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Phenylketonuria Michelle Bradley, Lourdes Al Ghofaily and Ramya Srinivasan Phenylketonuria (PKU) is a monogenic autosomal recessive disease. Mutations in the PAH locus encoding the phenylalanine hydroxylase enzyme lead to impaired functioning of the enzyme, hyperphenylalaninemia, and mental retardation. Hyperphenylalaninemia (HPA), one of the core traits of PKU can also result from mutations at regions distinct from the PKU locus. One form of non-PKU HPA is caused by a defect in the synthesis and recycling of tetrahydrobiopterin, a cofactor essential for the function of the PAH enzyme.1 HPA has thus been studied as a trait that exhibits both locus heterogeneity and allelic heterogeneity (in the PAH gene, for instance). PKU and other forms of HPA have also been found to be multifactorial; being the results of both genetic (mutant genotypes) and environmental (dietary phenylalanine) causes. High correlation between mutant genotype and variant phenotype has not been seen in the case of PKU, suggesting the roles of genotypes at other loci in addition to environmental factors1. In the 1980s the PAH gene was mapped to human chromosome 12q24.1 and over 400 mutant alleles have been detected. These, predominantly missense, are expressed at levels far below the wildtype and most genotypes are heteroallelic. Mutant PAH proteins have decreased stability and undergo a process of degradation triggered by structural abnormalities. Missense mutations lead to improper protein folding, altered oligomerization, and increased aggregation of mutant PAH. 1 The phenotype of affected individuals can be altered by the actions of chaperone proteins which can modulate the solubility of mutant PAH proteins. Chaperones provide a protective environment for partially folded proteins, thereby preventing them from entering non productive pathways. Variation in chaperone functioning among individuals can thus modify the disease phenotype associated with a particular missense mutation. Altered protein folding and degradation are therefore implicated in the pathogenesis of the variant phenotype and it is therefore difficult to correlate in vivo catalytic activity with the predicted effect of an allele. 1 In other words, PKU exhibits variable expressivity and discordance between phenotype and genotype is often seen. The homotetrameric PAH enzyme catalyzes the conversion of phenylalanine to tyrosine. The hydroxylation is the key determining reaction of a catabolic flux that eventually leads to the oxidation of phenylalanine to carbon dioxide and water. In normal individuals, this pathway accounts for 75% of the disposal of dietary phenylalanine. Metabolic homeostasis of the phenylalanine pool is actually a complex process involving intestinal absorption followed by hepatic uptake of dietary phenylalanine, its incorporation into proteins, and disposal via hydroxylation, transamination, and decarboxylation. 1 Affected individuals have impaired enzymatic function which leads to accumulation of phenylalaline. Excess phenylalaline has toxic effects on the development and functioning of the brain. This leads to mental retardation which is the major disease phenotype of PKU. However, not all affected individuals suffer from impaired cognitive development. IQ is a complex trait affected by many factors and levels do not always correlate with those predicted by the mutant PAH genotype. In addition, individuals with similar metabolic phenotypes may show distinct cognitive phenotypes. The discordance can be explained by variations in the functioning of the blood-brain barrier and modulation in the free phenylalanine content in the brain. The genotypes of loci involved in the mediated transport of phenylalanine into the brain are therefore among the factors that control the severity of mental retardation. 1 Phenylketonuria (PKU) is screened for early on in life. It is tested most commonly through the Guthrie microbial inhibition test. This test is done on all newborns in the country. A drop of blood is taken from the newborn's heel in the hospital and sent to a national lab where an excess of phenylalanine is tested for by growing a phenylalaninedependent culture of bacteria with the blood sample. If there is adequate bacterial growth, then it is a sign that there is a significant amount of phenylalanine in the newborn's blood. Normal range is about 1 mg/dl of phenylalanine. PKU is suspected at any level above 30 mg/dl. Because there are many other diseases that cause hyperphenylalaninemia, further testing must be done to diagnose PKU. For the purposes of genetic counseling, however, sequencing of the PAH gene is done to rule out or ascertain whether the newborn will develop PKU or any kind of hyperphenylalaninemia. The symptoms of PKU can result from defects in the biopterin pathways. This includes deficiencies in the metabolism of tetrahydrobiopterin (BH4)- both in its synthesis and recycling. BH4 is a required cofactor in the hydroxylation of various amino acids such as phenylalanine, tyrosine, and tryptophan. A defect in BH4 synthesis is due to deficiencies in any one of the following enzymes: guanosine triphosphate cyclohydrolase (GTPCH), 6-pyruvoyl tetrahydrobiopterin (DHPR), or pterin-4-acarbinolamine dehydratase (PCD). Hyperphenylalaninemia resulting from BH4 deficiency is passed down as an autosomal recessive disorder and not as an autosomal dominant disorder, as classic PKU is. There are some common symptoms between BH4 deficiency and PKU including mental retardation, irritability, abnormal movements and microcephaly. BH4 deficiencies only account for 2% of all cases of hyperphenylalaninemia, but they must be differentiated from PKU