Untreated PKU is characterized by severe intellectual disability, developmental delay, microcephaly, and seizures. Symptoms of intellectual disability typically appear by age 1 and individuals rarely achieve an IQ above 50. Prior to newborn screening programs, these clinical manifestations were commonly observed. However, early diagnosis and treatment have significantly reduced their occurrence.

Individuals with untreated PKU may exhibit hypopigmentation, such as fair hair, light skin color, and blue eyes. This is due to a decrease in the hydroxylation of tyrosine, which is essential for the formation of melanin pigment.

Early detection of PKU is crucial as it can be managed through dietary interventions. Since neonates with PKU may not exhibit symptoms, laboratory testing for elevated phenylalanine levels in the blood is necessary for detection. However, newborns with PKU often have normal phenylalanine levels at birth, as the mother clears excess phenylalanine from the fetus through the placenta. Elevated phenylalanine levels typically manifest after 24-48 hours of protein feeding, thus screening tests are usually conducted after this timeframe to avoid false negatives. Positive screening tests are confirmed through quantitative determination of phenylalanine levels.

Prenatal diagnosis is feasible for classic PKU, which is caused by various mutations in the gene encoding PAH. The prevalence of specific mutations varies among populations, and the disease often involves heterozygosity with different mutations in each allele. Despite the complexity, prenatal diagnosis can be achieved.

The primary treatment approach for PKU involves maintaining blood phenylalanine levels within the normal range. Since natural protein sources contain phenylalanine, it is impossible to meet the body's protein requirements without surpassing the phenylalanine limit in a regular diet. Therefore, synthetic amino acid preparations devoid of phenylalanine are used, supplemented with select low-phenylalanine natural foods like fruits, vegetables, and certain cereals. The amount is adjusted based on individual tolerance, as measured by blood phenylalanine levels. Early initiation of treatment helps prevent neurological damage more effectively, and appropriately treated individuals can attain normal intelligence. Care must be taken to avoid excessively low blood phenylalanine levels since phenylalanine is an essential amino acid. In PKU patients, phenylalanine cannot be converted to tyrosine, making tyrosine an essential dietary amino acid. Discontinuing the phenylalanine-restricted diet in early childhood can lead to poor performance on IQ tests. Adult PKU patients also experience a decline in IQ scores if the diet is discontinued. Hence, lifelong restriction of dietary phenylalanine is recommended. Individuals with PKU should also avoid aspartame, an artificial sweetener containing phenylalanine.

Maternal PKU syndrome occurs when women with PKU, not following a low-phenylalanine diet, become pregnant. High levels of phenylalanine in the mother have a teratogenic effect on the fetus, resulting in microcephaly and congenital heart abnormalities. Since these developmental responses occur during the initial months of pregnancy, controlling blood phenylalanine through diet must begin before conception and be maintained throughout pregnancy.

B. Maple syrup urine disease.
Central nervous system effects: Severe intellectual disability, developmental delay, microcephaly, and seizures are characteristic findings in untreated PKU. The affected individual typically shows symptoms of intellectual disability by age 1 year and rarely achieves an intelligence quotient (IQ) >50 (Fig. 20.19). [Note: These clinical manifestations are now rarely seen as a result of newborn screening programs, which allow early diagnosis and treatment.] c.
Hypopigmentation: Patients with untreated PKU may show a deficiency of pigmentation (fair hair, light skin color, and blue eyes). The hydroxylation of tyrosine by copper-requiring tyrosinase, which is the first step in the formation of the pigment melanin, is decreased in PKU because tyrosine is decreased.
2.
Newborn screening and diagnosis: Early diagnosis of PKU is important because the disease is treatable by dietary means. Because of the lack of neonatal symptoms, laboratory testing for elevated blood levels of phenylalanine is mandatory for detection. However, the infant with PKU frequently has normal blood levels of phenylalanine at birth because the mother clears increased blood phenylalanine in her affected fetus through the placenta. Normal levels of phenylalanine may persist until the newborn is exposed to 24–48 hours of protein feeding. Thus, screening tests are typically done after this time to avoid false negatives. For newborns with a positive screening test, diagnosis is confirmed through quantitative determination of phenylalanine levels.
3.
Prenatal diagnosis: Classic PKU is caused by any of 100 or more different mutations in the gene that encodes PAH. The frequency of any given mutation varies among populations, and the disease is often doubly heterozygous (that is, the PAH gene has a different mutation in each allele). Despite this complexity, prenatal diagnosis is possible (see p. 493).
4.
Treatment: Because most natural protein contains phenylalanine, an essential amino acid, it is impossible to satisfy the body’s protein requirement without exceeding the phenylalanine limit when ingesting a normal diet. Therefore, in PKU, blood phenylalanine level is maintained close to the normal range by feeding synthetic amino acid preparations free of phenylalanine, supplemented with some natural foods (such as fruits, vegetables, and certain cereals) selected for their low phenylalanine content. The amount is adjusted according to the tolerance of the individual as measured by blood phenylalanine levels. The earlier treatment is started, the more completely neurologic damage can be prevented. Individuals who are appropriately treated can have normal intelligence. [Note: Treatment must begin during the first 7–10 days of life to prevent cognitive impairment.] Because phenylalanine is an essential amino acid, overzealous treatment that results in blood phenylalanine levels below normal is avoided. In patients with PKU, tyrosine cannot be synthesized from phenylalanine, and, therefore, it becomes an essential amino acid and must be supplied in the diet. Discontinuance of the phenylalanine-restricted diet in early childhood is associated with poor performance on IQ tests. Adult PKU patients show deterioration of IQ scores after discontinuation of the diet (Fig. 20.20). Therefore, lifelong restriction of dietary phenylalanine is recommended. [Note: Individuals with PKU are advised to avoid aspartame, an artificial sweetener that contains phenylalanine.] 5. Maternal phenylketonuria: If women with PKU who are not on a low-phenylalanine diet become pregnant, the offspring can be affected with maternal PKU syndrome. High blood phenylalanine in the mother has a teratogenic effect, causing microcephaly and congenital heart abnormalities in the fetus. Because these developmental responses to high phenylalanine occur during the first months of pregnancy, dietary control of blood phenylalanine must begin prior to conception and be maintained throughout the pregnancy.
B. Maple syrup urine disease