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Metabolic Disorders

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HEREDITARY PROGRESSIVE DYSTONIA, AUTOSOMAL DOMINANT DOPA-RESPONSIVE DYSTONIA, SEGAWA DISEASE This rare form of dystonia, is caused by GTP cyclohydrolase deficiency. – PowerPoint PPT presentation

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Title: Metabolic Disorders


1
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2
Case history
  • 13 month old boy with developmental delay
  • NL at birth
  • Irritability Recurrent vomiting from 2 week age

3
Case history
  • Recurrent seizure with poor response to
    antiepileptic drugs from 3 month ago.
  • No sitting , no walking
  • speech delay
  • Relative parents

4
Physical examination
  • HT75.2 cm
  • WT10.300 kg
  • HC42cm
  • Prominent maxilla
  • Fair sparse hair

5
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

6
Lab data
  • CBC
  • TFT
  • VBG
  • ELECTROLYTES
  • LFT
  • TORCH
  • Ammonia
  • lactate
  • U/A
  • EEG AbNL
  • .

7
Lab data
  • Brain MRIa symmetrical increase of T2-weighted
    signal in the periventricular white matter

8
Classic Phenylketonuria
9
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

10
L-aminoacid transporter
  • Phenylalanines entry into the brain is mediated
    by the large neutral aminoacid carrier 1(LAT1).
  • Two other large neutral aminoacidstyrosine, a
    precursor of dopamine and norepinephrine, and
    tryptophan, a precursor of serotoninalso enter
    the brain via the LAT1 carrier.
  • High concentrations of phenylalanine can inhibit
    LAT1 from entering the brain, increasing the
    potential for
    neurotransmitter dysfunction.

11
Phenylketonuria
12
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,

13
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

14
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.

15
Clinical Features
  • 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

16
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

17
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 ,

18
  • Microcephaly
  • prominent maxillae with widely spaced teeth
  • enamel hypoplasia
  • Growth retardation
  • Persistant crying

19
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

20
Atlas Metabolic Diseases, Nyhan et al
21
Diagnosis DDx
22
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 2448 hr of life
    after feeding protein to reduce the possibility
    of false negative results, especially in the
    milder forms of the condition

23
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 ( gt2-3 HP)
  • .

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26
Rescreening
  • sick neonates
  • parenteral nutrition
  • Blood transfusion
  • Not sufficient protein intake

27
Pah deficiency may be classified to four
different type
  • Classical PKU
  • phe gt 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

28
Normal range 0.8-1.8 mg/dL
29
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

30
Diagnosis
  • Genotyping of phenylalanine hydroxylase (PAH) gt
    400 mutations

31
  • 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

32
Treatment
  • The goal of therapy is to reduce phenylalanine in
    the body
  • The diet should be started as soon as diagnosis
    is established.

33
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

34
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)

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Hyperphenylalaninemia 4-7MG/DL
  • NOMAL DIET
  • Vomiting
  • Family history of MR
  • Hypotonia / Hypertoinia
  • Monitor phe , montHly
  • pediatrician visit until 6 -12 m

37
Treatment
  • persistent phenylalanine gt6 mg should be
    treated.
  • Discontinuation of therapy, even in adulthood,
    may cause deterioration of IQ and cognitive
    performance
  • .

38
Transient Hyperphenylalaninemia
  • Isolated delay in the maturation of PAH
  • Challenged with dietary phe during the first year
    of life

39
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 gt 20 mg/dl classic pku
  • phe 10- 20 mg/dl mild pku
  • phe gt7 mg/dl Diet therapy

40
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.

41
  • Initial Dietary Therapy for Classic PKU means
    delete phenylalanie from diet as follows
  • phe(mg/dl) delete phe. Monitor
  • 10-20 48 hrs Q7d
  • 20-40 72 hrs Q7d
  • gt 40 96 hrs Q7d

42
  • When p.phe(2-6 mg/dl )
  • Guidelines for initial dietary phenylalanine
    content dependent on the maximum pretreatment
    plasma levels
  • Plasma phe(mg/dl) Dietary phe (mg/Kg)
  • (lt10) 70
  • (10-20) 55
  • (20-30) 45
  • (30-40) 35
  • (gt40) 25

43
Recommended phe (mg/kg/day) and protein
(g/kg/day) in pku patients
Ages (year) Phe(mg/kg/day) Protein(g/kg/day)
lt1 40-70 2
1-3 30-40 1.5
4-10 10-20 1.5
gt10 10-20 1.2
44
  • TREATMENT
  • The restriction of dietary phenylalanine before
    one week of age.

45
  • Babies with PKU may drink breast milk, while also
    taking their special metabolic formula,
  • Iron,zinc,calcium,
  • selenium
  • Carnitin lt 24 months
  • Fish oil,coenzyme Q10
  • Vitamin A,c,E,B12, B6,folinic acid
  • Vitamin D

46
Breast milk
  • 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

47
PHE content
  • Breast milk 53mg/100 PHE
  • Formula 60mg/dl
  • Cows milk 150mg/dl

48
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.

