Metabolic Disorders - Isfahan University of Medical Sciences

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Transcript Metabolic Disorders - Isfahan University of Medical Sciences

.
CASE
 13
HISTORY
month old boy with
developmental delay
 NL at birth
 Irritability& Recurrent
vomiting from 2 week age
CASE
HISTORY
Recurrent seizure with poor response to
antiepileptic drugs from 3 month ago.
 No sitting , no walking
 speech delay
 Relative parents

PHYSICAL
HT=75.2 cm
 WT=10.300 kg
 HC=42cm
Prominent maxilla
 Fair sparse hair
EXAMINATION
PHYSICAL EXAMINATION
Enamel hypoplasia
 Left internal strabismus
 Mild Eczematoid rash
 No organomgaly
 Hypertonic with hyperactive deep tendon
reflexes
 unusual odor of sweet and urine
 Ophtalmologist consult : NL retin , no cataract,
Left internal strabismus were seen

LAB DATA
 CBC
TFT
 VBG
 ELECTROLYTES
 LFT
 TORCH
 Ammonia
 lactate
 U/A
 EEG: AbNL
.

LAB

DATA
Brain MRI:a symmetrical increase of T2weighted signal in the periventricular white
matter
CLASSIC
PHENYLKETONURIA
PHENYLKETONURIA
Autosomal recessive
 Incidence :one of every 15,000 infants





PKU in most cases is caused by deficiency of hepatic
enzyme phenylalanine hydroxylase PAH
PAH catalyzes the conversion of phenylalanine to tyrosine
This pathway accounts for the catabolism of 75 % of
dietary phenylalanine
Tetrahydrobiopterin (BH4) is a cofactor required for PAH
activity
L-AMINOACID
TRANSPORTER
► Phenylalanine’s
entry into the brain is mediated by
the large neutral aminoacid carrier 1(LAT1).
► Two
other large neutral aminoacids—tyrosine, a
precursor of dopamine and norepinephrine, and
tryptophan, a precursor of serotonin—also enter the
brain via the LAT1 carrier.
►
High concentrations of phenylalanine can inhibit
LAT1 from entering the brain, increasing the potential
for neurotransmitter dysfunction.
Phenylketonuria
PHENYLKETONURIA
The defect of PAH

Elevated blood and urine phenylalanine and its
metabolites, phenylacetate and phenyllactate
The defect of recycling or regeneration BH4.
In 2% of infants with hyperphenylalaninemia,
THE

DEFECT OF RECYCLING OR REGENERATION
BH4
Analysis of DBS or urine for neopterin and
biopterin and measurement of
dihydropteridine reductase (DHPR) activity in
the DBS is essential for the exact diagnosis
and should be performed as early as possible
MISTAKE
IN EVALUATION OF
DHPR
► Diseases
that cause activation of the immune
system increase and methotrexate, trimetoprin
sulfamethoxazole decrease DHPR
► Some
patients with DHPR deficiency show a
normal neopterin and biopterin
► So DHPR activity is essential in all patients
with HPA, regardless of pterin
measurements.
C LINICAL F EATURES
Because of neonatal screening, overt clinical
manifestations are rare.
 the onset of PKU is insidious and may not cause
symptoms until early infancy.
 hallmark of the disease is intellectual disability

CLINICAL MANIFESTATIONS

Infants with cofactor deficiency are identified during
screening programs for PKU because of evidence of
HPA.
.

Neurologic manifestations, such as loss of head control,
truncal hypotonia ,drooling, swallowing difficulties, and
myoclonic seizures, develop after 3 mo of age despite
adequate dietary therapy
CLINICAL


FEATURES
Mental impairment worsens during myelination in
early childhood with increasing dietary exposure, but
stabilizes when brain maturation is complete.
25% may develop seizures- more with BH4
deficiency.





some patients had loss of motor function over time
Autism
aberrant behavior, and psychiatric symptoms
Hyperactivity.
Seizure,self mutilation ,
Microcephaly
 prominent maxillae with widely spaced teeth
 enamel hypoplasia
 Growth retardation
 Persistant crying

