This document discusses phenylketonuria (PKU), a genetic disorder caused by a deficiency in the enzyme phenylalanine hydroxylase. This enzyme is needed to break down the amino acid phenylalanine. Without it, phenylalanine builds up to high levels in the blood and brain, which can cause intellectual disability if not treated early. The document outlines the causes, symptoms, diagnosis through newborn screening, and lifelong treatment through a phenylalanine-restricted diet for PKU patients. It also discusses milder forms that do not require dietary treatment and the rare cases caused by a deficiency in the cofactor tetrahydrobiopterin.

1. DEFECTS IN METABOLISM
OF AMINO ACIDS :
PHENYLKETONURIA (PKU)
Dr.Padmesh.V

2.  Phenylalanine is an essential amino acid.
 Dietary phenylalanine not utilized for protein
synthesis is normally degraded by way of theTyrosine
pathway.
 Deficiency of the enzyme phenylalanine hydroxylase
(PAH) or of its cofactor tetrahydrobiopterin (BH4)
Accumulation of phenylalanine in body fluids & brain.

3.  The severity of hyperphenylalaninemia depends on the
degree of enzyme deficiency .
 May vary from very high plasma concentrations
( >20 mg/dL, classic phenylketonuria [PKU] ) to
mildly elevated levels, hyperphenylalaninemia
(2-6 mg/dL).

4. In affected infants with plasma concentrations >20 mg/dL
Excess phenylalanine is metabolized to Phenylketones
(Phenylpyruvate and Phenylacetate)
Excreted in the urine
(giving rise to the term phenylketonuria (PKU))

5.  The brain is the main organ affected by
hyperphenylalaninemia.
 The CNS damage in affected patients is caused by the
elevated concentration of phenylalanine in brain
tissue.
 The high blood levels of phenylalanine in PKU saturate
the transport system across the blood-brain barrier
causing inhibition of the cerebral uptake of other large
neutral amino acids such as tyrosine and tryptophan.

6.  All defects causing hyperphenylalaninemia are
inherited as autosomal recessive traits.
 Prenatal diagnosis is possible using specific
genetic probes in cells obtained from chorionic
villi biopsy.

7. Classic Phenylketonuria
(Plasma phenylalanine levels >20 mg/dL)

8.  Clinical Manifestations
 The affected infant is normal at birth.
 Profound mental retardation develops gradually if
the infant remains untreated.
 Cognitive delay may not be evident for the 1st few
months.
 In untreated patients, 50-70% will have an IQ
below 35, and 88-90% below 65.
Only 2-5% of untreated patients will have normal
intelligence.

9.  Clinical Manifestations
 Vomiting, sometimes severe enough to be
misdiagnosed as pyloric stenosis, may be an early
symptom.
 Older untreated children become hyperactive
with autistic behaviors, including purposeless
hand movements, rhythmic rocking, and
athetosis.

10.  Clinical Manifestations
 The infants are lighter in their complexion than
unaffected siblings.
 Some may have a seborrheic or eczematoid rash,
(mild and disappears as the child grows older).
 These children have an unpleasant MUSTY or
MOUSEY odour of phenylacetic acid.

11.  Clinical Manifestations
 Neurologic signs : Seizures (≈25%), spasticity,
hyperreflexia, and tremors.
 More than 50% have EEG abnormalities.
 Microcephaly, prominent maxillae with widely
spaced teeth, enamel hypoplasia, and growth
retardation.

12. Milder Forms of
Hyperphenylalaninemia /
Non-PKU Hyperphenylalaninemias
(Plasma phenylalanine levels >2 mg/dL,
but <20 mg/dL)

13.  These infants do not excrete phenylketones.
 But may still require dietary interventions.
 Possibility of deficiency of BH4 should be
investigated in all infants with the milder forms of
hyperphenylalaninemia.

14.  Diagnosis :
 Usually diagnosed through Newborn screening.
 If screening is positive  diagnosis should be
confirmed by quantitative measurement of plasma
phenylalanine concentration.
 Identification and measurement of phenylketones in
the urine has no place in any screening program.
 In countries where such programs are not in effect,
identification of phenylketones in the urine by ferric
chloride may offer a simple test for diagnosis of
infants with developmental and neurologic
abnormalities.

15.  Diagnosis :
 Once hyperphenylalaninemia is diagnosed,
additional studies for biopterin metabolism should
be performed to rule out biopterin deficiency as
the cause of hyperphenylalaninemia.

16.  Neonatal Screening for Hyperphenylalaninemia :
 The method of choice isTandem mass
spectrometry (MS/MS), which identifies all forms
of hyperphenyalaninemia with a low false-positive
rate, and excellent accuracy and precision.
 The addition of the phenylalanine/tyrosine molar
ratio has further reduced the number of false-
positive results.
 Diagnosis must be confirmed by measurement of
plasma phenylalanine concentration.

