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รltima actualizaciรณn: 7/30/2024
Aรฑos publicados: 1986, 1989, 1990, 1993, 1996, 1997, 1998, 1999, 2000, 2002, 2003, 2004, 2006, 2018, 2019, 2023
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.
Phenylketonuria (PKU) is an inborn error of metabolism that can be diagnosed during the first days of life with routine newborn screening. PKU is characterized by absence or deficiency of an enzyme called phenylalanine hydroxylase (PAH), responsible for processing the amino acid phenylalanine. Amino acids are the chemical building blocks of proteins and are essential for proper growth and development. With normal PAH activity, phenylalanine is converted to another amino acid, tyrosine. However, when PAH is absent or deficient, phenylalanine accumulates and is toxic to the brain. Without treatment, most people with PKU would develop severe intellectual disability. To prevent intellectual disability, treatment consists of a carefully controlled, phenylalanine-restricted diet beginning during the first days or weeks of life.
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 โmousyโ 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 tremors.
Untreated females with PKU who become pregnant are at high risk for having a miscarriage or having a baby that does not grow properly in the womb. Children of females with untreated PKU may have an abnormally small head (microcephaly), congenital heart disease, developmental abnormalities or facial differences. There is a strong relationship between the severity of these symptoms and high levels of phenylalanine in the mother. As a result, all females 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 caused by changes (variants) in the PAH gene. More than 300 different disease-causing variants in the PAH gene have been identified. Because the different variants 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 individualโs specific phenylalanine tolerance.
PKU is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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.
PKU can be diagnosed with routine newborn screening by measuring an elevated level of phenylalanine (concentrations above 1,200 ฮผmol/L (20 mg/dL) on a blood spot. PKU can also be diagnosed with molecular genetic testing that shows two disease-causing variants in the PAH gene.
Treatment
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 a carefully planned and monitored diet. Limiting the childโs 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 skin 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.
When someone with PKU stops controlling their dietary intake of phenylalanine, neurological changes usually occur, and IQ 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 PKU 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, sapropterin hydrochloride (Kuvan) 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 used in conjunction with a phenylalanine restricted diet.
In 2018, pegvaliase-pqpz (Palynziq) 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.
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]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOK
Cabello JF, Levy HL. Phenylketonuria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:488.
REVIEW ARTICLES
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.
JOURNAL ARTICLES
Muntau AC, Rรถschinger 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.
INTERNET
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number; 261600. Last Edit Date: 12/13/2022. https://www.omim.org/entry/261600?search=261600&highlight=261600 Accessed Nov 14, 2023.
Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [Updated 2017 Jan 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1504/ Accessed Nov 14, 2023.
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Aprende mรกs https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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