$Unique_ID{BRK04103} $Pretitle{} $Title{Phenylketonuria} $Subject{Phenylketonuria PKU Phenylalaninemia Phenylpyruvic Oligophrenia Foelling Syndrome Classical Phenylketonuria Hyperphenylalanemia PKU1 Phenylalanine Hydroxylase Deficiency Tetrahydrobiopterin Deficiency} $Volume{} $Log{} Copyright (C) 1986, 1989, 1990, 1993 National Organization for Rare Disorders, Inc. 65: Phenylketonuria ** IMPORTANT ** It is possible that the main title of the article (Phenylketonuria) is not the name you expected. Please check the SYNONYMS listing to find the alternate name and disorder subdivisions covered by this article. Synonyms PKU Phenylalaninemia Phenylpyruvic Oligophrenia Foelling Syndrome Classical Phenylketonuria Hyperphenylalanemia PKU1 Phenylalanine Hydroxylase Deficiency Information on the following diseases can be found in the Related Disorders section of this report: Tetrahydrobiopterin Deficiency General Discussion ** REMINDER ** The Information contained in the Rare Disease Database is provided for educational purposes only. It should not be used for diagnostic or treatment purposes. If you wish to obtain more information about this disorder, please contact your personal physician and/or the agencies listed in the "Resources" section of this report. Phenylketonuria (PKU) is a rare metabolic disorder of infancy caused by a deficiency of the liver enzyme phenylalanine hydroxylase. Impairment in the metabolism of the amino acid phenylalanine results in excess accumulation of phenylalanine in the fluids of the body. Phenylketonuria is a severe progressive disorder that can produce mental retardation if it is not treated early. With a carefully controlled diet, people with Phenylketonuria can avoid irreversible mental retardation. Symptoms Infants with Phenylketonuria typically appear normal at birth. Phenylpyruvic acid, a by-product of phenylalanine metabolism, may not be found in the urine during the first days of life. Some newborns (neonates) with this disorder may be weak and feed poorly. Other symptoms of Phenylketonuria in infants may include vomiting, irritability, and/or a red skin rash with small pimples (eczematoid). Infants with this disorder generally have a musty or "mousy" body odor caused by phenylacetic acid in the urine and/or perspiration. If children with Phenylketonuria are not treated, developmental retardation may be obvious at several months of age and patients are often short for their age. High levels of phenylalanine interfere with a chemical in the body that is responsible for maintaining pigmentation (melanin). Therefore, affected children usually have a fair complexion and light hair. Craniofacial abnormalities in untreated children with Phenylketonuria may include an abnormally small head (microcephaly), a prominent jaw (maxillae), widely spaced teeth, and/or impaired development of the enamel of the teeth. The skin may also become coarse. Occasionally other symptoms may include the loss of calcium from bones (decalcification), the webbing of fingers and/or toes (syndactyly), and/or flat feet. It is not understood why high levels of phenylalanine cause severe mental retardation in children with Phenylketonuria. The average IQ of untreated children is usually less than 50. Children whose mother has Phenylketonuria and carries a single defective gene for this disorder (heterozygotic), often have severe mental retardation. Neurological symptoms are present in only some patients with Phenylketonuria and may vary greatly. Seizures occur in about 25 percent of older children and abnormalities appear on brain wave tests (EEG) in 80 percent of patients. Jerky muscle movements (spasticity), abnormally tight muscles (hypertonicity), and/or increased deep tendon reflexes are among the most frequent neurological symptoms. About 5 percent of children with symptoms of Phenylketonuria become physically disabled. Slow writhing movements, involuntary muscle movements, and tremors occur in some cases. The process of surrounding nerve fibers with a fatty covering (myelinization) may be delayed but not absent in some children