PHENYLKETONURIA

Teacher-YanliZhang
Department:the third
hospital affiliated to
ZhengZhou university
PHENYLKETONURIA
 Genetic
PHENYLKETONURIA
 Occurs in 1 per 10,000 to 20,000
persons
PHENYLKETONURIA
 Autosomal recessive disease
 Phenylalanine cannot be converted
to tyrosine, blood Phenylalanine
elevate and Phenylpyruvic acid is
excrete in urine
ETIOLOGY
 CLASSIC PHENYLKETONURIA (PKU)
 complete or near-complete deficiency of phenyl-
alanine hydroxylase. Excess phenylalanine is
transaminated to phenylpyruvic acid or
decarboxylated to phenyl-ethylamine. These and
subsequent metabolites, along with excess
phenylalanine, disrupt normal metabolism and
cause brain damage.
 ETIOLIGY

PAH
Phenylalanine(PA) tyrosine dopamine
BH4

thyroxine
Phenylpyruvic acid
phenylephrine

Phenyl-ethylamine
ETIOLOGY
 Hyperphenylalaninemia due to cofactor
tetrahydrobiopterin (BH4) (malignant
Hyperphenylalaninemia)
 the defect resides in one of the enzymes
necessary for production or recycling of the
cofactor BH4. BH4 was then shown to be a
cofactor for phenylalanine, tyrosine, and
tryptophan hydroxylases. The latter two
hydroxylases are essential for biosynthesis
of the neurotransmitters dopamine and
serotonin .
 BH4 is also a cofactor for nitric oxide
synthase, which catalyzes the generation of
nitric oxide from arginine. Today, patients
with BH4 deficiency are diagnosed very early
in life because all patients with hyper­
phenylalaninemia are tested for the
possibility of this cofactor deficiency.
Clinical Manifestations
 CLASSIC PHENYLKETONURIA (PKU)
 normal at birth
 1.  Mental retardation may develop gradually,
hyperactive with purposeless movements,
rhythmic rocking, and athetosis.
 2.  Vomiting, sometimes severe enough to be
misdiagnosed as pyloric stenosis
 3.  infants are blonder than un­
affected siblings. have fair skin and
blue eyes.
 4 unpleasant odor of phenylacetic
acid, which has been described as
musty or mousey.
 5.seizures, microcephaly, growth
retardation
Clinical Manifestations
 Hyperphenylalaninemia due to cofactor
tetrahydrobiopterin (BH4)
 similar and usually indistinguishable from
those of classic PKU
 loss of head control hypertonia, swallowing
difficulties, myoclonic seizures
 Plasma phenylalanine levels may be as high as
those in classic PKU or in the range of benign.
Diagnosis.
 1.The bacterial inhibition assay
method of Guthrie is widely used in
the newborn period to screen for
PKU.
Diagnosis.
 2. Blood phenylalanine
 3. urine for phenylpyruvic acid
 The criteria for diagnosis of classic
PKU are (1) a plasma
phenylalanine level above 20 mg/d
L (1.2 mM);
 (2) a decreased plasma tyrosine
level; (3) increased urinary levels of
metabolites of phenylalanine
(phenylpyruvic and
hydroxyphenylacetic acids)
 (4) a decreased concentration of
the cofactor tetrahydrobiopterin
 Hyperphenylalaninemia due to cofactor
tetrahydrobiopterin (BH4)
 1.           Measurement of neopterin (oxidative
product of dihydro-neopterin triphosphate) and
biopterin (oxidative product of dihydro- and
tetrahydrobiopterin) in body fluids especially urine
 1.            BH4 loading test
 2.            Gene study
Treatment
 CLASSIC PHENYLKETONURIA
 diet low in phenylalanine: The
optimal serum level to be
maintained probably lies between
3 mg/d L (0.18 mM) and 15 mg/dL
(0.9 mM). rigid diet control may be
relaxed after 6 yr of age
 Hyperphenylalaninemia due to cofactor
tetrahydrobiopterin (BH4)
 Low-phenylalanine diet. at least the first 2 yr
of life.
 Neurotransmitter precursors : Administration
of the Ldopa and 5-hydroxytryptophan
 BH4 replacement