BIOLOGY Volume 3 - A Guide to General Biology - 2004

25. APPLIED GENETICS

25.7. Human Genetics

25.7.4. Phenylketonuria

Phenylketonuria affects approximately one in every 10,000 Caucasian newborns, with one in 80 such infants acting as a carrier. The condition is less frequent in other ethnic groups.

Cause

Like cystic fibrosis, phenylketonuria is caused by an autosomal recessive mutation. Although this is a very severe condition, early Diagnosis and Treatment can prevent its devastating effects on human health. In individuals with phenylketonuria, The amino acid phenylalanine is not converted into another amino acid, Tyrosine:

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Healthy individuals possess the enzyme phenylalanine hydroxylase in their Liver Cells, whereas patients with phenylketonuria lack this enzyme. The Gene encoding it is located on chromosome 12. As a result of a mutation in this gene, phenylalanine accumulates in the patient's body. Excess phenylalanine has a toxic effect on the human Brain and impairs intellectual development. Newborns with phenylketonuria appear completely normal because, during prenatal development, excess phenylalanine crosses the Placenta and is metabolized by the mother's liver. If treatment is not initiated in early infancy, the pathology becomes apparent within the first few years of life. The most serious symptom is severe intellectual disability. Untreated patients may have an intelligence quotient (IQ) of less than 20. Before effective treatments were developed, over 1% of patients in psychiatric hospitals suffered from phenylketonuria, and few survived past the age of 30. In addition to intellectual disability, other symptoms include:

1) hyperactivity in children;

2) unsteady gait;

3) lighter Hair, Skin, and eyes compared to healthy relatives (in the absence of tyrosine, the brown skin pigment melanin is not synthesized);

4) skin lesions resembling infantile eczema;

5) epileptic seizures.

25.2. Analyze the following pedigree of phenylketonuria inheritance.

a) How can it be proven that phenylketonuria is controlled by a recessive gene?

b) How can it be proven that phenylketonuria is not sex-linked?

c) Based on the available data, which family members are heterozygous carriers?

d) Which other family members might be carriers?

e) Individuals numbered 10, 11, and 12 may be concerned about being potential carriers since their sister has phenylketonuria. If one of them asks you for the probability of this event, what would you answer? Think carefully!

Neonatal Screening for Phenylketonuria

It is critical that phenylketonuria is detected in the first days of life, because During the first six months, untreated infants develop irreversible brain damage despite a lack of initial symptoms. In 1963, a highly sensitive Blood test was developed to detect excess phenylalanine in the blood of affected individuals (typically a 30- to 50-fold increase). Testing is performed on the 4th day of life, using a blood sample obtained from a heel prick.

25.3. Why are infants not tested immediately after birth?

Carrier Detection and Prenatal Diagnosis

Modern DNA analysis Methods allow for population screening. Thanks to this, up to 95% of phenylketonuria carriers are identified. Prenatal Diagnosis of phenylketonuria is now possible by taking Cell samples from the chorionic villi or Amniotic Fluid and subsequently performing a DNA analysis. However, the necessity of this Procedure is questionable, since the fetus does not suffer from an excess of phenylalanine in utero, and treatment initiated from the first days of life prevents The Development of symptoms. Gene Therapy will likely become feasible in the future.

Treatment

The condition is managed by reducing The amount of phenylalanine in the patients' diet to the required minimum. Phenylalanine is an essential amino acid (meaning it cannot be synthesized from Other Amino Acids and therefore must be present in the diet for normal Protein Synthesis). Since patients' bodies cannot convert phenylalanine into tyrosine, tyrosine also becomes an essential amino acid for them and must be included in their food as well. To maintain the necessary balance during the first years of life, the levels of these amino acids in the patient's blood are continuously monitored. In adulthood, once brain development is complete, an excess of phenylalanine is no longer harmful, and patients can return to a normal diet. Adhering to the diet is challenging because it excludes bread, sweets, orange juice—everything children love; however, failing to follow the diet leads to irreversible consequences.

25.4. Why is it fortunate for phenylketonuria patients that phenylalanine is an essential amino acid?

25.5. Adults with phenylketonuria no longer need to follow a restricted diet. Why is it important for female patients planning a Pregnancy to return to a phenylalanine-restricted diet?