Deletions of the genes CFHR1 and 3

[MPGN-C3G]

My son is 7 and has DDD: C3 is extremely low, sC5b-9 is extremely high, C3Nef is positive and he has a homozygote deletions of the genes CFHR1 and 3. Is the reason of his DDD the gene deletion of the C3Nef? I have heard that C3Nef can disappeare in the course of time and this makes me hope that my son can get healthy. But is the reason is the gene deletion, does he have any chance? Have you heard at all about DDD patients who got healthy? What is the life expectation with DDD? Thank you very much in advance!

[linfuller Ambassador]

The exact causes of the disease is something the experts are still figuring out. Genetics and the complement system are both very complex. Every patient is unique, which is part of what makes this a tricky question. In the end, most people don't know for sure why they have the disease.

I don't know much about those genes and the role they play, but my guess is that you will find that both the genes and the C3Nef play a part. Was your testing done at University of Iowa? If so, Richard Smith is very helpful in understanding these complexities. If it was done elsewhere, you might try to contact that lab for more info. I strongly recommend attending the family conference held at University of Iowa in October - they usually cover topics like this, and you would have the opportunity to talk to the researchers personally.

My family has hereditary C3G. We carry the same gene mutation in C3 that is believed to be disease causing. Yet, each of us has had a unique experience and outcome. Yes, there are things that overlap. But my 50 year old brother has only minor hematuria and proteinuria, while I was approaching kidney failure by the age of 35. My son and I have some similarities on our complement analysis, but many differences. While our doctors can make guesses about long-term outcome, it is just extremely hard to predict. And ours all stems from the same mutation. You can imagine how complex it is with patients who share far fewer similarities than we do.

As for the C3Nef, the levels do fluctuate. Some of my reports show higher levels, others lower. Some patients are able to stabilize and stay that way for many years - in others the disease is much more aggressive. Again, that seems to be hard to predict. The best thing you can do for your son is to find the most knowledgeable specialists you can, and work with them closely. That may require some travel - knowledgable specialists are hard to find for C3G patients. Help your son be as healthy as possible - getting a lot of sleep and treating infections early seem to be really important.

[MPGN-C3G in reply to linfuller]

Dear Linfuller,

Thank you so much for your kind reply! I am so sorry that you family has such a sad story. Our genetic test has been done in Germany and no one can tell me what this means. They say that this combination is tipical for a cetain form of aHUS but not for DDD. They also say that 5% of the population has this gene deletion and only very few of them have health problems. So, they cannot explain how it relates to DDD.

I am in contact with Dr. Nester in Iowa, I will try to get her opinion. I have already asked Prof. Licht in Canada, he could not give me an answer although he is one of the leading exterts in this feild.

Yes, I would like so much to visit the family conference, I have heard a lot about it, but I cannot leave my sone and my younger daughter for so long to make a trip to the U.S.

I wish you and your family all the best!!! You seem to have accepted the disease. I am still trying to do this...

[DavidF_NKF Partner in reply to MPGN-C3G]

Hi MPGN-C3G,

Thank you very much for joining the community and asking your question. While you did not post it as a question to our C3G Expert Panel, I will send it to them. Their answer will be posted when I receive it.

Thank you again for writing and please stay engaged.

Linfuller- thank you for your typically excellent response!

[linfuller Ambassador]

MPGN-C3G, aHUS and C3G are both products of a problem in the same part of the complement system, so in a way that makes sense. Dr. Nester is wonderful & you are in good hands with her. Like I said, there are simply so many unknowns with this disease. As much as we want answers, many of them just don’t exist yet. I know it is frustrating & hard to face such an uncertain future for your son.

I understand not being able to travel so far! But there is a conference in the UK every year, I believe. That would be at least a little closer - maybe a possibility? Andy Longfellow is the person to ask about that if you are interested. I believe you can message him on here, or you can find him on Facebook.

I wish you & your family the best, as well. I do believe better days are coming for our families. Soon. As for acceptance, I’ve lived with this disease my whole life. It’s simply all I know. It takes my breath away when I think of all I have lost to it (so I don’t do that much!) But for the loved ones I have lost, I have found a family of fellow patients around the world, some of whom are very dear to me. For all the things I’ve missed out on, this disease has also presented me with opportunities and experiences I never dreamed of. It’s how you frame it - I could dwell on the terrible parts. I certainly would be entitled to do so. But that wouldn’t make me happy or give me back anything I’ve lost. What I can do is use it to propel me to take action, to help myself & others. I can take the good that comes with the bad & find joy, because that’s just how life works.

Give yourself time to grieve. Your life will not look like expected, and it’s ok to mourn for that. But then - get up & get on with it, because there’s still a lot of good to look forward to. Worrying is natural, but in the end only robs you of the good you have now. Sending you lots of hugs.

[MPGN-C3G in reply to linfuller]

Dear Linfuller,

Thank you so much for these words... They give me some consolation. You are so strong! And you are completely right. We should do the best of all things we experience. And I certainly could do my best and maybe I could even accept all this if I myself were affected. But it is my son who has DDD and I feel guilty somehow... Are these my genes that make him ill? Or was it an illness when he was small and had to go to the kindergarden and was exposed to so many viruses? Will he have less chances in his life than his friends? Can he have a family? A job that he likes? How long can he live with this disease? I hope he can still become happy despite DDD. But how can I be happy knowing that my son suffers? My life has become a fight. I have been fighting for Soliris for almost a year. Now, the insurance will pay for it till May. My son feels better at the moment. But I still have to fight for some further months with Soliris and I have no idea what happens if I lose... I have heard that patients feel much worse then. So, maybe it was wrong to fight for Soliris? He takes so many pills in the course of the day. What do they do with his body in the long term? It is a huge responsibility to decide for my son which medicine he should take and which not......

