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Diagnosis: Phenylketonuria

Synonyms: PKU


Date of publication: 2014-04-29
Version: 3.0

ICD 10 code


The disease

Phenylketonuria (PKU) is an inherited, congenital, metabolic disease caused by impaired levels, or absence, of an enzyme needed for the conversion of the amino acid phenylalanine into the amino acid, tyrosine. High levels of phenylalanine in the blood injure the brain, and without treatment children with phenylketonuria suffer severe brain damage.

The disease was identified in 1934 by Norwegian physician Asbjörn Fölling while investigating two siblings who were subject to seizures and had severe intellectual disabilities. In the 1950s the German physician Horst Bickel showed that brain damage could be prevented by adhering to a low phenylalanine diet from an early age and throughout life. In the 1960s, a simple blood screening test to identify newborns with phenylketonuria was developed by American microbiologist Bob Guthrie. Since 1965, all newborns in Sweden have been screened for the disease.


In Sweden, approximately five children with phenylketonuria are born every year. This corresponds to five per 100,000 births. Since the introduction of neonatal testing in 1965, a total of 260 children with the condition have been identified in Sweden.


Phenylketonuria is caused by mutations in the PAH gene. PAH is located on the long arm of chromosome 12, (12q22-q24.2) and controls the formation of (codes for) the enzyme phenylalanine hydroxylase (PAH). Phenylalanine hydroxylase normally breaks down phenylalanine into tyrosine, used by the brain to produce important signalling agents. Phenylalanine is one of the twenty amino acids which form the constituent parts of all proteins. It is present in all naturally-occurring protein, including both the body’s own proteins and proteins in food. The mutation in PAH causes abnormalities in the phenylalanine hydroxylase enzyme. The type of mutation determines whether the enzyme is completely or partially inactive. On a normal diet, children with phenylketonuria experience rapidly increasing levels of phenylalanine in the blood and brain, and low levels of tyrosine, resulting in brain damage.

Tetrahydrobiopterin (BH4) is a coenzyme which is necessary for normal functioning of the PAH enzyme. In certain cases, BH4 supplements in high doses can have a positive effect on phenylalanine hydroxylase activity so that children with the condition can consume more natural protein without phenylalanine levels in their blood rising. In some people with high levels of phenylalanine the functionality of this coenzyme is affected, but the resulting condition does not share the same signs and symptoms as phenylketonuria and may be treated with BH4 supplements only or with BH4 in combination with a special diet. This disease is called hyperphenylalaninemia.


The inheritance pattern of phenylketonuria is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.


In phenylketonuria the child has no symptoms at birth. At approximately six months of age the first symptoms appear. The first sign of the disorder may be that the child’s urine has a peculiar smell, caused by the secretion of increased amounts of phenylketone, an abnormal by-product produced when phenylalanine is broken down. During the first year of life it becomes increasingly clear that the child has a progressive cognitive impairment. Severe epilepsy manifests. As pigment production is impaired, the child will be fair-haired.

A child with phenylketonuria who does not receive treatment will suffer behavioural problems and severe cognitive impairment, often in combination with difficult-to-treat epileptic seizures. However, damage can be prevented by the early introduction of the correct diet, making it possible for the child to develop normally.

Phenylketonuria does not present in one way only and its severity depends on how enzyme activity is affected by the mutation. Sometimes the individual retains a residual ability to break down phenylalanine. For this reason the need for, and content of, a special diet varies between individuals with the condition. Some people can eat almost normal amounts of protein while others manage only very small amounts. There are also milder forms of the condition where phenylalanine levels are not elevated enough to require treatment.


Currently (2013) elevated phenylalanine levels can be detected in newborns through a routine blood test (a PKU test), taken when the child is older than 48 hours. In Sweden all newborns are offered the test, either before discharge or at a later visit to the hospital. It is also important that children born outside Sweden, and in certain cases adults with disabilities, are offered a PKU test. Even if children are older when they are diagnosed and their brains have already been affected, it is still possible to prevent further injury.

When a newborn with suspected phenylketonuria is identified, further tests are required to confirm that the child has the disease, and if so, which type. This is done by DNA-based testing and by analyzing amino acids in the blood. By identifying the mutation it is possible to confirm the specific genetic abnormality, which is a great help in providing correct treatment. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.