CLINICAL FEATURES





Abnormalities of gait, sitting
posture, and stance
. spasticity, hyperreflexia,
tremors.
Frequently have blond
hair,pale skin and blue eyes
eczematous rash.
"mousy" odor due to increased
phenylacetic acid.
Cataract
Atlas Metabolic Diseases, Nyhan et al
DIAGNOSIS & DDX
NEONATAL SCREENING FOR
HYPERPHENYLALANINEMIA
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, however, that the blood for screening
be obtained in the 1st 24–48 hr of life after feeding
protein to reduce the possibility of false negative results,
especially in the milder forms of the condition

DIAGNOSIS
•
Newborn Screening – Virtually 100%
The most useful method for newborn screening is tandem
mass spectrometry
•
Phe cut-off for diagnosis by TMS is 2.1-4mg/dl
•
•
•
•
Blood Phenylalanine is high,Tyrosine level will be low or
low normal
Plasma phenylalanine/tyrosine ratio ( >2-3 HP)
.
RESCREENING
► sick
neonates
► parenteral nutrition
► Blood transfusion
► Not sufficient protein intake
PAH
DEFICIENCY MAY BE CLASSIFIED TO FOUR
DIFFERENT TYPE
Classical PKU
phe > 20 mg/dL.
mild PKU
 phe 10 to 15 mg/dL



Moderate PKU

phe 15 to 20 mg/d
Mild Hyperphenylalanemia
 phe 2.5(4) to 10 mg/dl
Normal range
0.8-1.8 mg/dL
HYPERPHENYLALANAEMIA





Classic Phenlyketonuria (6%)
Benign
 Partial hydroxylase deficiency (6-30%)
 Transient PAH deficiency
 Phenylalanine transaminase deficiency
Malignant
 Dihydropteridine reducatase deficiency
 Tetrahydrobiopterin synthesis deficiency
Tyrosinaemia
 Transient tyrosinaemia
 Tyrosinosis
Liver disease
 Galactose 1-phosphate uridyltransferase
deficiency
DIAGNOSIS
•
Genotyping of phenylalanine hydroxylase
(PAH): > 400 mutations
► There
is also a lack of consensus about the severity of
hyperphenylalaninaemia
► Most
clinical centrs use one of three phenylalanine
threshold:
► Greater
than 6mg/dl
► Greater than 7mg/dl
► Greater than 10mg/dl
TREATMENT


The goal of therapy is to reduce phenylalanine in the
body
The diet should be started as soon as diagnosis is
established.
TREATMENT
►.
First, whether the patient has a defect in
BH4 synthesis or recycling
► whether
the patient can be treated with diet
restrictions only
► whether can be helped with BH4 alone or
together with a restricted diet
TREATMENT
.
patients who do need strict dietary treatment
(PKU)

patients who do not need any treatment
(non-PKU HPA)

patients who may be treated with BH4
(BH4-responsive PKU)

HYPERPHENYLALANINEMIA 4-7MG/DL
NOMAL DIET



Vomiting
Family history of MR
Hypotonia / Hypertoinia
Monitor phe , montHly
pediatrician visit until 6 -12 m
TREATMENT


.
persistent phenylalanine >6 mg should be treated.
Discontinuation of therapy, even in adulthood, may
cause deterioration of IQ and cognitive performance
TRANSIENT HYPERPHENYLALANINEMIA


Isolated delay in the maturation of PAH
Challenged with dietary phe during the first
year of life
PROTEIN CHALLENGE TEST :
At age : 5 months

one yr

3-days intake of 100-180 mg/Kg/d of phenylalanine
 check phe. 72hr after :

if : phe > 20 mg/dl classic pku

phe :10- 20 mg/dl mild pku

phe :>7 mg/dl Diet therapy

MILDER FORMS OF HPA, NON-PKU HPA
Group of infants with initial plasma concentrations of
phe between 2-20 mg/dL.
 These infants do not excrete phenylketones.
 Clinically, these infants may remain asymptomatic, but
progressive brain damage may occur gradually with age.
 These patients have milder deficiencies of phenylalanine
hydroxylase or its cofactor (BH4) than those with classic
PKU.



