patients. However, it was difficult to explain the peripheral tissue changes solely through a neurogenic mechanism, they said. Persistent local inflammation has been observed, along with raised levels of proinflammatory cytokines in blister fluid from the affected limb.

The underlying cause of such changes remained obscure, but a heritable component had been suggested, sparking the theory that some people might be genetically predisposed. 

So the researchers conducted an observational study looking for single nucleotide polymorphisms (SNP) in DNA samples from 34 patients who had been diagnosed with CRPS-1 compared with a control group of 39 people with chronic back pain. Results were then confirmed in a further 50 CRPS-1 patients. Across all the groups, average age was mid 40s to mid 50s, range 20 to 86.

Genetic Variants More Common Among CRPS-1 Patients

The findings, published in the Journal of Medical Genetics , revealed that a single SNP in each of four genes (ANO10, P2RX7, PRKAG1, and SLC12A9) normally expressed in peripheral blood macrophages was more common in those with CRPS in both patient groups than it was in the back pain group. In all, 25 of 84 (29.8%) patients who had had CRPS-1 for more than a year expressed these variations in at least one of the four genes, whereas none of the variations was evident in the control group with back pain. 

This suggested that these four specific SNPs are each able to increase the risk of a person developing CRPS-1 after injury, according to the researchers. Also, it suggested the possibility that "a permissive genetic background is an important factor in the development of CRPS-1".

They noted that there may be "plausible biological explanations" for their findings, as ANO10, P2RX7, and SLC12A9 are expressed in immune cells, particularly monocytes, macrophages, and neutrophils, which are involved in the types of symptoms characteristic of CRPS-1. There were also "good grounds" to expect that these rare alleles would alter protein function. 

Possible Different Mechanisms of Disease in Males and Females

The results also revealed, unexpectedly, that more male (8 of 14, 57.1%) than female (17 of 70, 24.3%) patients expressed these rare SNP alleles (p=0.023), even though CRPS-1 is three- to four-fold more common in females than males. 

Although the discrepancy would need to be confirmed in a larger group, the researchers said it "raises the possibility of different mechanisms of disease in males and females". It also suggested that therapeutic responses might be influenced by sex. 

Genetics May Be Only Part of the Story

The team pointed out that as an observational study, the research did not allow definitive conclusions to be drawn about cause and effect. They acknowledged that their genetic results "may be only part of the CRPS-1 story". In particular, autoimmune disease, like chronic pain syndromes, is more common in women than men, and recent studies strongly suggest that this could be causative in some cases of CRPS-1.

However, they concluded that the findings "support an underlying genetic predisposition" to CRPS-1 in up to a third of cases, with this effect being most prominent in males.

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