Current treatment allows children with the condition to develop normally. The most common type of phenylketonuria is treated by a protein-reduced diet, tailor-made for each individual. The diet is designed to restrict the intake of phenylalanine, although small amounts of the substance are needed for normal growth. Children with the condition get this by eating root vegetables, vegetables, fruit and special low-protein products in exactly the right amounts for their needs, but without giving rise to dangerous levels of phenylalanine.

Children with a normal diet get protein from meat, eggs, cheese, milk, nuts and dried legumes but the main source of protein for children with phenylketonuria is a specially-made, phenylalanine-free mixture of amino acids, which comes in various forms. Depending on the type of amino acid mixture being used, the child may require additional vitamins, essential fatty acids and trace elements. Children with milder forms of the disease, young people and adults on a less restricted diet and pregnant women nearing full-term may eat natural protein-rich food in controlled amounts.

Natural food products with low levels of protein include fruits and some vegetables but for variation, and to experience a feeling of fullness while consuming little protein, there are products which contain starch instead of ordinary flour. These can replace pasta and bread, for example.

A child with phenylketonuria must eat regularly, and the different foodstuffs should be carefully measured or weighed. Successful dietary treatment requires time, knowledge and care, and will probably need to be continued throughout life. To be able to control the child’s daily intake of phenylalanine, parents should receive advice from a dietician who will teach them how to calculate the protein and phenylalanine content in food.

Others in contact with the child, including teachers, preschool staff and school catering staff, must also be informed about the disorder and the importance of adhering to the diet. Advice and support from a dietician familiar with the disease are necessary. Specialist dietary expertise is also required in the team treating the child, which includes a paediatrician, clinical pathology physician, psychologist and social worker. They should be able to give support and practical advice to the person with the disease, and also to the family, as dietary treatment affects everyday life in many ways.

Depending on the severity of the condition and the success of treatment, blood tests to measure phenylalanine levels are taken weekly for several years, being reduced to twice a month for older children. The treatment is life-long. The first patients with phenylketonuria to have received life-long treatment starting at birth are now (2013) approaching 50 years of age. Since it is not known what would happen to an adult if his or her phenylalanine levels were allowed to rise, the current recommendation is for a lifelong diet, to keep phenylalanine levels under control.

For children with cognitive deficits resulting from late diagnosis (for example unscreened immigrant children), special educational support from pre-school age onward is important. Early habilitation is essential to stimulate the child’s development. Early contact should be established between the child and family and a habilitation team, which includes professionals with special expertise in how disability affects everyday life, health and development.

Support and treatment are offered within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. They also include information about support offered by the local authority. Parents and siblings may also receive support. The family may also need help in coordinating interventions.


Pregnant women supply the foetus with nutrition, including amino acids, through the placenta. The foetus is very sensitive to elevated phenylalanine concentrations, and is entirely dependent on the mother to break down excess phenylalanine. If the mother has high phenylalanine values her otherwise healthy foetus will also have elevated levels and may develop cardiac defects or brain damage. To avoid these complications, the mother’s phenylalanine level must be regulated before conception takes place. It is important that a woman with phenylketonuria plans her pregnancy and ensures that she adheres to a low-protein diet that poses no threat to her own or her baby’s health. Dietary control should begin prior to conception and continue throughout the pregnancy.

New forms of treatment

An approved medication, sapropterin, has been available since 2008. For some people it can reduce the amount of phenylalanine in the blood and so can complement or replace dietary treatments. Sapropterin is a synthetic copy of the coenzyme tetrahydrobiopterin (BH4) and is given in tablet form to improve the child’s ability to break down phenylalanine. It may be given to the child from birth onwards. Currently (2013) the usual Swedish subsidies for medication do not apply to sapropterin and it can be prescribed only to children under the age of 18 after a special dispensation from the relevant county council.

Treatment with supplements of large neutral amino acids (LNAA) in food can form a complement to the usual dietary regime. The objective is to reduce the absorption of phenylalanine in the intestines and brain. Treatment cannot replace the usual diet but it can be a complement for adults with the condition who find it difficult to adhere to a strict dietary regime.

There is much research into alternatives to the dietary treatment of phenylketonuria. There is still a long way to go before such treatments become available to everyone with the disease. (See under Research and development.)

Practical advice

The Swedish PKU Association and Swedish PKU health-care teams both offer advice and practical assistance. (Contact information is given under “National and local resources” and under “Organizations for the disabled/patient associations.”)

Specially prepared recipes, in accordance with dietary rules, have been collected in a cookery book. (In Swedish only. See under “Information material”).

