Mutations F508del and R553X

Question

Dear expert team,
Our son has been diagnosed to suffer from CF at the beginning of January at the age of 9 weeks, after we had been admitted to hospital with a hemoglobin value of 6. The little boy became 2 blood transfusions and takes zinc tablets since then, as he also had a zinc deficiency. The poor gain of weight (only 3500 grams at the age of 8 weeks with a birth weight of 2900 grams) has not been taken for serious from the pediatricians. The sweat test value was 90 and had been confirmed with 84. We have been discharged with Kreon, zinc tablets, double dosage of D3 and the wish to visit once a week a physiotherapist. At a further appointment, genetic testing had been done. The mutations F508del and R553X came out.
Now my question about this. You answered in 2012, that with that combination the involvement of the lung until about the 12th year of life would be less compared to the homozygous form with F508del. Is this still correct? Our CF center mentioned the drug Ataluren to be at the horizon. Do you really think that it will still be licensed after so many years for the usage in case of CF? One can read in the Internet, that in case of 2 different mutations, always the milder one determines the picture of the illness. Is this correct? If yes, Ataluren would not help us further.
Before easter he had again been in hospital with an alkalosis. We have been told that this would mostly be due to the infection, as our son had vomited markedly some days before. As this had been 1-3 times a day and he had directly been breast fed afterwards, in order to compensate the loss, we can only hardly imagine this. What is your opinion about this? We have only been advised to start with feeding purree once a day and to add a bit of salt. Additionally, our son had strong cough and rhinitis. Due to the cough and the fear to get a pneumonia we had only gone to the hospital.
During this stay in hospital, the next visit in the CF center was planned to be. After we questioned it, we got yesterday now our inhalation device. We ask ourselves by now, if we are well cared for in this center. One reads about other patients, that they start inhalation directly and should do daily physiotherapy at home. A recommendation for inhalation has not yet been made concretely. How is this done in your center?
Many thanks in advance for your help,
Yours sincerely,
Mit freundlichen Grüßen,
V.S. mother oft he child

Answer

Dear questioner,
first of all: I will soon answer in detail your question about the mutation combination R553X/F508del – before this, it is important in my opinion:
1. Your judgment, that physiotherapy is important, is completely correct:”…daily physiotherapy (at home) should be done…”. Please turn also to the physiotherapist who you visit once a week. The care for the illness of CF that involves all parts of the body is most effective in a team of many specialists, at the beginning it is for sure not completely clear to you, who is doing exactly what in your CF center. Please ask the physiotherapist and report the physician (“ Mr Miller said that we should do this or that at home, and we are doing exactly this now…”).
2. Your judgment, that inhalation should follow a plan, is also correct – please ask for the plan. Here I think this is the duty of the physician in charge – what and when and how often is information you should know.
I think, that you are well cared for in any CF center in Germany, and as you have to visit it regularly, it does not make sense, to go to a center far away (especially if you are travelling with a baby). While the therapy itself (thus, e.g. which drugs have to be prescribed) is well balanced in Germany between the single centers, the organization quality is different in the different CF centers, there is knowingly a range (here a link [in German]: https://muko.info/mukoviszidose-institut/qualitaetsmanagement-fuer-mukoviszidose/zertifizierungsverfahren/mukozert-cf-einrichtungen.html).
Now to the combination of mutations F508del/R553X: both are typical, classical CFTR-mutations, that go along with the whole panel of CF symptoms. You have read in the Internet, that “in case of two different mutations, always the milder one dominates.” That is true, if it deals with a combination of a severe and a mild mutation: patients with F508del/R347P are pancreatic sufficient, as R347P is a mutation that is combined with pancreatic sufficiency. This is not important for you: F508del as well as R553X are classical disorders in the CFTR gene, none of both is mild.
Furthermore, predictions for the single patient about the course of the illness are not allowed: for example the lung function at the age of 12 depends on many other factors, even in a group of patients with the same CFTR defect. The most important factor is the therapy. I know patients with CF (mutation genotype F508del/F508del), who finished their studies at university and are working fulltime. Other patients with F508del/F508del are on transplantation list. Comparisons of groups of patients with different CFTR mutations are only of research interest, for an individual prognosis of the severity of the illness this information is not usable if two severe mutations are underlying (because one cannot conclude from the mutation, if one has the patient with fulltime work or not).

In spite of this it is important to know the mutation genotype: for R553X there are other molecular therapeutics than for F508del – Ataluren for R553X versus Orkambi for F508del. You can find an overview here [in German]: https://muko.info/mukoviszidose-institut/klinische-studien/cf-studien-in-deutschland.html.
With this I do not want to encourage you to take part in one of those studies – drugs have side effects and very small patients have justifiably special protection. For the topic “molecular therapeutics” (thus Ataluren and similar substances) your CF physician can inform you the best.
Therefore in conclusion – for both mutations, that your son carries, is true:
1. It deals with two typical CFTR mutations, none of them is mild
2. Future of molecular therapies: they are treated by different drugs (F508del needs something else than R553X), therefore the mutation genotype is important to know
3. Your find the contact people for the conventional therapeutical measures, which are very successful in case of CF, in your CF center – depending on the detailed question and depending on the center the person to contact may vary.
Please take part in conventional therapy - and do not lose courage due to the actual confusion, that I can conclude from your question. Please take into accounit: normally, children have only one pediatrician; you, however, have a team of different specialties, that is going to care for the health of your son as well as possible. This is more difficult, however makes sense.
I wish you and your son all the best!
Frauke Stanke

24.06.2016