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$Unique_ID{BRK04103}
$Pretitle{}
$Title{Phenylketonuria}
$Subject{Phenylketonuria PKU Phenylalaninemia Phenylpyruvic Oligophrenia
Foelling Syndrome Classical Phenylketonuria Hyperphenylalanemia PKU1
Phenylalanine Hydroxylase Deficiency Tetrahydrobiopterin Deficiency}
$Volume{}
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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
     [phone]

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. [phone].

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
     [phone]

     Phenylketonuria Parents Group
     518 Paco Drive
     Los Altos, CA  94022
     [phone]

     National Phenylketonuria Foundation
     P.O. Box 5129
     Pasadena, TX  77508
     [phone]

     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
     [phone]

     National Association for Retarded Citizens of the U.S.
     P.O. Box 6109
     Arlington, TX 76005
     [phone]
     [phone]

     National Institute on Mental Retardation
     York University
     Kinsmen NIMR Building
     4700 Keele Street, Downview
     Toronto, Ont. M3J 1P3
     Canada
     [phone]

For Genetic Information and Genetic Counseling Referrals:

     March of Dimes Birth Defects Foundation
     1275 Mamaroneck Avenue
     White Plains, NY 10605
     [phone]

     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.