49
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

50
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 .

51
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

52
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
  • .

53
Phenylalanine ammonia lyase
  • is a bacteria-derived enzyme that catalyses the
    conversion of L-phenylalanin to transcinnamic
    acid and ammonia without a cofactor requirement

54
Gene theraphy
  • Restoration of hepatic PAH activity in PKU mouse
  • Transplantation of cells with fully functional
    PAH/BH4 metabolism
  • Liver transplantation

55
PKU - Future
  • Glycomacropeptide
  • (A protein derived from cheese whey )
  • BH4 (Kuvan 100 mg ,Schircks)
  • Large neutural amino acids
  • Pheneylalanine ammonia lyase
  • Gene theraphy

56
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 .

57
plasma phenylalanine levels
58
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.

59
  • During febrile illness with high Phe
  • Not change diet
  • Stop animal protein lt6years
  • Wait for children gt6years

60
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.

61
  • 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 lt6 mg/dL at least three months before
    conception and remain at 2 to 6 mg/dL during
    pregnancy.

62
Monitoring during pregnancy
  • twice 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

63
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.

64
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

65
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

66
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

67
PKU- SummaryDiagnosis
  • Confirm Dx (HPLC)
  • Exclude transient tyrosinemia
  • Exclude BH 4 deficiency
  • Challenged diagnosis 5-12 months
  • R/O Transient hyperphenylalaninemia,

68
PKU- SummaryTreatment
  • There is no cure.
  • A strict diet control is necessary .
  • Provide enough phenylalanine.
  • Provide multivitamins, minerals (selenium)
  • Carnitin ,Fish oil

69
PKU- SummaryMonitoring
  • Phe level
  • Growth
  • Development
  • Neurologic status

70
Drugs contain phe.
  • Acetaminophin
  • Amoxicillin Cholestyramine
  • Pseudoephedrine Penicillin v
  • Ibuprofen Gayafenazin
  • Anti acid ( Al mg) Dimenhydronate
  • Ranitidin , Famotidin Lactolose
  • Trimethoprimsulfametoxazol
  • Methoteraxate

71
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

72
sapropterin
73
Follow up
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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

77
Outcome
  • Some affected patients have learning disabilities
    and behavior problems
  • High phenylalanine concentrations appear to cause
    subclinical visual impairment

78
Treatment of malignant PKU
GTPCH LDOPAC TRYPTOPHAN BH4
PTPC LDOPAC Tryptophan BH4
DHPR LDOPAC tryptophan -------- Folinic acid
79
Treatment of malignant PKU

DHPR age medicine Mg/kg/day
neonate L DOPA 1-3mg/kg/day
carbidopa 10-20
5hydroxytryptophan 1-2mg/kg/day
Folinic acid 15-20/day
1-2years L DOPA 4-7mg/kg/day
carbidopa 10-20
5hydroxytryptophan 3-5mg/kg/day
Folinic acid 15-20







80
Treatment of malignant PKU

.gt1-2years L DOPA 8-15mg/kg/day
carbidopa 10-20
5hydroxytryptophan 6-9mg/kg/day
Folinic acid 15-20



81
  • Folinicacid Folidar 15 mg
  • Trytophan 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

82
Trytophanldopa carbidopa
  • Tablet not broken
  • Gradually increase
  • Not suddenly stop or beginning

83
Special formula
84
  • BH4 deficiency

85
BH4 loading test
  • Is not mandatory in patients without neurologic
    problem

86
BH4 loading test
  • In newborns the test should be performed before
    introducing the low-Phe diet and at elevated
    blood Phe levels (gt 7mg/dl)
  • In infant or adult PKU patients on a
    Phe-restricted diet, the diet needs to be
    modified by increasing the protein intake (egg or
    milk powder before and during the
    test).

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In European countries
  • A 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.

89
BH4 loading test
  • If phe reduced by 2030), BH4 20 mg/kg per day
    is continued for a further 13 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

90
BH4 loading test
  • Rapid normalization of phe ? GTPCH , PTPS
  • Slow normalization of phe ? BH 4 responsive pku
  • No decrease in phe ? classic pku

91
  • 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.

92
  • 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.

93
  • 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.

94
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 (gt30)
    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.

95
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).

96
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

97
  • 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

98
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 (41)
  • Clinical manifestations usually occur around 56
    yr of age and are heralded by dystonia of the
    lower limbs, which may spread to all extremities
    within a few years.

99
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.

100
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

101
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

102
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.

103
  • ?? ??? ?? ?? 20 ?? ?? ?? ?? ????

??? ?? ???
1 12 3
2 24 6
2 26 6.5
2 28 7
2 32 8
2 36 9
3 40 10
3 48 12
3 60 15
4 72 18
4 80 20
104
  • BH4 during 5-10 minut

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Any Questions?

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Phenylalanine hydroxylating system
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Treatment malignant pku
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