for appropriate treatment. Interestingly, although BH4 deficiencies and PKU are due to different causes, BH4 supplements can provide a sufficient therapy for "up to 10% of individuals with classic PKU" 2,3. Among some of the first symptoms to appear in babies suffering from PKU include behavioral and social problems, seizures and neurological deficits such as uncontrolled movements, hyperactivity, eczema, microcephaly, stunted growth, and a characteristic "musty" odor due to the excess phenylalanine in urine, breath, or skin. Even in cases of early-detected PKU, some mild form of mental retardation can be expected. The goal of treatment for the hyperphenylalaninemias is to keep the concentrations of phenylalanine and tyrosine in the blood at relative steady levels. This method will try to prevent the cognitive deficits that are attributable to PKU. The blood concentrations should be between 120 to 360 µmol/L (2-6 mg/dL) or 40 to 240 µmol/L (1-4 mg/dL). These levels are considered safe for normal brain function. Studies have proven that if a strict low phenylalanine diet is not followed closely, especially while the child is still young, and if the phenylalanine level in the blood is allowed to rise above the recommended levels, some brain impairment is inevitable. A diet restricted in phenylalanine should be started as soon as possible after birth and continued at least into adolescence or for life 4. Studies have proved that people who have an enzyme activity level below 25% and go off the strict diet have an increased chance of decreasing their IQ levels. This is compared to others with above 25% enzyme activity that also went off the diet. This second group maintained or increased their IQ levels 5. The restricted phenylalanine diet needs to be adjusted in order to suit the individual needs for each patient. These needs are based on their own tolerance for phenylalanine and as well as appropriate protein and energy levels for each patient age. Blood concentrations of phenylalanine within the recommended levels and normal nutritional status cannot be achieved by a low-protein diet alone, but with the addition of a phenylalanine-free medical formula. The diet must continuously be adjusted so that growth and nutritional status are unaffected and that a deficiency of phenylalanine or tyrosine is not created. The diet might also have to be adjusted in order to account for growth, illness, activity, etc. Plasma phenylalanine and tyrosine concentrations must be monitored regularly6. The treatment for patients with PKU is not easy, but through the help of a caring and supportive medical team the correct treatment and care can be administered. Since PAH deficiency is inherited in an autosomal recessive manner, unaffected parents of a child with PAH deficiency are obligate heterozygotes. People who are heterozygotes for PAH carry one disease causing PAH allele, and since the disease requires two affected alleles in order to be expressed they never develop hyperphenylalaninemia. The siblings of an affected child will have a 25% chance of being affected themselves, a 50% chance of being a carrier, and a 25% chance of having two normal alleles of PAH. Since PAH deficiency is a highly treatable disease and most of the affected patients have a normal intelligence and live normal lives they often reproduce. All the offspring of a person with PAH deficiency will be an obligate carrier. It depends on the partner if the offspring will be affected or remain a carrier for PKU. If the other parent is a carrier for PAH deficiency then the child will have a 50% chance of being affected or a heterozygote. If two affected people decide to have a child then the offspring will definitely have the PAH deficiency. If the affected parent is the mother then additional problems can arise during the pregnancy. For maternal PKU a strict diet is necessary prior to conception in order to prevent the fetus from having birth defects as a result of the mother’s phenylalanine levels during the pregnancy. This will protect the fetus from having brain damage and intellectual development problems later in life. For mothers who start the low phenylalanine diet post-conception, the chances increase that their babies will have a heart defect. Prenatal care is used to determine which complications will arise when the child is born, so that proper steps can be taken to ensure the best postnatal care for the child. This is most common approach for unplanned pregnancies which do not allow the mother modulate her diet before conception7. References: 1. Monogenic traits are not simple: lessons from phenylketonuria. TIG July 1999, volume 15, No. 7. 2. Scriver CR, Kaufman S (2001) The hyperphenylalaninemias. In: Scriver CR, Beaudet AL, Sly SW, Valle D (eds) Childs B, Kinzler KW, Vogelstein B (assoc eds) The Metabolic and Molecular Bases of Inherited Disease, 8 ed. McGraw-Hill, New York, Ch. 77 3. Bernegger C and Blau N (2002) High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002. Mol Genet Metab 77:304-13 4. Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H, Bremer HJ (1998) Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 157:824-30 5. Greeves, L. G.; Patterson, C. C.; Carson, D. J.; Thom, R.; Wolfenden, M. C.; Zshocke, J.; Graham, C. A.; Nevin, N. C.; Trimble, E. R. : Effect of genotype on changes in intelligence quotient after dietary relaxation in phenylketonuria and hyperphenylalaninaemia. Arch. Dis. Child. 82: 216-221, 2000. 6. Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H, Bremer HJ (1998) Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 157:824-30 7. Levy HL, Lobbregt D, Platt LD, Benacerraf BR (1996) Fetal ultrasonography in maternal PKU. Prenat Diagn 16:599-604