Ribbon diagram of a monomer of human PAH depicting the locations of the amino acid replacements newly identified in Korean PAH patients. Substituted amino acid residues are denoted with red-colored balls. Predicted structural changes in human PAH induced by novel mutations.
A Changing p. Ala to threonine is expected to weaken the hydrophobic interactions among Ala, Tyr, Tyr and p. B Changing p. As shown in Table 1 , all three patients with the p. ArgCys mutation showed BH4 responsiveness: patient 30 with p. ArgCys and p. GlyAsp, patient 31 with p. ValMet, and patient 33 with p. An additional three patients with p. GlyArg and p. ValMet, p. ArgGln, and homozygous p. Ile65Thr mutation also showed BH4 responsiveness Table 1. In the present study, we identified 27 different mutations in 33 unrelated Korean PKU patients, including four novel mutations.
ArgGln, p. This finding was consistent with the previous report of Lee et al. In Europe, there are several prevalent founder alleles that represent the expansion, migration, and genetic drift of European population Zschocke, Particularly, the p. However, this mutation was not found in the present study. Instead, p. In the present study, we also identified four novel mutations in 33 unrelated PKU Korean patients. Three of the 66 alleles 4. It remains to be seen whether uncharacterized alleles correspond to molecular defects that are embedded in the intronic regions and cause splicing aberrations or to impairments of the 5'-end promoter or regulatory regions and 3'-end polyadenylation regions.
Large deletions or duplications of the PAH gene may also be sources of the defective alleles that remain to be specified. The breakpoint junction of the deletion mutation identified in the present study was also different from those of European populations, i.
Considering the relatively high number of deletions of exons 5 and 6 in our current population, we postulate a founder effect of this mutation in the Korean population. In addition, Korean PKU patients with p. ArgCys showed BH 4 responsiveness Lee et al.
Arg is located near the cofactor binding region but does not interact directly with the cofactor, so the p. ArgCys mutation may lead to relatively mild structural deformities. The patient with p. ArgGln showed BH 4 responsiveness. Even though p. AlaThr has sufficient residual enzyme activity to ensure responsiveness. Although there was only one p. Ile65Thr is associated with near-normal levels of enzymatic activity and BH4 responsiveness.
Of the 27 different mutations described herein, the p. Ile65Thr and p. AlaThr mutations were responsive to BH 4. Without treatment, these children develop permanent intellectual disability. Seizures, delayed development, behavioral problems, and psychiatric disorders are also common.
Untreated individuals may have a musty or mouse-like odor as a side effect of excess phenylalanine in the body. Children with classic PKU tend to have lighter skin and hair than unaffected family members and are also likely to have skin disorders such as eczema.
Less severe forms of this condition, sometimes called variant PKU and non-PKU hyperphenylalaninemia, have a smaller risk of brain damage. People with very mild cases may not require treatment with a low-phenylalanine diet.
Babies born to mothers who have PKU and uncontrolled phenylalanine levels women who no longer follow a low-phenylalanine diet have a significant risk of intellectual disability because they are exposed to very high levels of phenylalanine before birth. These infants may also have a low birth weight and grow more slowly than other children. Other characteristic medical problems include heart defects or other heart problems, an abnormally small head size microcephaly , and behavioral problems.
Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss. The occurrence of PKU varies among ethnic groups and geographic regions worldwide.
Most cases of PKU are detected shortly after birth by newborn screening, and treatment is started promptly. As a result, the severe signs and symptoms of classic PKU are rarely seen. Mutations in the PAH gene cause phenylketonuria. The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase.
However, without treatment with a low-phenylalanine diet, these infants will develop mental retardation and behavioral problems. Other common symptoms of untreated classic PKU include seizures, developmental delay, and autism.
Boys and girls who have classic PKU may also have eczema of the skin and lighter skin and hair than their family members who do not have PKU.
Babies born with less severe forms of PKU moderate or mild PKU may have a milder degree of mental retardation unless treated with the special diet. If the baby has only a very slight degree of PKU, often called mild hyperphenylalaninemia, there may be no problems and the special dietary treatment may not be needed.
PKU is usually diagnosed through newborn screening testing that is done shortly after birth on a blood sample heel stick. However, PKU should be considered at any age in a person who has developmental delays or mental retardation.
This is because, rarely, infants are missed by newborn screening programs. PKU is treated by limiting the amount of protein that contains phenylalanine in the diet. However, as these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup hinders the development of the brain, causing mental retardation.
The mainstream treatment for classic PKU patients is a strict PHE-restricted diet supplemented by a medical formula containing amino acids and other nutrients. Patients who are diagnosed early and maintain a strict diet can have a normal life span with normal mental development. However, recent research suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, and bone pathology are slightly suboptimal.
PKU is commonly included in the newborn screening panel of most countries, with varied detection techniques. Most babies in developed countries are screened for PKU soon after birth. A rarer form of hyperphenylalaninemia occurs when PAH is normal, but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin BH 4 by the patient. This cofactor is necessary for proper activity of the enzyme. The coenzyme called biopterin can be supplemented as treatment.
Those who suffer from PKU must be supplemented with tyrosine to account for PAH deficiency in converting phenylalanine to tyrosine sufficiently.
Dihydrobiopterin reductase activity is to replenish quinonoid-dihydrobiopterin back into its tetrahydrobiopterin form, which is an important cofactor in many metabolic reactions in amino acid metabolism. Those with this deficiency may produce sufficient levels of PAH, but since tetrahydrobiopterin is a cofactor for PAH activity, deficient dihydrobiopterin reductase renders any PAH enzyme non-functional.
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