Фенилкетонурия (ФКУ) — наследование, причины, диагностика

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Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism and is characterized by mild to severe mental disability in untreated patients.




The prevalence of PKU shows considerable geographic variation. It is estimated to be 1/10,000 live births in Europe with a higher rate in some countries (Ireland, Italy). Prevalence is particularly high in Turkey: 1/4,000 live births. PKU is far rarer in the Finnish, African and Japanese populations.

Clinical description

In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty odor. Untreated patients subsequently develop intellectual disability, behavioral disorders (hyperactivity) and motor disorders. Patients often have fair coloring as a result of tyrosine deficiency. The most common form of the condition is known as classical phenylketonuria (see this term) and is characterized by severe symptoms. A mild form has also been described (mild PKU; see this term), and an even milder form known as mild hyperphenylalaninemia (mild HPA or non-PKU HPA; see this term). A subset of patients with milder phenotypes has been found to be responsive to tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylation (BH4-responsive HPA, see this term).


PKU is caused by a wide range of mutations in the PAH gene (12q22-q24.2) coding for phenylalanine hydroxylase. Non-PAH mutations have been reported to cause a disorder known as hyperphenylalaninemia due to BH4 deficiency (see this term). Mutation frequency varies among different ethnic groups. Lower levels or absence of the phenylalanine hydroxylase enzyme underlie the clinical manifestations, as a result of toxic accumulation of phenylalanine in the blood and brain.

Diagnostic methods

The disorder is usually diagnosed through neonatal screening programs.

Differential diagnosis

PKU should be distinguished from BH4 deficiency.

Genetic counseling

Transmission is autosomal recessive. Genetic counseling should be provided to affected families.

Management and treatment

The mainstay of treatment is a low-phenylalanine diet and amino acids mixture for the forms that require treatment. The recommended maintenance level is usually between 120 and 360 micromol/L in newborns, with treatment considered essential in older patients with levels above 600 micromol/L. There is, however, no consensus concerning the level of phenylalanine above which treatment should be initiated and recommendations vary from country to country.


Prognosis is variable.

Expert reviewer(s): Pr Nenad BLAU — Last update: May 2012

Rare Disease Database


NORD gratefully acknowledges Paldeep S. Atwal, MD, FACMG, FRCP(UK), FRCP(Glasg), Clinical & Biochemical Geneticist, Director, The Atwal Clinic: Genomic & Personalized Medicine, for assistance in the preparation of this report.

Synonyms of Phenylketonuria

  • classical phenylketonuria
  • hyperphenylalanemia
  • phenylalanine hydroxylase deficiency
  • phenylalaninemia
  • PKU

General Discussion

NORD Video: Phenylketonuria

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Signs & Symptoms

Infants with PKU typically appear normal at birth. With early screening and dietary treatment, affected individuals may never show symptoms of PKU. However, untreated newborns not diagnosed in the first days of life may be weak and feed poorly. Other symptoms may include vomiting, irritability, and/or a red skin rash with small pimples. Developmental delay may be obvious at several months of age. The average IQ of untreated children is usually less than 50. Intellectual disability in PKU is a direct result of elevated levels of phenylalanine in the brain which causes the destruction of the fatty covering (myelin) of individual nerve fibers. It can also cause depression by reducing brain levels of dopamine and serotonin (neurotransmitters).

Untreated infants with PKU tend to have unusually light eye, skin, and hair color due to high phenylalanine levels interfering with production of melanin, a substance that causes pigmentation. They may also have a musty or “mousy” body odor caused by phenyl acetic acid in the urine or sweat.

Neurological symptoms are present in some untreated patients with PKU, including seizures, abnormal muscle movements, tight muscles, increased reflexes, involuntary movements, or tremor.

Untreated females with PKU who become pregnant are at high risk for having a miscarriage or problems with fetal growth (intrauterine growth retardation). Children of women with untreated PKU may have an abnormally small head (microcephaly), congenital heart disease, developmental abnormalities, or facial abnormalities. There is a strong relationship between the severity of these symptoms and high levels of phenylalanine in the mother. As a result, all women with PKU who have stopped treatment should resume treatment before conception and continue on it throughout pregnancy, managed by a metabolic geneticist and dietician.


PKU is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene copy and one abnormal gene copy, they will be a carrier for the condition, but will not have symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk is the same for males and females.

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More than 300 different changes (mutations) in the PKU gene have been identified. Because the different mutations result in varying degrees of PAH enzyme activity, and therefore varying degrees of phenylalanine elevation in blood, the diet of each child must be adjusted to the individual’s specific phenylalanine tolerance.