Initial Dietary Therapy for Classic PKU means delete
phenylalanie from diet as follows
phe(mg/dl)
10-20
 20-40
 > 40

delete phe.
48 hrs
72 hrs
96 hrs
Monitor
Q7d
Q7d
Q7d
When p.phe(2-6 mg/dl )
 Guidelines for initial dietary phenylalanine content
dependent on the maximum pretreatment plasma levels :

Plasma phe(mg/dl)
 (<10)
 (10-20)
 (20-30)
 (30-40)
 (>40)

Dietary phe (mg/Kg)
70
55
45
35
25
RECOMMENDED PHE (MG/KG/DAY) AND
PROTEIN (G/KG/DAY) IN PKU PATIENTS
Ages (year)
Phe(mg/kg/day)
Protein(g/kg/day)
<1
40-70
2
1-3
30-40
1.5
4-10
10-20
1.5
>10
10-20
1.2
TREATMENT
► The restriction of dietary phenylalanine before one
week of age.

Babies with PKU may drink breast milk, while
also taking their special metabolic formula,
Iron,zinc,calcium,
 selenium
 Carnitin < 24 months
 Fish oil,coenzyme Q10
 Vitamin A,c,E,B12, B6,folinic acid
 Vitamin D

BREAST
Breast milk has lower content phe in
compared with standard formula
 It has optimal PHE/Tyr ratio
 It contains LCPUFAs
 First special formula then breast fed
 It contain 200-1000nmol/li BH4

MILK
PHE
CONTENT
Breast milk 53mg/100 PHE
 Formula
60mg/dl
 Cows milk 150mg/dl

TREATMENT
Because phenylalanine is not synthesized by the body,
overtreatment may lead to phenylalanine deficiency
manifested by lethargy, failure to thrive, anorexia,
anemia, rashes, diarrhea, and death;
 tyrosine is an essential amino acid and its adequate
intake must be ensured.

TREATMENT
Long chain polyunsaturated fats (LCPUFA) :
Because of restricted animal protein, low LCPUFA and
docosahexanoic acid (DHA), which may compromise
neurodevelopment .



supplementation for 12 months with LCPUFA
including DHA improved visual function
supplementation with fish oil (omega-3 LCPUFA) for
three months improved the motor skills of children
LARGE NEUTRAL AMINO ACIDS (LNAAS)

Arginine, histidine, isoleucine, leucine, lysine, methionine,
threonine, tryptophan, tyrosine and valine) compete with
phenylalanine for the same amino transporter at the
blood brain barrier.
 Prekunil tablet compete with phe
 2 tablet for 10 kg

Supplementation with LNAAs may therefore significantly
reduce the influx of phenylalanine into the brain in
patients with PKU .
LARGE
NEUTRAL AMINO ACIDS
(LNAAS)
LNAA supplementation (250-500mg/kg/day)
may significantly reduce phenylalanine in
plasma due to competitive inhibition of
phenylalanine absorption in the small intestine
.
 LNAA should not be substituted for amino
acid mixtures, but rather should be used in
selected patients to improve metabolic control


There is amino acid mixtures in PKU formula
GLYCOMACROPEPTIDE(GMP)



.
GMP is a natural protein found in sweet cheese
whey that is rich in LNAA.
is rich in specific essential aminoacids but
contains no tyrosine, tryptophan,or
phenylalanine
Studies have demonstrated the efficacy and
palatability of a GMP diet in patients with PKU
PHENYLALANINE

AMMONIA LYASE
is a bacteria-derived enzyme that catalyses
the conversion of L-phenylalanin to
transcinnamic acid and ammonia without a
cofactor requirement
GENE
THERAPHY
Restoration of hepatic PAH activity in PKU
mouse
 Transplantation of cells with fully functional
PAH/BH4 metabolism
 Liver transplantation

PKU - FUTURE






Glycomacropeptide
(A protein derived from cheese whey )
BH4 (Kuvan 100 mg ,Schircks)
Large neutural amino acids
Pheneylalanine ammonia lyase
Gene theraphy
MONITORING

The NIH Consensus Development Conference on PKU
recommended testing at:
weekly intervals during the first year,
 twice monthly from 1 to 12 years of age
 monthly after 12 years of age .

PLASMA PHENYLALANINE LEVELS
neonates through 12 yr of age
• 2-6mg/dl
After 12 yr
• 2-10
prgnancy
• 2-6
HIGH

PHENYLALANINE
&LOW TYROSINE
May be due to
intercurrent illnesses, trauma,fever
 high phenylalanine intake,
 inadequate intake of amino acid mixture, total energy,
and/or protein
 Obesity .


