The difference in plasma cGMP levels between RP patients and controls (RP twice that in controls) is very clear, and the corresponding ROC curve suggests that the cGMP test readily finds diseased patients. Still, at this point we cannot claim that the higher level is a direct consequence of the disease. Differential blood cGMP levels have previously been seen in a variety of situations, for instance, in connection with natriuretic drugs for acute heart failure,
58 blood pressure–altering drugs,
59 preeclampsia,
60 migraine,
61 and in relation to the circadian rhythm,
63 where the cGMP levels may in turn be dependent on melatonin levels.
62 With a possible connection to this, the ROC specificity aspect indicates that some healthy subjects may appear as having the disease. Yet, we find it compelling that subjects with a mutation in
PDE6A, a gene coding for a cGMP-hydrolyzing enzyme highly expressed in the retinal photoreceptors,
65 present with high levels of the nonhydrolyzed substrate as well as with reduced photoreceptor function. We are currently analyzing whether retinas from animal RP models do release their high cGMP into culture medium, and note that this seems to be the case (unpublished results, but see Lolley et al.
66). It is hence possible that the lack of cGMP hydrolysis results in increased extracellular cGMP that manages to find its way to the circulation. One may argue that patients with a loss of measurable retinal functions as in this case should not have any photoreceptors left to produce cGMP. However, results from a
PDE6A mutant canine model suggests that ERGs may be severely affected well in advance to structural loss of photoreceptors,
67 and the present clinical finding does not as such exclude the presence of rod photoreceptors, albeit in reduced numbers. Moreover, our results agree with those of Martinez-Fernandez de la Camara et al.
15 where the serum cGMP levels of a group of RP patients are increased by approximately 65% compared with a control group.
15 In the latter study, the RP mutations in question are not reported, however, and at least some may thus be unrelated to
PDE6 gene mutations as such, which would appear inconsistent with our conclusions. On the other hand, as mentioned in the Introduction, several RP models with mutations in genes, including but not only
PDE6, display high photoreceptor cGMP, suggesting this is a common denominator for a number of RP types,
18,21,68 although at this point we do not know the underlying mechanisms. Since one may expect high similarity between photoreceptor pathology of human homologue models and that of RP patients, high cGMP in photoreceptors, and possibly in the circulation, might therefore appear also in larger patient groups, independently of the exact mutation.