Affected Populations

The reported incidence of PKU from newborn screening programs ranges from one in 13,500 to 19,000 newborns in the United States. PKU affects people from most ethnic backgrounds, although it is rare in Americans of African descent and Jews of Ashkenazi ancestry.

Standard Therapies


The goal of treatment for PKU is to keep plasma phenylalanine levels within 120-360 umol/L (2-6 mg/dL). This is generally achieved through carefully planned and monitored diet. Limiting the child’s intake of phenylalanine must be done cautiously because it is an essential amino acid. A carefully maintained diet can prevent intellectual disability as well as neurological, behavioral, and dermatological problems. Treatment must be started at a very young age or some degree of intellectual disability may be expected. However, even some late-treated children have done quite well. Studies have repeatedly demonstrated that children with PKU who are treated with a low phenylalanine diet before the age of three months do well, with an IQ in the normal range.

If people with PKU stop controlling their dietary intake of phenylalanine, neurological changes usually occur. IQs may decline. Other problems that may appear and become severe once dietary regulation is stopped include difficulties in school, behavioral problems, mood changes, poor visual-motor coordination, poor memory, poor problem-solving skills, fatigue, tremors, poor concentration, and depression.

After years of controversy, there now is nearly universal acceptance among clinicians that the diet needs to be continued indefinitely, and that adults with PKU who stopped the diet in childhood or beyond should return to the diet. Many young adults have restarted the diet and found improvement in mental clarity as a result of lowered blood phenylalanine levels.

Because phenylalanine occurs in practically all natural proteins, it is impossible to adequately restrict the diet using natural foods alone without compromising health. For this reason, special phenylalanine-free food preparations are helpful. Foods high in protein, such as meat, milk, fish and cheese are typically not allowed on the diet. Naturally low protein foods such as fruits, vegetables, and some cereals are allowed in limited quantities.

In 2007, Kuvan (sapropterin hydrochloride) was approved by the U.S. Food and Drug Administration (FDA) to treat PKU. Kuvan is an oral pharmaceutical formulation of BH4, the natural cofactor for the PAH enzyme, which stimulates activity of the residual PAH enzyme to metabolize phenylalanine into tyrosine. Kuvan is to be used in conjunction with a phenylalanine restricted diet. Kuvan is manufactured by BioMarin Pharmaceutical Inc.

In 2018, Palynziq (pegvaliase-pqpz) was approved by the FDA for adults with PKU. Palynziq is an injectable enzyme therapy for patients who have uncontrolled blood phenylalanine concentrations on current treatment. Palynziq is manufactured by BioMarin Pharmaceutical Inc.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, in the main, contact:

For information about clinical trials conducted in Europe, contact:

NORD Member Organizations

  • Children’s PKU Network
    • 3306 Bumann Rd
    • Encinitas, CA 92024 United States
    • Phone: (858) 775-9978
    • Toll-free: (800) 377-6677
    • Email: [email protected]
    • Website: http://www.pkunetwork.org/
  • National PKU Alliance
    • 2809 E. Hamilton Ave. #311
    • Eau Claire, WI 54701 USA
    • Phone: (715) 437-0477
    • Email: [email protected]
    • Website: http://www.npkua.org
  • National PKU News
    • 6869 Woodlawn Avenue NE #116
    • Seattle, WA 98115-5469
    • Phone: (206) 525-8140
    • Email: [email protected]
    • Website: http://www.pkunews.org

Other Organizations

  • Cook for Love, Inc.
    • 30 Seneca Street
    • Dobbs Ferry, NY 10522
    • Phone: (914) 674-1025
    • Email: [email protected]
    • Website: http://www.cookforlove.org
  • Genetic and Rare Diseases (GARD) Information Center
    • PO Box 8126
    • Gaithersburg, MD 20898-8126
    • Phone: (301) 251-4925
    • Toll-free: (888) 205-2311
    • Website: http://rarediseases.info.nih.gov/GARD/
  • Medical Home Portal
    • Dept. of Pediatrics
    • University of Utah
    • Salt Lake City, UT 84158
    • Phone: (801) 587-9978
    • Email: [email protected]
    • Website: http://www.medicalhomeportal.org
  • NIH/National Institute of Child Health and Human Development
    • 31 Center Dr
    • Building 31, Room 2A32
    • Bethesda, MD 20892
    • Toll-free: (800) 370-2943
    • Email: [email protected]
    • Website: http://www.nichd.nih.gov/


Cabello JF, Levy HL. Phenylketonuria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:488.

Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:1105-8.Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2198-9.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2390, 2396-7.

Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 8th Ed. New York, NY; McGraw-Hill Companies, Inc; 2001:Chapter on Phenyketonuria.

Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:952-3.

Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:87-9.