Tyrosine is an essential amino acid in PKU,
tyrosine concentrations may be low, which may
have a negative effect on thyroxine,
catecholamine, and melanin synthesis.

During febrile illness with high Phe
 Not change diet
 Stop animal protein <6years
 Wait for children >6years
MONITORING



Phenylalanine and tyrosine, amino acids, vitamins,
minerals, and essential fatty acids should be
monitored regularly
Osteopenia — Approximately 40 percent or more of
young adults with PKU have a low peak bone mass
Outcome — Dietary treatment appears to reverse all
signs of PKU except cognitive impairment that has
already occurred.
► Pregnancy
and PKU
► Elevated
phe concentration during early pregnancy
can result in phe embryopathy.
► spontaneous abortion, mental retardation,
microcephaly (small head), and/or congenital heart
disease ,LBW,facial dysmorfism,
► The
NIH Consensus Development statement
recommended that phe levels should be reduced to
levels <6 mg/dL at least three months before
conception and remain at 2 to 6 mg/dL during
pregnancy.
MONITORING
► twice
DURING PREGNANCY
weekly, or a minimum of once weekly.
► Maternal
plasma tyrosine should be
maintained between 0.9 and 1.8 mg/dL.
►
Tyrosine supplementation may be needed
to maintain this range
TREATMENT
.
Hyperprolactinemia occurs in patients with BH4
deficiency and may be due to dopamine deficiency in the
hypothalamic region.
 Measurement of serum prolactin levels may be a
convenient method for monitoring adequacy of
neurotransmitter replacement in affected patients.

GREEN GROUP






The foods in this group can be eaten without calculation of
phenylalanine content:
Fruits: Apples, pears, watermelon, cherries
Vegetables: Green lettuce, cucumbers, tomatoes, carrots
Dairy: Butter, margarine
Grains: Low-protein flour, low-protein bread, low-protein noodles,
low-protein crackers, low-protein rice
Beverages: Lemonade, soft drinks (without aspartame), tea, mineral
water
YELLOW GROUP





The foods in this group contain medium levels of phenylalanine, and
phenyalanine intake should be calculated:
Fruits: Bananas
Vegetables: Potatoes, french fries, potato chips
Dairy: PKU milk, ice cream
Beverages: Concentrated fruit juices
RED GROUP






The foods in this group contain high levels of phenylalanine and
should not be eaten by patients with phenylketonuria:
Meat (sausage), fish, eggs
Nuts, soybeans, lentils, peas, beans (and products made from these
foods)
Dairy: Milk, cheese (including soft, white, fresh cheese, also known
as quark or pot cheese)
Grains: Porridge, regular bread, regular noodles
Other: Chocolate
PKU- SUMMARY
DIAGNOSIS:
Confirm Dx (HPLC)
 Exclude transient tyrosinemia
 Exclude BH 4 deficiency
 Challenged diagnosis :5-12 months
 R/O Transient hyperphenylalaninemia,

PKU- SUMMARY
TREATMENT
There is no cure.
 A strict diet control is necessary .
 Provide enough phenylalanine.
 Provide multivitamins, minerals (selenium)
 Carnitin ,Fish oil

PKU- SUMMARY
MONITORING
Phe level
 Growth
 Development
 Neurologic status

DRUGS
CONTAIN PHE.
 Acetaminophin
 Amoxicillin
Cholestyramine
 Pseudoephedrine
Penicillin v
 Ibuprofen
Gayafenazin
 Anti acid ( Al mg)
Dimenhydronate
 Ranitidin , Famotidin
Lactolose
Trimethoprimsulfametoxazol
 Methoteraxate

SIDE EFFECT OFOTHER MEDICATION
Some drugs such as trimetoprin 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
 Amoxicillin has lower PHE

sapropterin
Follow up
OUTCOME

Dietary treatment appears to reverse all signs of PKU except
cognitive impairment that has already occurred.

