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Research Notes: Phenylketonuria (PKU) and HyperphenylalaninemiaSee also: Tetrahydrobiopterin deficiency From the eMedicine.com article on PKU: Background: Phenylketonuria (PKU) is an inborn error of protein metabolism that results from an impaired ability to metabolize the essential amino acid phenylalanine. Classic PKU is present when plasma phenylalanine levels exceed 20 mg/dL (1200 mmol/L) without treatment. Lesser degrees of elevation of plasma phenylalanine are considered in the chapter on Hyperphenylalaninemia. Elevated phenylalanine levels negatively impact developmental function, and individuals with classic PKU are almost always mentally retarded unless levels are controlled through dietary treatment. In the United States and many other countries, PKU is detected by newborn screening, and treated individuals have normal intelligence. Pathophysiology: The majority of individuals with PKU have a deficiency of the enzyme phenylalanine hydroxylase. Phenylalanine hydroxylase deficiency is inherited in an autosomal recessive manner. The mechanism by which elevated phenylalanine levels cause mental retardation is not known, though restriction of dietary phenylalanine ameliorates this effect if initiated within a few weeks of birth. This also results in normal cognitive development. A strong relationship exists between control of blood phenylalanine levels in childhood and intelligence quotient (IQ). Subtle neuropsychological deficits in children with treated PKU are under investigation. Some investigators have attributed these deficits to small residual neurotransmitter abnormalities. A small percentage of children with elevated phenylalanine levels exhibit normal phenylalanine hydroxylase but have a deficiency in synthesis or recycling of the enzyme's cofactor, tetrahydrobiopterin (see Tetrahydrobiopterin deficiency). This condition is termed malignant PKU. The biopterin cofactor is also required for hydroxylation of tyrosine (a precursor of dopamine) and tryptophan (a precursor of serotonin). Thus, individuals with tetrahydrobiopterin cofactor deficiency have more significant neurological problems that are not fully corrected by dietary phenylalanine reduction. Frequency: In the US: Incidence of classic PKU is approximately 1 in 15,000 births. Internationally: Disease frequency varies by population. Turkey has the highest incidence in the world with approximately 1 in 2600 births. High incidence is also reported in the Yemenite Jewish population, as well as in regions of northern and eastern Europe, Italy, and China. Mortality/Morbidity: Most untreated individuals with PKU have severe mental retardation. After the discovery of PKU, routine testing of institutionalized patients who are mentally retarded identified a 1% incidence of PKU in this group. Well-treated patients should have IQs within approximately 5-8 points of their siblings. Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment. Treated patients with PKU often experience subtle performance and attention and behavioral changes when phenylalanine levels exceed 6 mg/dL. Race: In the United States, PKU is most commonly present in Caucasians. Worldwide, PKU is most common in Caucasians and Asians. Sex: No sex predilection exists. Women with PKU must maintain phenylalanine levels between 2-6 mg/dL during pregnancy to avoid birth defects and mental retardation in their infants. Age: PKU most commonly is diagnosed in newborns by newborn screening programs. Consider PKU at any age in an individual who is developmentally delayed or mentally retarded because infants are missed by newborn screening programs on rare occasions. History:
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Causes: PKU is caused by autosomal recessive inheritance due to mutations in the enzyme phenylalanine hydroxylase. The enzyme locus is on chromosome arm 12q. Over 100 known mutations exist, and mutation frequency varies among ethnic groups. Genotype and phenotype are broadly related (ie, reproducible mild vs severe mutations), but unrelated individuals with identical mutations have some degree of variability in phenylalanine tolerance. ... Lab Studies:
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Procedures: Older textbooks and protocols occasionally called for phenylalanine-loading studies to help determine if a child still required phenylalanine restriction after 1 or more years; however, as the treatment range for phenylalanine levels has decreased, these studies generally have been abandoned. Medical Care: Most patients are treated in a specialty metabolic clinic, usually under the auspices of a genetics or pediatric endocrinology clinic. Treatment consists of dietary restriction of phenylalanine with tyrosine supplementation. The extent of phenylalanine restriction necessary for normal outcome remains controversial. Phenylalanine levels are followed at regular intervals, from 1-2 times weekly in neonates to once per month in older children and adults. Most US facilities recommend that phenylalanine levels be maintained from 2-6 mg/dL (120-360 mmol/L). Some adults with untreated phenylketonuria (PKU) who are mentally retarded adults may show improvement in behavior and physical manifestations when treated with a phenylalanine-restricted diet. Consultations:
Diet: The mainstay of the diet consists of phenylalanine restriction and supplementation of other essential amino acids, vitamins, minerals, and energy intake, using medical foods and low-protein foods. Aspartame also must be eliminated. Phenylalanine is one of the primary components of aspartame. It is found in many artificially sweetened foods and soft drinks, as well as some vitamins and medicines. A 12-oz can of aspartame-sweetened diet drink contains approximately 105 mg of phenylalanine (ie, 25-50% of the usual daily intake). The age at which the diet may be discontinued is somewhat controversial. Most US facilities no longer recommend discontinuation of the diet at any age. Most newborns with PKU require 40-60 mg/kg/d of dietary phenylalanine to maintain normal growth. Breastfeeding is usually possible and should not be stopped unless instructed to do so by a local health official or treatment facility. As growth slows, the phenylalanine requirement falls, and most older children and adults tolerate 200-400 mg/d. Providing some natural phenylalanine is essential in order to prevent deficiency of this essential amino acid. The diet requires elimination of all high-protein foods, such as meat, dairy, nuts, and legumes. Starches, including bread, potatoes, corn, and beans also must be restricted (a slice of bread or small order of fries contains approximately 120-150 mg phenylalanine). Essential amino acids, vitamins, and minerals must be supplemented using medical foods. Currently, most are consumed as a powder dissolved in liquid (ie, formula). Newer supplements, including capsules, amino acid bars, and amino acids cooked into foods, are becoming available. Energy and variety are provided by low-protein foods, including fruits and nonstarchy vegetables, as well as specially ordered low-protein foods. Low-protein foods include pastas, breads, imitation cheese, baking mixes, and other foods especially designated for low-protein diets. These foods are covered by medical benefits in some states. Because most patients prefer a standard American diet, most teens and older children (in our clinic) cheat by failing to limit quantities of high-protein, nonmeat foods, such as potatoes (eg, fries, chips, mashed potatoes), pasta, bread, and pizza crust (minus the cheese); however, few teens who were well managed as children will cheat by consuming meat. Activity: Normal activity is expected with adherence to treatment. Medication Avoid drugs containing aspartame. The efficacy of very high-dose tyrosine supplementation is under investigation. Reports conflict over whether or not this may ameliorate neuropsychological deficits of the prefrontal cortex observed in children with treated phenylketonuria (PKU). Up to one half of children with classic PKU may respond to administration of the biopterin cofactor, with lowering of plasma phenylalanine levels by approximately one third. However, this cannot yet replace dietary restriction of phenylalanine, even if that restriction can be relaxed slightly. Biopterin is not yet FDA approved in the United States and is not yet available outside of clinical trials. Animal studies are in progress on an injectable form of phenylalanine ammonium lyase, an alternate enzyme capable of substituting for phenylalanine hydroxylase. Drug Category: Drugs acting at the blood brain barrier - Some evidence suggests that consumption of high doses of other large neutral amino acids can increase competition with phenylalanine for crossing the blood brain barrier into the brain, thus decreasing phenylalanine levels in the brain. Large neutral amino acids (PhenylAde-PreKunil) - Adults and older teenagers refusing diet can be prescribed a preparation of high-dose large neutral amino acids. The long-term outlook merits further study. Young women of childbearing age need to realize this drug does not protect their fetus from the teratogenic effects of phenylalanine. This preparation does not contain lysine, an essential amino acid, and lysine deficiency has been reported. Individuals taking PreKunil continue to require nutritional assessment, because teens and adults who are "off diet" often