Hello! I am the mother of a 6-year-old suffering from phenylketonuria. After a long struggle, we finally got a genetic test and therefore I have a question. After the second tests (because the first one found only one R408W mutation), my child was found to have another Q226X mutation, which is described in the WWW.PAHDB database, but information on clinical significance is not present, therefore it is not possible to present the correlation at the moment phenylotype-gene. Therefore, the question arises what form of phenylketonurri my son has, as the results of phenylalanine concentration without dieting are minimally elevated.
Hello madam!
Unfortunately, in the case of most genetic diseases, it is not possible to establish an absolute correlation between genotype and phenotype, that is, based on the results of genetic testing only, to predict the severity of the disease with certainty. This is also the case with phenylketonuria. Therefore, the form ofphenylketonuriais determined primarily based on the clinical picture (tolerated dietary phenylalanine level - classic, moderate, mild phenylketonuria, mild hyperphenylalaninaemia and the effectiveness of tetrahydrobiopterin treatment - phenylketonuria BH4 - " sensitive "or" insensitive ").
The result of the genetic test of course provides us with valuable information about the type of defect in a given gene, from which we can draw general conclusions about the degree of damage to the function of a gene product. In the case of the commonmutation in the PAHgene, which causes the change of the amino acid (a building block of the protein) of arginine to tryptophan at position 408 in phenylalanine hydroxylase (R408W), the protein structure is disturbed, causing an almost complete loss of its enzymatic activity.
Much less frequentmutation Q226Xcauses premature "rewriting" of the genetic code of DNA into an RNA "template" at position 226, on the basis of which a protein is then formed. Based solely on the results of a genetic test, one would expect a severe course of the disease in a person who has these two mutations.
However, as I have already mentioned, the medical literature describes cases of patients with phenylketonuria, inhave failed predictions of the course of the disease based on the type of genetic defect detected. Paradoxically, the presence of two different "heavy" mutations may result in symptoms that are less severe than those predicted for each of these mutations separately.
There are various hypotheses that explain this state of affairs. It is enough to mention that phenylalanine hydroxylase consists of four subunits (in the case of a normal protein, the same, the so-called homotetramer), so it must be important what two mutations will "meet" in a given patient - that is, how the altered subunits of such an abnormal protein will work together .
It is also believed that the severity of the disease is influenced by changes in other genes. I assume that both mutations detected in your child are found on each of the two copies of the PAH gene (one copy is inherited from the father and the other from the mother). If you and the child's father have performed a genetic test and one of you is a he althy carrier of the Q226X mutation, and the other - the R408W mutation, this is the situation here. If you have not performed such a test, it cannot be ruled out that both mutations detected in your son are found together on only one copy of the gene. A "milder" mutation should then possibly be sought on the second copy of the gene. This situation could also explain the mild course of your son's illness.
If you have any further questions, please do not hesitate to contact me for genetic counseling.
Regards, Dr. Krystyna Spodar
Remember that our expert's answer is informative and will not replace a visit to the doctor.
Krystyna SpodarKrystyna Spodar - specialist in the field of clinical genetics at NZOZ Genomed, ul. Ponczowa 12, 02-971 Warsaw, www.nzoz.genomed.pl, e-mail: [email protected]
The expert answers questions about genetic diseases and congenital malformations, inheritance, and prenatal diagnosis.
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