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De la Cruz F, Koch R. Genetic Implications for newborn screening for phenylketonuria. Clin Perinatol. 2001;28:419-24.

van Spronsen FJ, Smit PG, Koch R. Phenylketonuria: tyrosine beyond the phenylalanine diet. J Inherit Metab Dis. 2001;24:1-4.

Griffith P. Neuropsychological approaches to treatment policy issues in phenylketonuria. Eur J Pediatr. 2000;159:Suppl 2:S82-86, comment Eur J Pediatr. 2000;159:Suppl 2:S87-88.

Van Spronsen FJ, van Rijn M, Bekhof J, et al. Phenylketonuria: tyrosine supplementation in phenylalanine restricted diets. Am J Clin Nutr. 2001;73:153-57.


Muntau AC, Röschinger W, Habich M, et al. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002;347:2122-32.

Seashore MR. Tetrahydrobiopterin and dietary restriction in mild phenylketonuria. N Engl J Med. 2002;347:2094-95.

American Academy of Pediatrics, Committee on Genetics. American Academy of Pediatrics:Maternal phenylketonuria. Pediatrics. 2001;107:427-28.

National Institute of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics. 2001;108:972-82.

Rohr FJ, Munier AW, Levy HL. Acceptability of a new modular protein substitute for the dietary treatment of phenylketonuria. J Inherit Metab Dis. 2001;24:623-30.

Erlandsen H, Stevens RC. A structural hypothesis for BH4 responsiveness in patients with mild forms of hyperphenylalaninemia and phenyketonuria. J Inhab Metab Dis. 2001;24:213-30.

Kalsner LR, Rohr FJ, Strauss KA, et al. Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids. J Pediatr;2001;139:421-27.


McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number; 261600. Last Edit Date: 11/01/2017. https://www.omim.org/entry/261600?search=261600&highlight=261600 Accessed May 29, 2019.

Years Published

The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.

The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.

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Conditions Classic Phenylketonuria

Phenylketonuria (PKU) is a condition in which the body cannot break down one of the amino acids found in proteins. PKU is considered an amino acid condition because people with PKU cannot break down the amino acid called phenylalanine. If left untreated, PKU can cause brain damage or even death. However, if the condition is detected early and treatment is begun, individuals with PKU can lead healthy lives.

Phenylketonuria is a condition with multiple forms, each of which have different treatments and outcomes. Classic phenylketonuria is only one form of the condition. You can read about a different form of the condition, hyperphenylalanemia, here.

Condition Type

Amino Acid Disorders


In the United States, one in every 10,000 to 15,000 babies is affected by phenylketonuria (PKU). The occurrence of PKU varies among ethnic groups and regions. PKU is more common in individuals with Irish, northern European, Turkish, or Native American ancestry. It is less common in people of African, Japanese, or Ashkenazi Jewish backgrounds.

Also known as

  • PKU
  • Hyperphenylalaninemia – classic type
  • Phenylalanine hydroxylase deficiency
  • PAH deficiency
  • Phenylketonuria

Follow-Up Testing

Your baby’s doctor may ask you if your baby is showing any of the signs of PKU (see Early Signs below). If your baby has certain signs, your baby’s doctor may suggest starting immediate treatment.

If your baby’s newborn screening result for phenylketonuria (PKU) was out of the normal range, your baby’s doctor or the state screening program will contact you to arrange for your baby to have additional testing. It is important to remember that an out-of-range screening result does not necessarily mean that your child has the condition. An out-of-range result may occur because the initial blood sample was too small or the test was performed too early. However, as a few babies do have the condition, it is very important that you go to your follow-up appointment for a confirmatory test. Because the harmful effects of untreated PKU can occur soon after birth, follow-up testing must be completed as soon as possible to determine whether or not your baby has the condition.

Follow-up testing will involve checking your baby’s urine and blood samples for harmful levels of acids and toxins. Certain acids and toxins build up in the body when a child has an amino acid condition, so measuring the levels of these substances in your baby’s body can help doctors determine if your baby has a condition. High amounts phenylalanine in the blood might indicate that your baby has PKU.

About Classic Phenylketonuria

  • Early Signs
  • Treatment
  • Expected Outcomes
  • Causes
Early Signs

Different forms of phenylketonuria vary in their severity of signs. Classic phenylketonuria (PKU) is the most severe form. Babies with PKU usually seem healthy at birth. Signs of PKU begin to appear around six months of age.

Signs of classic PKU include:

  • Irritability
  • Seizures (epilepsy)
  • Dry, scaly skin (known as eczema)
  • “Musty” or «mouse-like” body odor
  • Pale hair and skin
  • Developmental delays

Many of these signs may occur when your baby eats foods that their body cannot break down. They can be triggered by long periods of time without eating, illnesses, and infections.

If your baby shows any of these signs, be sure to contact your baby’s doctor immediately.

