such as potatoes and corn are generally acceptable in controlled amounts, but the quantity of phe consumed from these foods must be monitored. a corn-free diet may be prescribed in some cases. a food diary is usually kept to record the amount of phe consumed with each meal, snack, or drink. an "exchange" system can be used to calculate the amount of phe in a portion of food from the protein content identified on a nutritional information label. lower-protein "medical food" substitutes are often used in place of normal bread, pasta, and other grain-based foods, which contain a significant amount of phe. many fruits and vegetables are lower in phe and can be eaten in larger quantities. infants may still be breastfed to provide all of the benefits of breastmilk, but the quantity must also be monitored and supplementation for missing nutrients will be required. the sweetener aspartame, present in many diet foods and soft drinks, must also be avoided, as aspartame contains phenylalanine. different people can tolerate different amounts of phe in their diet. regular blood tests are used to determine the effects of dietary phe intake on blood phe level. nutritional supplements supplementary "protein substitute" formulas are typically prescribed for people pku (starting in infancy) to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. tyrosine, which is normally derived from phenylalanine and which is necessary for normal brain function, is usually supplemented. consumption of the protein substitute formulas can actually reduce phenylalanine levels, probably because it stops the process of protein catabolism from releasing phe stored in the muscles and other tissues into the blood. many pku patients have their highest phe levels after a period of fasting (such as overnight) because fasting triggers catabolism. a diet that is low in phenylalanine but does not include protein substitutes may also fail to lower blood phe levels, since a nutritionally insufficient diet may also trigger catabolism. for all these reasons, the prescription formula is an important part of the treatment for patients with classic pku. evidence supports dietary supplementation with large neutral amino acids (lnaas). the lnaas (e.g. leu, tyr, trp, met, his, ile, val, thr) may compete with phe for specific carrier proteins that transport lnaas across the intestinal mucosa into the blood and across the blood–brain barrier into the brain. its use is limited in the us due to the cost but is available in most countries as part of a low protein / phe diet to replace missing nutrients. another interesting treatment strategy is casein glycomacropeptide (cgmp), which is a milk peptide naturally free of phe in its pure form cgmp can substitute for the main part of the free amino acids in the pku diet and provides several beneficial nutritional effects compared to free amino acids. the fact that cgmp is a peptide ensures that the absorption rate of its amino acids is prolonged compared to free amino acids and thereby results in improved protein retention and increased satiety compared to free amino acids. another important benefit of cgmp is that the taste is significantly improved when cgmp substitutes part of the free amino acids and this may help ensure improved compliance to the pku diet. furthermore, cgmp contains a high amount of the phe-lowering lnaas, which constitutes about 41 g per 100 g protein and will therefore help maintain plasma phe levels in the target range. enzyme substitutes in 2018, the fda approved an enzyme substitute called pegvaliase which metabolizes phenylalanine. it is for adults who are poorly managed on other treatments. tetrahydrobiopterin (bh4) (a cofactor for the oxidation of phenylalanine) when taken by mouth can reduce blood levels of this amino acid in some people. mothers for women with pku, it is important for the health of their children to maintain low phe levels before and during pregnancy. though the developing fetus may only be a carrier of the pku gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. the child may develop congenital heart disease, growth retardation, microcephaly and intellectual disability as a result. pku-affected women themselves are not at risk of additional complications during pregnancy. in most countries, women with pku who wish to have children are advised to lower their blood phe levels (typically to between 2 and 6 mg/dl) before they become pregnant, and carefully control their levels throughout the pregnancy. this is achieved by performing regular blood tests and adhering very strictly to a diet, in general monitored on a day-to-day basis by a specialist metabolic dietitian. in many cases, as the fetus' liver begins to develop and produce pah normally, the mother's blood phe levels will drop, requiring an