17.  Blood phenylalanine in affected infants with PKU
may rise to diagnostic levels as early as 4 hr after
birth even in the absence of protein feeding.
 It is recommended that the blood for screening be
obtained in the FIRST 24-48 hr of life after feeding
protein to reduce the possibility of false-negative
results, especially in the milder forms of the
condition.

18.  Treatment
 Goal of therapy:To reduce phenylalanine levels in plasma
& brain.
 Infants with persistent (more than a few days) plasma
levels of phenylalanine >6 mg/dL should be treated with a
phenylalanine-restricted diet similar to that for classic
PKU.
 Formulas low in or free of phenylalanine.
 The diet should be started as soon as diagnosis is
established.

19.  Treatment
 Because phenylalanine is not synthesized endogenously,
small amounts of phenylalanine should be added to the
diet to prevent phenylalanine deficiency.
 Dietary deficiency of phenylalanine is manifested by
lethargy, failure to thrive, anorexia, anemia, rashes,
diarrhea, and even death.
 Tyrosine becomes an essential amino acid in this disorder
and its adequate intake must be ensured.

20.  Treatment
 Plasma phenylalanine levels to be maintained:
 In neonates through 12 yr of age: Between 2 - 6 mg/dL
 In older individuals: Between 2 - 10 mg/dL
 Discontinuation of therapy, even in adulthood, may cause
deterioration of IQ and cognitive performance 
Therefore phenylalanine-restricted diet should be
continued for life.

21.  Treatment
 Oral administration of Tetrahydrobiopterin (BH4) may
result in reduction of plasma levels of phenylalanine in
some patients with PAH deficiency.
 Sapropterin, a synthetic form of BH4 is approved by
the Food and Drug Administration (FDA) to reduce
phenylalanine levels in PKU.
At a dose of 10 mg/kg/day, it reduces phenylalanine
levels in up to 50% of patients.

22. Hyperphenylalaninemia
due to Deficiency of
the Cofactor BH4

23.  In 1-3% of infants with hyperphenylalaninemia, the defect
resides in 1 of the enzymes necessary for production or recycling
of the cofactor BH4.
 If these infants are misdiagnosed as having PKU, they may
deteriorate neurologically despite adequate control of plasma
phenylalanine.
 In addition to acting as a cofactor for PAH, BH4 is also a cofactor
for tyrosine hydroxylase and tryptophan hydroxylase, which are
involved in the biosynthesis of dopamine and serotonin.
 Therefore, patients with hyperphenylalaninemia due to BH4
deficiency also manifest neurologic findings related to
deficiencies of the neurotransmitters dopamine and serotonin.

24.  Clinical Manifestations
 Clinical manifestations of the neurotransmitter disorders
differ greatly from those of PKU.
 Neurologic symptoms of the neurotransmitter disorders
often manifest in the 1st few months of life.
 Include extrapyramidal signs with choreoathetotic or
dystonic limb movements, axial and truncal hypotonia,
hypokinesia, feeding difficulties, and autonomic problems.
 Mental retardation, seizures, hypersalivation, and
swallowing difficulties are also seen.
 The symptoms are usually progressive and often have a
marked diurnal fluctuation.

25.  Diagnosis
 1. Measurement of neopterin and biopterin in body
fluids, especially urine.
 In addition, examination of cerebrospinal fluid (CSF) reveals
decreased levels of dopamine, serotonin, and their
metabolites in all patients with BH4 deficiency.
 2. BH4 loading test;
 3. Enzyme assay: The activity of dihydropteridine
reductase can be measured in the dry blood spots on
the filter paper used for screening purposes.

26.  Treatment
 The goals of therapy are:
 To correct hyperphenylalaninemia, and
 To restore neurotransmitter deficiencies in the CNS.
 Plasma phenylalanine should be maintained as close to normal
as possible (<6 mg/dL).
 This can be achieved by a combination of a low phenylalanine
diet and oral supplementation of BH4.
 Infants with GTP cyclohydrolase or 6-PTS deficiencies respond
more readily to BH4 therapy (5-10 mg/kg/day) than those with
dihydropteridine reductase deficiency. In the latter patients,
doses as high as 20 mg/kg/day may be required.

27.  Treatment
 Lifelong supplementation with neurotransmitter
precursors such as L-dopa and 5-hydroxytryptophan,
along with carbidopa.
 Supplementation with folinic acid in patients with
dihydropteridine reductase deficiency.
 Some drugs such as trimethoprim-sulfamethoxazole,
methotrexate, and other antileukemic agents are known to
inhibit dihydropteridine reductase enzyme activity and
should be used with great caution in patients with BH4
deficiency.

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