Cognitive outcome — Affected children who are treated by dietary
restriction tend to have IQ scores in the average range.
However, their IQ scores are lower than unaffected controls.
Cognitive outcome appears to be correlated with the extent of
control of blood phenylalanine
1.9-4.1 point reduction in iQ every 100umol/l increase in mean
PHE
iQ depends on genetic




OUTCOME
Some affected patients have learning disabilities and
behavior problems
 High phenylalanine concentrations appear to cause
subclinical visual impairment

TREATMENT
OF MALIGNANT
GTPCH
LDOPAC
TRYPTOPH
AN
PTPC
LDOPAC
Tryptophan BH4
DHPR
LDOPAC
tryptophan
PKU
BH4
--------
Folinic acid
DHPR
TREATMENT
OF MALIGNANT
age
medicine
Mg/kg/day
neonate
L DOPA
1-3mg/kg/day
carbidopa
10-20%
5hydroxytrypt
ophan
1-2mg/kg/day
Folinic acid
15-20/day
L DOPA
4-7mg/kg/day
carbidopa
10-20%
5hydroxytrypt
ophan
3-5mg/kg/day
Folinic acid
15-20
1-2years
PKU
TREATMENT
.>1-2years
OF MALIGNANT
L DOPA
8-15mg/kg/day
carbidopa
10-20%
5hydroxytrypt
ophan
6-9mg/kg/day
Folinic acid
15-20
PKU

Folinicacid

Trytophan
Folidar 15 mg
cincofar50- 100mg
3-4 times a day
Cinemet 100 10% carbidopa 3-4 times a day
 Parkin c
100m 10% carbidopa 3-4 times a day


BH4
100mg
5-20mg/kg/day approximate 1.5gr
TRYTOPHAN&LDOPA
CARBIDOPA
Tablet not broken
 Gradually increase
 Not suddenly stop or beginning

SPECIAL
FORMULA
0-1yr
•Comida A
1-8yr
•Xp_Maxamaid
8-14
•Xp_analog
•Comida pku B
•Comida B
•Xp_Maxamum
BH4 deficiency
BH4

LOADING TEST
Is not mandatory in patients without
neurologic problem
BH4
LOADING TEST
► In
newborns the test should be performed
before introducing the low-Phe diet and at
elevated blood Phe levels (> 7mg/dl)
► In
infant or adult PKU patients on a Pherestricted diet, the diet needs to be modified
by increasing the protein intake (egg or
milk powder before and during the test).
IN EUROPEAN
►A
COUNTRIES
striking normalisation (within 8 h) in phe
indicates BH4 deficiency.
► A reduction of less than 20% implies that the
patient is a non-responder
► A reduction on blood Phe of at least 30% in
response to BH4 indicates a clinically
significant effect.
BH4 LOADING TEST
► If
phe reduced by 20–30%), BH4 20 mg/kg per
day is continued for a further 1–3 weeks with
daily blood phenylalanine monitoring,
► at
which time the patient is declared to be
responsive or non-responsive (discontinue
treatment).
► Not restricted diet in BH4 deficiency
► Increase Phe tolerance is due to BH4 deficiency
BH4 LOADING TEST :
Rapid normalization of phe → GTPCH , PTPS
 Slow normalization of phe → BH 4 responsive pku
 No decrease in phe → classic pku

BH4 loading test
The frequency of BH4-responsiveness is
highest in patients with
mild (non-PKU) HPA
mild PKU
resulting from PAH mutations that allow for
residual enzyme activity.
► Conversely, the response rate among patients
with classic is very low.
► In


the USA.
BH4 is not given to newborn babies
urine and a filter-paper-dried blood are obtained
for measurements of urinary neopterin and biopterin
and red blood cell dihydropteridine reductase to
assess the possibility of a defect associated with
BH4 deficiency.
► nu
► BH4
deficiency influences the synthesis of
catecholamines, serotonin and nitric oxide in the
central nervous system (CNS), and measurement of
their metabolites in cerebrospinal fluid (CSF) is
important for the diagnosis of different forms (severe v.
mild) of BH4 deficiencies.
► Not
only the absolute levels of 5-hydroxyindoleacetic
acid and homovanillic acid in CSF, but also differences
in the ratios of neurotransmitter levels provide
important diagnostic information relating to the
severity and
outcome of BH4 deficiency.
TREATMENT
Oral administration of BH4 to patients with milder forms
may reduce plasma levels of phenylalanine without the
need to remain on a low phenylalanine diet.
 Significant reduction in phenylalanine (>30%) also
observed in some patients with classic PKU following
administration of a single dose of oral BH4 (10 mg/kg).
 The response to BH4cannot be predicted consistently on
the basis of genotype, especially in compound
heterozygous patients.

