Mild form

Question

Hello, my 8-year-old daughter was diagnosed to be heterozygous for the Delta F508 and heterozygous for the complex allele TG12 T5. Which evolution, which prognosis for the future can be expected, knowing that she already has respiratory (asthma) and digestive (flatulencies, constipations) problems. Thank you.

Réponse

Hello,

Several CFTR gene mutations exist and have variable consequences on the CFTR protein and its functions. Over 1900 CFTR gene mutations are described actually. A classification of these mutations has been proposed, based on the mutation’s consequences on the function of the protein (“functional” classification). Six mutations classes are generally described, resulting in quantitative or qualitative CFTR abnormalities. Among CFTR functions, the most important is to be a chloride channel.

Your daughter has 2 CFTR gene mutations: F508del and TG12 T5.

The first one (F508del) is the most frequent mutation found in CF patients (around 70%) and is a ‘class 2’ mutation. It corresponds in the CFTR gene to a deletion that leads to a deletion of an amino acid (phenylalanine) at the position 508 of the protein. The abnormal CFTR is then eliminated within the cell. The result is an absence of the protein, and, consequently, of the chloride channel activity.

The T5 mutation is classified as ‘5th class’ leading to a reduced amount of CFTR. However, CFTR protein is well positioned and still has a chloride channel activity. When a T5 variant is identified, the complete variant (TG)m(T)n is studied to determine number of (TG) associated. In fact, very schematically, the disease severity increases with the number of (TG). Thus, TG12 associated with T5 (TG12 T5) is classically associated with a ‘mild’ form of the disease, which could include infertility in males, delayed respiratory symptoms and rarely gastrointestinal tract symptoms. However, the symptoms vary among patients.

These ‘mild’ forms of the disease are actually better referenced, as they are revealed by the neonatal screening. There is, however, no reliable indicator of the long-term evolution so far. In the majority of the cases, the evolution is modest with few symptoms. However, a delayed evolution towards a more classic form sometimes arises.

This explains the follow-up of your daughter in the CF center, as well as the lifestyle precautions which are often recommended (to avoid potential harmful environmental factors for the respiratory tract, such as active or passive smoking; or prevention and detection of a dehydration which can be favored by an abnormally salted sweat).

You may ask to consult a geneticist or a geneticist counselor who will be able to discuss with you about these mild form of the disease. For more information, you could consult the CFTR2 website (CFTR2 : www.cftr2.org).


I hope to have answered your questions and do please fill free to reply if you do have more questions.

Best regards

Harriet Corvol

Reference: Castellani et al., Journal of Cystic Fibrosis, 2008.

18.11.2013