with Phenylketonuria. In male adults with Phenylketonuria, sperm counts may be low. Females with this disorder often have spontaneous abortions or fetal growth delays (intrauterine growth retardation). Children of women with Phenylketonuria may have an abnormally small head (microcephaly) and/or congenital heart disease. There may be some relationship between the severity of these symptoms and high levels of phenylalanine in the mother. Laboratory tests in children with Phenylketonuria typically confirm plasma levels of phenylalanine that are 10 to 60 times above normal levels. Plasma Tyrosine levels are abnormally low in the blood plasma while urinary levels of phenylalanine metabolites (i.e., phenylpyruvic acid and other phenolic acids) are abnormally high. Substances such as dopamine, serotonin, and melanin are reduced when measured by laboratory tests. There are several different varieties of Phenylketonuria or Hyperphenylalaninemias characterized by elevated plasma phenylalanine levels (not as high as those in Phenylketonuria). For example, in Tetrahydrobiopterin deficiency, neurological deterioration occurs even when phenylalanine levels are controlled (see Related Disorder Section below). Prenatal diagnosis of Phenylketonuria is available, and routine neonatal screening is required by law in the United States and in most hospitals in developed countries. The test requires a drop of blood taken from the baby's heel. Causes Phenylketonuria is inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If one receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children will be carriers, but healthy as described above. Twenty-five percent of their children will receive both normal genes, one from each parent, and will be genetically normal. The defective gene that causes Phenylketonuria is located on the long arm of chromosome 12. The symptoms of Phenylketonuria develop because of a defective liver enzyme, phenylalanine hydroxylase. This enzyme enables phenylalanine to be metabolized into tyrosine. The other forms of Hyperphenylalaninemia, which have symptoms that are different from those of Phenylketonuria, are the result of various deficiencies of other enzymes that are closely related to phenylalanine hydroxylase. The exact mechanism of mental retardation in Phenylketonuria is not known. Normal brain development may be disturbed by a high level of phenylalanine. It has been suggested that there may be an impairment in the process of laying down the fatty covering on nerve fibers in the brain (myelinization). It is also thought that disturbances in the formation of grouping of nerves (neuronal migration) in the first 6 months of life may contribute to the mental retardation associated with Phenylketonuria. Abnormally high levels of phenylalanine may also be caused by a deficiency of tetrahydrobiopterin because of insufficient amounts of either biopterin or dihydropterin reductase. Tetrahydrobiopterin is involved in the production of neurotransmitters (chemicals in the brain) such as serotonin, dopamine, and norepinephrine. Low levels of these neurotransmitters could account for the progressive neurological deterioration of children with Tetrahydrobiopterin in spite of controlled plasma phenylalanine. (For more information on Tetrahydrobiopterin Deficiency, see Related Disorders section of this report.) Affected Population Phenylketonuria is a rare disorder that affects males and females in equal numbers. It is estimated that Phenylketonuria occurs in 1 in 11,600 newborns in the United States. Phenylketonuria affects people from most ethnic backgrounds, although it is rare in Americans of African descent and Jews of Ashkenazi ancestry. Related Disorders Symptoms of the following disorders can be similar to those of Phenylketonuria. Comparisons may be useful for a differential diagnosis: Tetrahydrobiopterin Deficiency is a rare inherited neurological disorder of infancy that causes abnormally high levels of phenylalanine due to a deficiency of tetrahydrobiopterin. The symptoms of this disorder usually include neurological