Metabolic Disorders

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Case history

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

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Case history

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

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Physical examination

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

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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

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Lab data

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

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Lab data

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

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Classic Phenylketonuria
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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

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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.

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Phenylketonuria
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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,

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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

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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.

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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

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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

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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 ,

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

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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

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Atlas Metabolic Diseases, Nyhan et al
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Diagnosis DDx
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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

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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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Rescreening

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

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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

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Normal range 0.8-1.8 mg/dL
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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

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Diagnosis

• Genotyping of phenylalanine hydroxylase (PAH) gt
  400 mutations

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• 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

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Treatment

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

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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

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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

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Treatment

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

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Transient Hyperphenylalaninemia

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

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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

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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.

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• 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

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• 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

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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
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• TREATMENT
• The restriction of dietary phenylalanine before
  one week of age.

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• 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

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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

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PHE content

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

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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.

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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

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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 .

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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

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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
• .

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Phenylalanine ammonia lyase

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

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Gene theraphy

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

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PKU - Future

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

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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 .

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plasma phenylalanine levels
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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.

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

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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.

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• 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.

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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

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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.

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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

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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

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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

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PKU- SummaryDiagnosis

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

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PKU- SummaryTreatment

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

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PKU- SummaryMonitoring

• Phe level
• Growth
• Development
• Neurologic status

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Drugs contain phe.

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

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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

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sapropterin
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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

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Outcome

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

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







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Treatment of malignant PKU

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



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• 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

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Trytophanldopa carbidopa

• Tablet not broken
• Gradually increase
• Not suddenly stop or beginning

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Special formula
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• BH4 deficiency

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BH4 loading test

• Is not mandatory in patients without neurologic
  problem

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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.

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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

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BH4 loading test

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

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• 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.

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• 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.

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• 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.

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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.

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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).

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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

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• 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

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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.
• 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.

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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.

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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

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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

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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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• ?? ??? ?? ?? 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
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• 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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