fail to consume sufficient protein to meet essential amino acid and vitamin/mineral requirements. Adult Dose Dose (number of tablets) is individualized by body weight (kg) X 0.4. For example, an individual who weighs 50 kg would receive 20 tab daily (ie, 50 kg X 0.4 = 20 tab). Divide daily dose into 3-4 doses administered with meals or snacks. Pediatric Dose <15 years: Not recommended Contraindications - Pregnancy Follow-up In/Out Patient Meds: Avoid aspartame (an artificial sweetener). Aspartame is widely used in medicines, vitamins, beverages, and other substances. Complications: Subtle attention and performance deficits in organization and planning persist in treated patients. These deficits are related to phenylalanine levels and may interfere with academic achievement. A few patients experience psychological problems, including poor self-esteem. Agoraphobia and more severe problems have been described, especially in women who have discontinued the diet. Because phenylalanine competes with tryptophan (the precursor of serotonin) for entry into the brain, psychological symptoms may have a biological basis and improved dietary control is recommended. Prognosis: Prognosis for normal intelligence is excellent with dietary treatment. However, school functioning can be mildly impaired in some children, particularly when dietary control is poor. Patient Education: Teach parents how to administer the diet at home and involve all caregivers as well. Children should begin involvement in their dietary planning as soon as they are developmentally ready. Medical/Legal Pitfalls:
Special Concerns: Pregnancy - Birth defects, microcephaly, and mental retardation are common in infants of mothers with phenylketonuria if the mother's phenylalanine levels are not controlled during pregnancy. Women must maintain phenylalanine levels from 2-6 mg/dL during pregnancy. From the eMedicine.com article on hyperphenylalaninemia: Background: Hyperphenylalaninemia is defined broadly as the presence of blood phenylalanine levels exceeding the limits of the upper reference range (2 mg/dL or 120 mmol/L) but trailing the levels found in patients with phenylketonuria (PKU). Phenylalanine levels exceeding 20 mg/dL (1200 mmol/L) are considered diagnostic for PKU. This chapter describes nonphenylketonuric hyperphenylalaninemia, which includes phenylalanine levels between 2 mg/dL and 20 mg/dL. Phenylalanine levels of 6 mg/dL (360 mmol/L) or less in patients consuming an unrestricted diet generally indicate a benign condition. No dietary phenylalanine restrictions usually are recommended for individuals with levels in this range. In contrast, dietary restriction may be indicated for patients whose phenylalanine levels are more than 12 mg/dL (725 mmol/L); chronic phenylalanine levels in this range reportedly cause measurable intellectual impairment in children. Dietary treatment is somewhat controversial for children with phenylalanine levels in the intermediate range of 7-11 mg/dL (425-660 mmol/L). For example, one study noted that most centers in the United States recommend restricting dietary phenylalanine when levels exceed 10 mg/dL (600 mmol/L). Many also recommend treatment for levels exceeding 8-9 mg/dL (480-545 mmol/L). The British Medical Research Council Working Party on PKU recommends dietary phenylalanine restriction when levels consistently exceed 6.6-10 mg/dL (400-600 mmol/L). ... Mortality/Morbidity:
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... Medical Care: If available, patients should be evaluated at a PKU treatment center. The extent of the hyperphenylalaninemia determines the nature and frequency of follow-up. Many patients with hyperphenylalaninemia show an excellent response to treatment with tetrahydrobiopterin cofactor (also known as biopterin or BH4). In many cases, the residual enzyme activity is stabilized and dietary phenylalanine restriction can be relaxed. However, not all children with hyperphenylalaninemia respond to biopterin. Animal studies are underway for injectable phenylamine ammonium lyase, an enzyme substitute. This shows promise as an alternative treatment to control phenylalanine levels. Consultations: If dietary treatment is necessary, refer the patient to a dietitian experienced with PKU (usually a member of a PKU treatment team). Refer families of affected infants to a medical geneticist or genetic counselor to review the inheritance of hyperphenylalaninemia. Diet:
Medication
Follow-up ... In general, patients should avoid consuming aspartame because phenylalanine is a primary component of aspartame. Prognosis: Prognosis is excellent for normal development when treated as indicated. ... Special Concerns:
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