abnormalities, lack of muscle tone, loss of coordination, seizures, and/or delayed motor development. (For more information on this disorder, choose "Tetrahydrobiopterin" as your search term in the Rare Disease Database.) There are many other disorders of infancy with symptoms that are similar to those of Phenylketonuria. However, the screening test that is done for this disorder in almost every hospital allows physicians to diagnose this disorder and distinguish it from other neuromuscular or metabolic disorders. Therapies: Standard A test for Phenylketonuria prior to birth is available, and routine screening of newborns is performed in virtually all hospitals in developed countries. It is also possible to detect if a child is carrying a single defective gene that causes Phenylketonuria (heterozygotes). The goal of treatment for Phenylketonuria is to keep plasma phenylalanine levels within the normal range. This is generally achieved through carefully planned 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 mental retardation as well as neurological, behavioral, dermatological, and/or brain (EEG) abnormalities. Treatment must be started at a very young age (under 3 months), or some degree of mental retardation may be expected. Many studies have demonstrated that children with Phenylketonuria who are treated with a low phenylalanine diet before the age of 3 months do well, with an average IQ of 100. If treatment is begun after the age of 2 or 3 years, only hyperactivity and seizures may be controlled. The child's behavior and plasma levels of phenylalanine must be monitored regularly. If people with Phenylketonuria stop controlling their dietary intake of phenylalanine, neurological changes usually occur during adolescence and adulthood. IQs may decline after a peak at the end of the controlled diet periods. Other problems that may appear and become severe once dietary regulation is stopped include difficulties in school, behavioral problems, poor visual-motor coordination, poor problem-solving skills, low developmental age, and/or abnormalities during brain wave testing (EEG). There is some controversy over the age at which dietary treatment can be discontinued in people with Phenylketonuria, but it is becoming clear that high levels of phenylalanine continue to harm the brain even after fatty coverings have developed around nerve fibers in the brain (myelinization). Phenylalanine intake should probably be limited indefinitely, with possibly some relaxation of dietary control. Because phenylalanine occurs in practically all natural proteins, it is impossible to meet the child's nutritional requirements by diet alone without exceeding the phenylalanine allowance. For this reason, special phenylalanine free food preparations are extremely important. These preparations include Lofenolac (for a low phenylalanine diet), and Phenyl- free (for phenylalanine free food). Both are available from Mead Johnson. Low protein foods such as fruits, vegetables, and some cereals are allowed. If the intake of phenylalanine is too severely limited in people with Phenylketonuria, the symptoms of phenylalanine deficiency may develop. These may include fatigue, aggressive behavior, severe loss of appetite (anorexia), and sometimes anemia. Both the child's behavior and plasma levels of phenylalanine must be monitored regularly. Severe forms of hyperphenylalaninemia are treated in the same way as classical Phenylketonuria. Milder forms appear to require no treatment. In tetrahydrobiopterin deficiency, a phenylalanine free diet alone does not prevent neurological deterioration. Supplementation with levodopa, carbidopa, and 5-hydroxytrytophan, in addition to dietary control, may be beneficial in these cases. Genetic counseling will be of benefit for patients with Phenylketonuria and their families. Therapies: Investigational Scientists are involved in the research and development of improved medical foods for adults with Phenylketonuria. Trials were begun in 1985 on the use of enzyme reactors for management of Phenylketonuria. In this procedure, which closely