Dear Linfuller, I am so grateful for your calming words. Sending you lots of hugs, too!

[linfuller Ambassador in reply to MPGN-C3G]

The guilt is completely natural and normal. I do understand - my son is also a patient. I know without a doubt he inherited this illness from me. I worry about his future, too. It is hard to have a sick child, regardless of the illness.

My advantage in all this, in some ways, is that I've lived with it so intimately and for so long. What I have learned is that the guilt is normal, but also useless, and letting go of it frees your time and energy to be put towards more productive things. There was no way to know, and there was nothing I could have done differently. I wouldn't trade my amazing son and his imperfect body if the alternative was not having him in my life at all. I'm actually grateful I didn't know, and didn't have to face that decision. This is just what was meant to be for us. My son will have a much more difficult choice on his hands when it comes to becoming a parent, but I will support him either way. There are many ways to have a family, and I have faith that he will find his way. I know I would rather my parents gave me exactly the life I had, rather than not giving me a life at all if they had known what the future held. Life is a gift, even when it is hard. Maybe more so. Sometimes it is better to just not know these things.

Another thing I have learned - I am the third generation in my family dealing with this disease. My son is the 4th. We've faced more difficulties than I can even put into words - but we have also all had productive, fulfilling lives. Many other patients who were diagnosed as children will tell you the same. They have careers, families, friends. He will be ok. He will have hard things to deal with, challenges that his peers may not. But he will handle them, and his chance at a fulfilling life are as good as anyone else's. We cannot protect our kids from struggle (even though we want to), and I think we shouldn't. Those challenges build character, and we are better for it. Take a deep breath, Mom. He will be ok, and it isn't your fault.

As for Soliris...I feel your pain on that one. It is so incredibly frustrating to have to fight for the only treatment that gives us a shot at a relatively normal life. It makes me incredibly angry for anyone, but especially children, to be subjected to kidney failure and a lifetime of transplant maintenance because they are denied an effective medication for financial reasons. I so hope you can get further treatment. All you can do is make the best decisions possible with the information and resources you have at the time. It is helping him now, and you will do everything you can to keep him on it as long as possible. That's the best you can do for him. On a side note, have you investigated any of the clinical trials for the new C3G drugs? I know children aren't included in many at this time, but the opportunity might come up soon. It is a scary step, but it might be worth looking into if there aren't any other options.

I'll be thinking of you both. Take care of you, so you can take care of him. You are more than welcome to message me if you want my contact info. Reach out anytime!

[MPGN-C3G in reply to linfuller]

Dear Linfuller,

Thank you so much for your story! It is heartbreaking. I have read it many times and each time I have to cry. It is so good to know that you can live a relatively normal life and retain optimism despite the disease. I hope that my son will think the same when he is aware of what DDD means. I hope he will think that it is better to live with a disease than not to live at all. I hope he will be as strong as you are...

As for the new treatments: I was contacted by Achillion in summer, they promised that studies with children are in a pipeline and I hoped so much we can take part. But in November they told me that they have a permission from the FDA only for children older than 12. So, we have to wait for some years and hope that their drug will be available in Germany one day. Until then I will fight for Soliris to prevent the fast damage of his kidneys. I hope we can do it for so long and I hope the new drug will be affordable.

Thank you so much again! I will take you into my prayers and I hope we can meet one day.

[DavidF_NKF Partner]

Hi MPGN-C3G,

The answer from our C3G Expert Panel to your question is below. Thank you very much for sending this question. We wish you and your son the best.

Thank you for your question. DDD is a subtype of C3 Glomerulopathy. The other common subtype is C3GN. A low blood level of C3, which is a key protein in the complement system, is common in both DDD and C3GN, especially early in the disease. Soluble C5b-9 (sC5b-9) can also be elevated, and as a general rule is more often elevated in C3GN than in DDD. Deletion of the genes CFHR1 and CFHR3 does NOT cause DDD or C3GN. In fact, deletion of these two genes is common. About ~3-5% of healthy European-Americans, ~2% of healthy Chinese and ~15% of healthy African-Americans have no copies of CFHR1 and CFHR3.

On the other hand, the C3Nef is the most likely association with your sons disease. C3Nef stands for ‘C3 nephritic factor’. It is an autoantibody your son has made to a protein of the complement system called C3bBb. Another name for C3bBb is C3 convertase, because this protein complex ‘converts’ C3 into smaller proteins. Normally, C3 convertase exists for only about 90 seconds before it is inactivated. When C3Nef are present in an individual such as your son, it presumably prevents this quick inactivation, and as a result, more C3 is ‘converted’ to the smaller proteins and C3 is “used up” (resulting in a low level).

You are correct that C3Nefs can change over time and even disappear, which is something we follow in persons with C3Nefs. And yes, some people with DDD or C3GN will get healthy. If the disease remains active, however, a person with DDD or C3GN may lose enough kidney function to require dialysis. It is extremely unusual to die from this disease.

[MPGN-C3G in reply to DavidF_NKF]

Dear David,

Thank you so much for such a quick and cometent reply! Thanks a lot to the experts behind this answer! This means a lot to me to know that my son's disease is not caused by genes and that C3Nef might disappear. This knowledge gives me some hope that there is still a chance (even if it is a very small chance) that he might get healthy. Thank you!!!