increased intake to remain within the safe range of 2–6 mg/dl. the mother's daily phe intake may double or even triple by the end of the pregnancy, as a result. when maternal blood phe levels fall below 2 mg/dl, anecdotal reports indicate that the mothers may experience adverse effects, including headaches, nausea, hair loss, and general malaise. when low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-pku mother. epidemiology country incidence australia 1 in 10,000 brazil 1 in 8,690 canada 1 in 22,000 china 1 in 17,000 czechoslovakia 1 in 7,000 denmark 1 in 12,000 finland 1 in 200,000 france 1 in 13,500 india 1 in 18,300 ireland 1 in 4,500 italy 1 in 17,000 japan 1 in 125,000 korea 1 in 41,000 netherlands 1 in 18,000 norway 1 in 14,500 philippines 1 in 102,000 poland 1 in 8,000 scotland 1 in 5,300 spain 1 in 20,000 sweden 1 in 20,000 turkey 1 in 2,600 united kingdom 1 in 10,000 united states 1 in 25,000 the average number of new cases of pku varies in different human populations. united states caucasians are affected at a rate of 1 in 10,000. turkey has the highest documented rate in the world, with 1 in 2,600 births, while countries such as finland and japan have extremely low rates with fewer than one case of pku in 100,000 births. a 1987 study from slovakia reports a roma population with an extremely high incidence of pku (one case in 40 births) due to extensive inbreeding. it is the most common amino acid metabolic problem in the united kingdom. history before the causes of pku were understood, pku caused severe disability in most people who inherited the relevant mutations. nobel and pulitzer prize winning author pearl s. buck had a daughter named carol who lived with pku before treatment was available, and wrote an account of its effects in a book called the child who never grew. many untreated pku patients born before widespread newborn screening are still alive, largely in dependent living homes/institutions. phenylketonuria was discovered by the norwegian physician ivar asbjørn følling in 1934 when he noticed hyperphenylalaninemia (hpa) was associated with intellectual disability. in norway, this disorder is known as følling's disease, named after its discoverer. følling was one of the first physicians to apply detailed chemical analysis to the study of disease. in 1934 at rikshospitalet, følling saw a young woman named borgny egeland. she had two children, liv and dag, who had been normal at birth but subsequently developed intellectual disability. when dag was about a year old, the mother noticed a strong smell to his urine. følling obtained urine samples from the children and, after many tests, he found that the substance causing the odor in the urine was phenylpyruvic acid. the children, he concluded, had excess phenylpyruvic acid in the urine, the condition which came to be called phenylketonuria (pku). his careful analysis of the urine of the two affected siblings led him to request many physicians near oslo to test the urine of other affected patients. this led to the discovery of the same substance he had found in eight other patients. he conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude that the compound contained a benzene ring. further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine. in 1954, horst bickel, evelyn hickmans and john gerrard published a paper that described how they created a diet that was low in phenylalanine and the patient recovered. bickel, gerrard and hickmans were awarded the john scott medal in 1962 for their discovery. pku was the first disorder to be routinely diagnosed through widespread newborn screening. robert guthrie introduced the newborn screening test for pku in the early 1960s. with the knowledge that pku could be detected before symptoms were evident, and treatment initiated, screening was quickly adopted around the world. ireland was the first country to introduce a national screening programme in february 1966, austria also started screening in 1966 and england in 1968. in 2017 the european guidelines were published. they were called for by the patient organizations such as the european society for phenylketonuria and allied disorders treated as phenylketonuria. they have received some critical reception. etymology and pronunciation the word phenylketonuria uses combining forms of phenyl + ketone + -uria; it is pronounced /ˌfiːnaɪlˌkiːtəˈnjʊəriə, ˌfɛn-, -nɪl-, -nəl-, -toʊ-/. research other therapies are currently under investigation, including gene therapy. biomarin is currently conducting clinical trials to investigate peg-pal (pegylated recombinant phenylalanine ammonia lyase or 'pal') is an enzyme substitution therapy in which the missing pah enzyme is replaced with an analogous enzyme that also breaks down phe. peg-pal is now in phase 2 clinical development.