resembles dialysis, an enzyme that breaks down phenylalanine (phenylalanine hydroxylase) is produced from plant cells or small microbes. This enzyme is then chemically attached to other chemicals (fixed matrix) and placed in contact (indirectly) with the patient's blood. The enzyme, capable of rapidly metabolizing phenylalanine, lowers the levels of this enzyme in the blood. This treatment is expected to be useful primarily for pregnant women with Phenylketonuria and for the treatment of sudden peaks of phenylalanine levels that may occur with infections or other physiologically stressful conditions. For further information concerning this procedure, patients may have their physicians contact: Clara Ambrus, M.D., Ph.D. Children's Hospital 140 Hodge Ave. Buffalo, New York 14222 (716) 878-7704 Tetrahydro-L-biopterin dihydrochloride (designated RS 5678) is available for the experimental treatment of tetrahydrobiopterin deficiency phenylalaninemia. For more information, patients may have their physicians contact: Dr. B. Schirchs Schachenstrasse 4 CH 8907 Wettswil a. A. Switzerland Tel. 01 700 1645. This disease entry is based upon medical information available through April 1993. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder. Resources For more information on Phenylketonuria, please contact: National Organization for Rare Disorders (NORD) P.O. Box 8923 New Fairfield, CT 06812-1783 (203) 746-6518 Phenylketonuria Parents Group 518 Paco Drive Los Altos, CA 94022 (415) 941-9799 National Phenylketonuria Foundation P.O. Box 5129 Pasadena, TX 77508 (713) 487-4802 Phenylketonuria Collaborative Study Children's Hospital of Los Angeles P.O. Box 54700 Los Angeles, CA 90054 NIH/National Institute of Child Health and Human Development (NICHD) 9000 Rockville Pike Bethesda, MD 20205 (301) 496-5133 National Association for Retarded Citizens of the U.S. P.O. Box 6109 Arlington, TX 76005 (817) 261-4961 (800) 433-5255 National Institute on Mental Retardation York University Kinsmen NIMR Building 4700 Keele Street, Downview Toronto, Ont. M3J 1P3 Canada (416) 661-9611 For Genetic Information and Genetic Counseling Referrals: March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue White Plains, NY 10605 (914) 428-7100 Alliance of Genetic Support Groups 35 Wisconsin Circle, Suite 440 Chevy Chase, MD 20815 800-336-GENE 301-652-5553 References MENDELIAN INHERITANCE IN MAN, 10th Ed.: Victor A. McKusick, Editor: Johns Hopkins University Press, 1992. Pp. 1629-1638. THE METABOLIC BASIS OF INHERITED DISEASE, 6th Ed.: Charles R. Scriver, et al., Editors; McGraw Hill, 1989. Pp. 318-329. CECIL TEXTBOOK OF MEDICINE, 19th Ed.: James B. Wyngaarden and Lloyd H. Smith, Jr., Editors; W.B. Saunders Co., 1990. Pp. 1101-2. THE MERCK MANUAL, 16th Ed.: Robert Berkow Ed.; Merck Research Laboratories, 1992. Pp. 2235-2236. BIRTH DEFECTS ENCYCLOPEDIA, Mary Louise Buyse, M.D., Editor-In-Chief; Blackwell Scientific Publications, 1990. Pp. 1382-1383. NELSON TEXTBOOK OF PEDIATRICS, 14th Ed.; Richard E. Behrman et al; W.B. Saunders Co., 1992. Pp. 307-309. BIOCHEMICAL AND NEUROPHSYCHOLOGICAL EFFECTS OF ELEVATED PLASMA PHENYLALANINE IN PATIENTS WITH TREATED PKU. Krause W., et al. J Clin Inv Jan 1985; 75(1):40-48. PRELIMINARY SUPPORT FOR THE ORAL ADMINISTRATION OF VALINE, ISOLEUCINE AND LEUCINE FOR PHENYLKETONURIA. Jordan M.K., et al. Devel Med Child Neurology 1985; 27:33-39. LOSS OF INTELLECTUAL FUNCTION IN CHILDREN WITH PHENYLKETONURIA AFTER RELAXATION OF DIETARY PHENYLALANINE RESTRICTION. Seashore M., et al. Pediatrics Feb 1985; 75(2):226-232. ABNORMALITIES IN AMINO ACID METABOLISM IN CLINICAL MEDICINE. Nyhan, W.L., Norwalk, Connecticut: Appleton-Century-Crofts, 1984. TETRAHYDROBIOPTERIN DEFICIENCIES: PRELIMINARY ANALYSIS FROM AN INTERNATIONAL SURVEY. Dhondt J.L., J Pediatr (April 1984; 104(4)). Pp. 501-8. PHENYLKETONURIA AND ITS VARIANTS: S. Kaufman; Adv Hum Genet (1983;13). Pp. 217-97. DIET TERMINATION IN CHILDREN WITH PHENYLKETONURIA. A REVIEW OF PSYCHOLOGICAL ASSESSMENTS USED TO DETERMINE OUTCOME. Waisbren S.E., et al. J Inherited Metab Dis (1980; 3(4)). Pp. 149-53.