SAPROPTERIN
A biologically active synthetic form of BH4
 Main mechanism seems to be stabilisation of
the PAH tetramer , prevent proteolytic
degradation and thermal inactivation

Side effect
 headache (20%), pharyngolaryngeal pain
(15%), nasopharyngitis (14%), vomiting (13%),
and diarrhoea (10%).
SAPROPTERIN
► The
starting dose is 10 mg/kg once daily for
up to one month; in patients who do not
respond, the dose may be increased to 20
mg/kg once daily for up to one month .
► The
final dose can be adjusted within a range
of 5 to 20 mg/kg per day, titrated to blood
phenylalanine level
► 1-Restericted
diet is not needed in Biopterin
defects
► 2- BH4 with low dose 1-10 mg/kg/d (higher
doses need in Classic PKU with 10-20
mg/kg/d)
3- DHPR deficiency patients do not respond to
BH4 therapy and need special diet.
► 4-
Normalization of Neurotransmitters are
needed to add L-Dopa/Carbidopa, 5-HT, and
Selegiline ,MAO inhibitor for DHPR Def.)
5-Folinic acid replacement is needed for DHPR
deficiency
HEREDITARY PROGRESSIVE DYSTONIA, AUTOSOMAL
DOMINANT DOPA-RESPONSIVE DYSTONIA, SEGAWA
DISEASE
This rare form of dystonia, is caused by GTP
cyclohydrolase deficiency.
 It is inherited as an autosomal dominant trait and is more
common in females than males (4:1)
 Clinical manifestations usually occur around 5–6 yr of
age and are heralded by dystonia of the lower limbs,
which may spread to all extremities within a few years.

HEREDITARY PROGRESSIVE
DYSTONIA
Torticollis, dystonia of the arms, and poor coordination
may precede dystonia of the lower limbs in some
patients.
 Early development is generally normal.
 The symptoms usually have an impressive diurnal
variation, becoming worse by the end of the day and
improving with sleep.

HEREDITARY PROGRESSIVE
DYSTONIA
Parkinsonian signs may also be present or develop
subsequently with advancing age.
 Patients may be misdiagnosed as having cerebral palsy.
 Late presentation in adult life has also been reported

LABORATORY FINDINGS
No HPA, but reduced levels of BH4 and neopterin are
found in the spinal fluid.
 Dopamine and its metabolites (homovanillic acid) may
also be reduced in the spinal fluid.
 The asymptomatic carrier :ratio of plasma phenylalanine
to tyrosine after an oral dose of phenylalanine (100
mg/kg); the ratio increases significantly (≈3 times above
normal value at 2 hr) in the asymptomatic carrier

DIAGNOSIS &TREATMENT
Dx may be confirmed by reduced levels of BH4 and
neopterin in the spinal fluid, by measurement of the
enzyme activity, and by identification of the gene defect
 The striking diurnal pattern of dystonia is an important
clinical finding
 Treatment with L-dopa in conjunction with a peripheral
dopa decarboxylase inhibitor usually produces dramatic
improvement.

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‫ورن‬
‫اب‬
‫قرص‬
‫‪3‬‬
‫‪12‬‬
‫‪1‬‬
‫‪6‬‬
‫‪24‬‬
‫‪2‬‬
‫‪6.5‬‬
‫‪26‬‬
‫‪2‬‬
‫‪7‬‬
‫‪28‬‬
‫‪2‬‬
‫‪8‬‬
‫‪32‬‬
‫‪2‬‬
‫‪9‬‬
‫‪36‬‬
‫‪2‬‬
‫‪10‬‬
‫‪40‬‬
‫‪3‬‬
‫‪12‬‬
‫‪48‬‬
‫‪3‬‬
‫‪15‬‬
‫‪60‬‬
‫‪3‬‬
‫‪18‬‬
‫‪72‬‬
‫‪4‬‬
‫‪20‬‬
‫‪80‬‬
‫‪4‬‬

BH4 during 5-10 minut
ANY QUESTIONS?
;
PHENYLALANINE
HYDROXYLATING SYSTEM
TREATMENT
MALIGNANT PKU
Kuvan
5 hydroxy
triptophan
•5-10mg/kg/day
•5-9mg/kg/day
CARBIdopa10-100
25-250
•8 - 10mg/kg/day
Folinic acid (DPRT)
•12.5mg