If you are looking for the signs of hyperphenylalaninemia, another form of PKU, you’ll find them on the hyperphenylalaninemia page.


Dietary Treatment

Your baby will need to be on a restricted diet to avoid phenylalanine, a building block of proteins that individuals with phenylketonuria (PKU) cannot break down. Phenylalanine is found in all foods that contain protein and also in artificial sweeteners. The dietary treatment for PKU includes specific medical foods: a phenylalanine-free medical formula that is given regularly throughout the day, as well as foods modified to be low in protein. A registered dietician will help you plan a low-protein diet, that avoids high levels of phenylalanine, and gives your baby the nutrients he or she needs for healthy growth.

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Supplements and Medication

Your baby’s doctor may prescribe a low protein formula. As your baby gets older, their doctor may prescribe a medication that contains BH4. BH4 is a substance naturally produced by the body, but your baby’s body might not make enough of it. Taking BH4 supplements may help break down the phenylalanine that builds up. Your baby’s doctor will need to write a prescription for these supplements. BH4 does not work in everyone with PKU. A trial period on the drug with evaluation by a physician is necessary.

Expected Outcomes

If phenylketonuria (PKU) is detected at birth, early treatment can prevent the signs of the condition mentioned in the Early Signs section. This is why it is so important to screen for PKU at birth.

If babies start treatment several weeks after birth, some signs of PKU can be avoided.

If treatment is started after six months of age, babies are at risk for severe intellectual disabilities.

It is important to treat PKU, even if treatment is started after noticing signs and symptoms, in order to help prevent permanent brain damage.


When we eat food, enzymes help break it down. Some enzymes break down protein into its building blocks, called amino acids. Other enzymes break down these amino acids. In classic phenylketonuria (PKU), the enzyme phenylalanine hydroxylase (PAH) is not working correctly.

PAH’s job is to break down the amino acid phenylalanine. Babies with PKU either do not make enough or make non-working PAH. When PAH does not work correctly, the body cannot break down phenylalanine and it builds up in the blood. Everyone has some phenylalanine in their blood, but high levels can be toxic.

PKU is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for PKU, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with PKU is rare, when both parents are carriers, they can have more than one child with the condition. Learn more about autosomal recessive inheritance.

Support for Classic Phenylketonuria

  • Support Services
  • Accessing Care
  • Families’ Experiences
Support Services

Support groups can help connect families who have a child or other family members affected with phenylketonuria (PKU) with a supportive community of people who have experience and expertise in living with the condition. These organizations offer resources for families, affected individuals, health care providers, and advocates:

  • National PKU Alliance
  • Intermountain PKU and Allied Disorders Association (Facebook page)
  • Children’s PKU Network

The New England Genetics Collaborative created a website called «GEMSS: Genetics Education Materials for School Success.» When your child reaches school age, you can provide teachers and school administration with this resource specifically for children with PKU.

Accessing Care

Work with your baby’s doctor to determine the next steps for your baby’s care. Your baby’s physician may help you coordinate care with a doctor who specializes in metabolism, a dietician who can help plan your child’s specialized diet, and other medical resources in your community. Some children with phenylketonuria (PKU) have developmental delays. If you think that your baby is not meeting their developmental milestones, ask your baby’s doctor about the next steps in accessing a developmental evaluation and care.

Because PKU is a genetic condition, you may want to talk with a genetics specialist. A genetic counselor or geneticist can help you understand the causes of the condition, discuss genetic testing for PKU, and understand what this diagnosis means for other family members and future pregnancies. Speak with your baby’s doctor about getting a referral. The Clinic Services Search Engine offered by the American College of Medical Genetics and Genomics (ACMG) and the Find a Genetic Counselor tool on the National Society of Genetic Counselors (NSGC) website are two good resources for you or your baby’s health care provider to use to identify local specialists.

Families’ Experiences

Kristin Vanags writes about her son Joseph who was diagnosed with phenylketonuria (PKU) through newborn screening. Currently at age three, Joseph is healthy and happy. His mom is growing more and more confident that her family will be able to manage the condition. Read Joseph’s story on the Georgia PKU Connect website.

Anna Parker was diagnosed with PKU through newborn screening. Now a healthy elementary school teacher, Anna considers herself blessed to have a treatable condition. Watch a video about her story here.

References & Sources

Visit the Screening, Technology And Research in Genetics (STAR-G) Project for more information on classic phenylketonuria

Visit Genetics Home Reference from the National Library of Medicine for more condition information

ACT Sheets

Healthcare professionals can learn more about confirmatory testing by reading the American College of Medical Genetics and Genomics’ Algorithm for Diagnosis and ACT Sheet, a guide for follow-up after newborn screening. You can visit this page of the ACMG website here.

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