National and regional resources in Sweden

Special laboratories for testing children with congenital metabolic abnormalities include the Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SE-171 76 Solna, Sweden, tel: +46 8 517 700 00. Also, the Department of Clinical Chemistry, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden, tel: +46 31 342 38 25.

Screening of blood tests from neonates is carried out at the PKU Laboratory, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm.

There are PKU health-care teams in five of Sweden’s regional hospitals. Members of these teams include doctors, dieticians, nurses, psychologists and counsellors with special knowledge and experience of children with phenylketonuria.

The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

The Children’s Hospital in Lund, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 046 17 10 00.

Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

The Children’s Clinic at Norrland University Hospital, SE-901 85 Umeå, Sweden.Tel: +46 90 785 00 00.

Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00.

Testing of adults with phenylketonuria is carried out at metabolic centres at Swedish university hospitals, where physicians and dieticians can assess the results of treatment and give new information on diet and other treatments.

Resource personnel


Specialist physician Svetlana Lajic, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 780 00.

Specialist physician Anna Nordenström, Astrid Lindgren Children’s Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Specialist physician Ricard Nergårdh, Astrid Lindgren Children’s Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Specialist physician Rolf Zetterström, Centre for Inherited Metabolic Diseases (CMMS), Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden.

Dieticians Carina Heidenborg and Erika Forsell, Astrid Lindgren Children’s Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Specialist physician Mikael Oscarson, Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 70 00.


Associate Professor Olov Ekwall, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Specialist physician Annika Reims, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Dieticians Johanna Ekengren, Karina Eftring and Ellen Karlge-Nilsson, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Planning is under way into how care of adults with phenylketonuria shall be organized.


Specialist physician Maria Halldin, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00.

Dieticians Agnes Pal and Christine Gibson, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00.

Associate Professor Andreas Kindmark, Clinic for Metabolic Diseases, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00.


Specialist physician Domniki Papadopoulo, The Children’s Hospital in Lund, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00.

Dieticians Elisabeth Sjökvist and Marika Kanthe, The Children’s Hospital in Lund, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00.

Specialist physician Li X Zhou, Department of Internal Medicine, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 17 10 00.


Specialist physician Olof Sandström, The Children’s Clinic, Norrland University Hospital, SE-901 85 Umeå, Sweden. Tel: +46 90 785 00 00.

Dietician Inger Öhlund, The Children’s Clinic, Norrland University Hospital, SE-901 85 Umeå, Sweden. Tel: +46 90 785 00 00.

Associate Professor Per Dahlqvist, Medicine Centre, Norrland University Hospital, SE-901 85 Umeå, Sweden. Tel: +46 90 785 00 00.

Courses, exchanges of experience, recreation

The Swedish PKU Association organizes family meetings and publishes an information sheet on phenylketonuria. See address under “Organizations for the disabled/patient associations etc.”

Ågrenska’s families programme arranges stays for children and young people with disabilities and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. A number of programmes every year is also provided for adults with rare diseases. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations etc.

The Swedish PKU Association. Contact Eva Falk-Carlsson, Kalmarsundsparken 29, SE-392 47 Kalmar, Sweden. Tel: +46 480 226 20, email: eva.falkcarlsson@pku.se, and Maria Nordh, Villa Myspys, SE-705 97 Glanshammar, Sweden. Tel: +46 19 46 51 11, email: maria.nordh@pku.se, www.pku.se.

Rare Diseases Sweden, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, fax: +46 8 546 404 94, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se. Rare Diseases Sweden is a national association representing people with rare diseases and varying disabilities.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Industrivägen 7 (visitors address), Box 1181, SE-171 23 Solna, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

Courses, exchanges of experience for personnel

The Swedish Paediatric Society’s working group for metabolic diseases acts as an information forum, www.blf.net.

The European PKU Association, ESPKU, has annual meetings at specialist medical conferences, www.espku.org.

Research and development

Research on phenylketonuria is carried out at the Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, and The Queen Silvia Children’s Hospital in Gothenburg, Sweden.

Adult clinical trials are under way into a plant enzyme (PEG-PAL) which can break down phenylalanine. The substance is administered as a weekly injection and can be used to treat all types of phenylketonuria. Various methods have been tried to transfer cells with normal cell metabolisms to people with the disease. To date (2013) the only option has been a liver transplantation, which has been carried out in a few cases, with positive results. However, the risks associated with liver transplants are so great that it is really not a viable alternative. Instead, trials are now under way to transfer liver cells, via injections, to people with various types of congenital metabolic disorders. This is a much simpler, less risky method and may be a suitable form of treatment for phenylketonuria.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under, “Mer hos oss” in the column on the right-hand side.

