CF with two nonsense mutations

Question

Hello,

our son (5 weeks old) was born with meconium ileus and suffers from exocrine pancreatic insufficiency, which is being treated with pancreatin. By now, it is clear that he has CF. The genetic test showed a compound heterozygosity with nonsense mutation in exons 6 and 11 (heterozygous nonsense mutation in exon 6b (p.Q250X, apparently a very rare mutation) and in exon 11 (G542X)).

Our questions:

Are there any studies about the course of the disease in CF patients like our son, with two stop mutations?

Can we hope for the introduction of PTC124, with the result that our son will not suffer from any further impairment especially of the lungs after taking it (provided that, with the currently known therapies, his problems with the pancreas and lungs will remain)?

Many thanks for your answer, and best wishes!

Answer

Hello,

[translator’s comment: information not directly relevant to the question has been omitted]

As to your question:

Less than 1% of all CF patients in Germany are compound heterozygous for two nonsense mutations in the CFTR gene. Worldwide, the G542X mutation is the most frequent nonsense mutation in the CFTR gene. Your son’s second mutation, Q250X, is extremely rare and not even listed in the CFTR Mutation Database yet. It is likely that you son is the only person in the world with a combination of Q250X and G542 X.

So far, studies on CF patients with two stop mutations have only been reported from Israel, since the stop mutation W1282X is very frequent in European Ashkenazi Jews. According to the experiences of Israeli CF doctors, that the CF disease pattern in patients with two stop mutations is comparable to that of CF patients who carry the most frequent mutation, F508del, on both CF chromosomes. In Germany, half of the CF patients are F508del homozygous.

The Hannover CF research group has examined eight adult CF patients with two stop mutations in the CFTR gene during the past 15 years. In all cases, the patients’ pancreases had not been working properly from the time of their births. The symptoms of the respiratory tracts were developed to varying degrees.

All patients took pancreatic enzymes with their meals, followed a diet rich in calories, and compensated the insufficient intake of lipophilic vitamins by taking vitamin compounds. All patients exercised and got physical therapy on a regular basis. Antibiotic therapy to treat chronic respiratory inflammations was necessary for some, but not all, patients.

PTC124 was developed for the treatment of stop mutations. It makes sure that the irregular stop codon is skipped during the CFTR protein synthesis and a full-length protein is produced. However, the cell has to produce a sufficient amount of the CFTR mRNA messenger. The cell’s quality control usually recognizes the anomalous CFTR mRNA messenger, though, and breaks it down again. In other words: even with PTC124 present, the CF cell produces less CFTR protein than a normal cell without CFTR stop mutation.

CFTR is part and parcel of our water and salt balance and carries chloride ions. Recently, results of the treatment of G542X CF mice with PTC124 were reported. 40% of the mice benefited from the treatment. They transported 20-40% of the wild type amounts of chloride. A clinical study involving Israeli CF patients with stop mutations showed similar results. Starting in the spring of 2009, the effectiveness and side effects of PTC124 will be tested in a large group of (adult) CF patients from Europe and North America.

So far, PTC has been applied only for a few weeks in the clinical studies. There are not yet any experiences with long-term PCT124 treatment.

As of now, one can therefore say that, with PTC124, a substance for the treatment of stop mutations is available for the first time. In roughly every other CF patient who was treated with PTC124 for a few weeks, the basic CF defect of the faulty chloride transportation shifted towards the threshold area between CF and non-CF. The reasons for the different responses among patients to the treatment are not yet known.

Kind regards
Prof. B. Tümmler

02.03.2009