As any DGKE patient old enough or any family members know it is simply that :
p.Trp322* (c966 D>A) is one at least 24 genetic mutations in one of the 10 DGKs , DGKE , which causes it to lose its function in stopping the sustained signalling by arachidonic acid, containing diacyclglycoserols, to elevate AADAG to activate protein kinase, cPKC, which in turn causes thrombotic factors VWF , plasminogen activator- 1 and platelets to activate on the endothelium to create a prethrombotic state and ultimately get inflamed and start a microangiopathy and damage the kidneys.
There can be other players too. Makes sense?
Hardly to the layperson but what is noticeable is that complement is not mentioned.
DGKE is a lipid system disorder.
DGKE disease will carry on for the majority of DGKE patients in that way. That is their kidney disease.
It starts at a very early age and there is no approved treatment it would seem
The TMA has similarities to aHUS.
But it can get even closer to cTMA for 20 to 30% of DGKE sufferers.
When their inflammation sends out microparticles the complement system detects and which then becomes active against their source. Going full complement as nature intends. Fine when controlled maybe but in those genetically vulnerable going full complement cannot be stopped; they get cTMA (including aHUS) . To be specific it is secondary to DGKE’s own TMA.
Unlike the other 70 to 80% of DGKE patients who don’t ignite complement , this splinter group need to have their complement inhibited. Once inhibited the cTMA disappears and if there are no “microparticles ” signalling it is likely that inhibition can be withdrawn..
Also likely to happen is that a new DGKE TMA may again breakout when complement is blocked and the conclusion might be that a complement inhibitor does not work and is withdrawn. It is fine line. ( See more about that in Article No 813.
If it seems as if the complement inhibitor does not work then it is because a complement inhibitor is not meant to inhibit what happens in the cells when mutated DGKE fails to do its job . That job is simply to stop. arachidonic acid containing diacylglycoserols to elevate.
DGKE needs its own treatment for all its patients to stop the second step in the process outlined. There are none known nor much evidence of an attempt to develop one to do that..
DGKE is currently in the classic rare disease orphan drug scenario which the vast majority of rare disease patients face.
Just as cTMA, including aHUS, once faced years ago .
.Eculizumab was not developed for aHUS. It was not in Alexions’s thoughts when the monoclonal antibody was developed.
It was repurposed. It worked for PNH another disease , could it work for aHUS , yes, Then it was repurposed for MG and also NMSOD all different except for the complement connection.
How much effort has there been in finding a drug which could be repurposed to control core DGKE disease not just its side effect cTMA.
Something safe and approved. Something that the DGKE patient community itself can gather around together. Much like aHUS patients did 20 years ago.
Admittedly Global Action has done little ( see this article) for DGKE patients other than empathise with the minority of them who overlap. The majority of DGKE patients with a kind of nephrotic syndrome or MPGN specifically, would or should be the concern of other advocacy groups supporting a much more common kidney disease than aHUS.
DGKE patients would be even more swamped in those groups than those in the aHUS community..
It is time, like it was for the few aHUS families around 20 years ago, for DGKE community to start their own advocacy. For mutual support yes, but to also raise awareness, may be have its own day, and seek a treatment.
There are also a small number of world leading experts in DGKE out there like Mathieu Lemaire and Victoria Brocklebank who might be the Richard Smith of the University of Iowa who connected with the Foundation for children with atypical HUS. There also could be a Bill and Cheryl Biermann in the current DGKE community.
This will not happen without someone standing up to change lives. Global Acton can help it start and then let the talents of the emerging group develop it as it did for aHUS advocacy. When has there ever been a DGKE patient conference even in the days of zoom etc.
But very soon under nomenclature plans it will be identified as its own TMA. If that is a threat or an opportunity for those with DGKE mutations they should let themselves be heard in the aHUS awareness day call to action.
They should then act, it is its own community.
The time has come.
Article No 814