Newsletters from Ågrenska on phenylketonuria, no. 359 (2009) and no. 270, (2006) on an adult view of the disease. (In Swedish only.) Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They may be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. They are also available at www.agrenska.se.

Ågrenska also produces special material on living with the disease as an adult.

Information on phenylketonuria is available in Swedish on the website www.pekou.se.

A newsletter can be requested from The Swedish PKU Association, which also lends out video films on phenylketonuria. (See address under “Organizations for the disabled/patient associations etc.”)

The PKU Laboratory, Karolinska University Hospital, SE-141 86 Stockholm, Sweden, produces an annual report.

The Swedish Department of Health and Welfare provides general advice on testing neonates for certain metabolic disorders in SOSFS 1988:20 (in Swedish only).

Books on diets for those with phenylketonuria can be ordered from the PKU Association. (See under “Organizations for the disabled/patient associations etc.”)

Ulla Johansson and Irene Mattisson, Mat med mindre protein, 1992. (In Swedish only.)

Gerda Lundberg, Varför kan jag inte äta samma mat som du, pappa. En bok för barn med PKU, 2004.(In Swedish only.) Published by the PKU Association.

Elisabeth Sjöqvist and Carina Heidenborg, Mycket gott med lite protein. Cookery book, 2009. (In Swedish only.)


A film on PKU, 2010. (In English, Turkish and Arabic.) For information contact the PKU Association, www.pku.se.


Albrecht J, Garbade SF, Burgard P. Neuropsychological speed tests and blood phenylalanine levels in patients with phenylketonuria: a meta-analysis. Neurosci Biobehav Rev 2009; 33: 414-421.

Harding C. Progress toward cell-directed therapy for phenylketonuria. Clin Genet 2008; 74: 97-104.

Kim W, Erlandsen H, Surendran S, Stevens RC, Gamez A, Michols-Matalon K et al. Trends in enzyme therapy for phenylketonuria. Mol Ther. 2004; 10: 220-224.

Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Bélanger-Quintana A, Couce ML et al. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics 2013; 131;e1881-1888.

Koch R, Henley W, Levy H, Matalon R, Rouse B, Trefz F et al. Maternal phenylketonuria: an international study. Mol Genet Metabol. 2000; 71: 233-239.

Levy HL, Ghavami M. Maternal phenylketonuria: a metabolic tetratogen. Tetratology 1996; 53: 176-184.

Poustie VJ, Wildgoose J. Dietary interventions for phenylketonuria. Cochrane Database Syst Rev 2010; 20: CD001304.

Somaraju UR, Merrin M. Sapropterin dihydrochloride for phenylketonuria. Cochrane Database of Syst Rev 2012; 12: CD008005. doi: 10.1002/14651858.CD008005.pub3.

Trefz FK, Scheible D, Frauendienst-Egger G. Long-term follow-up of patients with phenylketonuria receiving tetrahydrobioterin treatment. J Inherit Metab Dis 2010; 33:163-169.

van Spronsen FJ, Enns GM. Future treatment strategies in phenylketonuria Mol Genet Metab 2010; 99: 90-95.

Utz J R, Lorentz C P, Markowitz D, Rudser K D, Diethelm-Okita B, Erickson D et al. START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients. Mol Genet Metab 2012; 105: 193-197.

Waisbren S E, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A, Levy V. Phenylalanine blood levels and clinical outcomes in phenylketonuria: A systematic literature review and meta-analysis. Mol Genet Metab 2007; 92: 63-70.

Zschocke J. Phenylketonuria mutations in Europe. Hum Mutat. 2003; 21: 345-356.

Database references

OMIM (Online Mendelian Inheritance in Man)
Search: phenylketonuria, pku

GeneReviews (University of Washington)
www.genetests.org (select GeneReviews)
Search: phenylalanine hydroxylase deficiency

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Agne Larsson, Karolinska University Hospital, Huddinge, Sweden.

The material has been revised by Associate Professor Jan Alm and specialist physician Ricard Nergårdh, Astrid Lindgren Children’s Hospital, Stockholm.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-04-29
Version: 3.0
Publication of the Swedish version: 2013-12-18

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


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