Transcript hyperphenylalaninemia from deficiency of the cofactor bh4

Neonatal
hyperphenilalaninemia
Dr. Mahtab Ordooei
Amino acids
Essential
:
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanin
Threonine
Tryptophan
Valine










Nonessential AA:
Alanine 
Argininine 
Asparagine 
Asparticacid 
Citrulline 
Cystine 
Glutamine 
Ornithine 
Proline 
Serine 
Tyrosine 
Thyroid Hormon
Melanin
Phenylalanin hydroxilase
Phenylalanin
Thyrosine
Catecol Amin
+BH4
CO2 + H2O
HYPERPHENYLALANINEMIA FROM
DEFICIENCY OF THE COFACTOR BH4
BH4 is synthesized from guanosine
triphosphate through several enzymatic
reactions Four enzyme deficiencies
leading to defective BH4 formation have
been described. More than half of the
reported patients have had a deficiency
of 6-pyruvoyltetrahydropterin synthase
(PTPS).
Couse of the
hyperphenylalaninemia
Deficiency of the enzyme
phenylalanine hydroxylase or of its
cofactor tetrahydrobiopterin causes
accumulation of phenylalanine in
body fluids and the central nervous
system (CNS).
severity of hyperphenylalaninemia
The severity of hyperphenylalaninemia depends on
the degree of enzyme deficiency and may vary from
very high plasma concentrations (>20 mg/dL
or >1,200 μmole/L ,classic phenylketonuria [PKU )]
to mildly elevated levels (2–6 mg/dL or 120–360
μmole/L). In affected infants with plasma
concentrations >20 mg/dL, excess phenylalanine is
metabolized to phenylketones (phenylpyruvate and
phenylacetate)that are excreted in the urine, giving
rise to the term phenylketonuria (PKU)
TRANSIENT HYPERPHENYLALANINEMIA
OF THE NEWBORN
In a small number of newborns, plasma tyrosine
may rise to as high as 60 mg/dL (3,300 μmole/L)
during the 1st 2 wk of life. Most affected infants are
premature and are receiving high-protein diets. The
condition is presumably due to delayed maturation
of 4-HPPD enzyme Lethargy, poor feeding, and
decreased motor activity are noted in some
patients; most are asymptomatic and come to
medical attention because of a high blood
phenylalanine level, rendering the screening test for
PKU positive .Laboratory findings include marked
elevation of plasma tyrosine with a moderate
increase in plasma phenylalanine.
Manifestations Clinical
 Infants appear normal at birth.
 severe vomiting ) misdiagnosed
as HPS(
 Irritability, an eczematoid rash
and an unusual odor may be
observed in first few months.
 Dermatitis, intractable itching,
scleroderma-like changes even
in viscera
 They are fair haired, fair skinned ,
blue eyed in 90% of cases
 About a third of patients may have spastic
CP.
 Another one-third have mild signs.
 Another third have no neurological signs but
MR
 Hyperactivity is common.
 Seizures in 25% , EEG abnormal in 80%
 Purposeless movements, rythmic rocking ,
tremor and athetosis may be seen.
 The most important manifestation
is MR and in absence of treatment
they lose 50 IQ points in the first
year.
Diagnosis
♦Newborn screening is the best
method for early
detection of PKU.
♦ BH4 load with 20 mg/Kg and plasma PA and
tyrosine at 0,4,8 and 24h, fall in PA shows BH4
is deficient.
♦ Plasma biopterin measurement
♦ Neopterin and biopterin in urine
♦ Measurement of DHPR enzyme
BH4 loading test

Treatment with BH4 and normal
serum phenylalanin
BH4
dificient hyperphenylalaninemia.

Treatment with BH4 and decrease
serum phenylalanin (no normal level)
responsive to BH4
Neonatal hyperphenilalaninemia in Fars
Province, South of Iran
In a period of one year from Nov 2007 to Nov
2008 blood samples were withdrawn from all
newborns born in Fars province for
measurement of serum phenylalanine. The
samples with a serum level of  2 mg/dl
were referred to pediatric endocrine clinic for
confirmation and determination of the type
of hyperphenylalaninemia by quantitive
serum phenylalanine measurements by
using High-Pressure liquid chromatography
(HPLC) method.
Result
Nine cases out of 76996 newborns
had a serum phenylalanine
level >= 2mg/dl, of which 8 cases
were confirmed by HPLC.
Results of BH4 loading test
Patients’ no.
Ph. A. level at
diagnosis
(mg/dl)
Ph. A. level
before
BH4 test
(mg/dl)
Ph. A. level 4
hours
after BH4
test
(mg/dl)
Ph. A. level 8
hours
after BH4
test
(mg/dl)
Ph. A. 24 hours
after BH4
test
(mg/dl)
1
21
17.4
19
20
19.8
2
40
17.6
20.5
17.6
19
3
30
20
20
23
24
4
15
7
7
6
10
5
11.4
17
21
11.4
13
6
15
13
12
11
12
7
15
3.9
1.4
0.9
1.4
8
16
16.3
1.5
0.8
0.5