phe
DESCRIPTION
Hyperphenylalaninaemias (HPA) Patomechanism, types. BH 4 -dependent HPA (atypical/malignant PKU) Usually mild PKU/HPA Early CNS symptoms. Fe O 2. GTP. BH 4. BH 2. Tyr. Phe. Phenylketons FeCl 3. DOPA→DA→NA→A →→→ melanin. NormTRANSCRIPT
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Phe TyrPAH
BH4 BH2GTP
BH4-dependent HPA(atypical/malignant PKU)• Usually mild PKU/HPA• Early CNS symptomsFe
O2
PAH deficiency
Classic PKU Mild PKU Mild HPA (non PKU HPA)
Phe level (μmol/l) >600 (1200) 360-600 (600-1200)
120-360 (120-600)
Phe tolerance (mg/day) <400 400-800 >800
BH4 response BH4-responsive PKU/HPA
PhenylketonsFeCl3
DOPA→DA→NA→A→→→ melaninNorm
<120 μmol/l
Hyperphenylalaninaemias (HPA)Patomechanism, types
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Expected Szeged
Overall 1:4500-5000 (20 case/year)
16
PAH deficiency99%
Classic PKU 1:9000 (10 case/year)
10
HPA 1:9000 (10 case/year)
5
BH4 deficiency (atypical PKU) 1%
1:250000 (1 case/year)
1
Incidence of hyperphenilalaninamias
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• MS/MS (aminoacid & acylcarnitine)• Sampling on 3rd day of life• Primary parameter: blood Phe >102 μmol/l (norm < 120)
Secondary parameter: Phe/Tyr > 1.5• Clinical circumstances!• Transient hyperphenylalaninaemia
prematurity (Orn, C3 ↑) parenteral nutrition (Val, Leu, Thr ↑ hepatic disease (sepsis, galactosaemia,…) drugs
0. day, screening
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Positive result„normal” newborn
Blood Phe 102-360 μmol/l
Blood Phe >360 μmol/l
Clinical examination
week 1-3
Repeat screening
Phe ↑Phe norm
Further work-up for suspected HPA newborns
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• Call in the patient – no diet!• Detalied clinical history, family anamnesis• Physical examination
• Usually few or no symptoms• Mild Phe elevation + feeding difficulty, hypotonia, myoclonus,
seizure, salivation → atypical PKU?• Laboratory studies
• Blood Phe, Phe/Tyr (MS/MS)
• urine FeCl3, GC-MS
• BH4 test• DNA extraction for mutation analysis
• EEG
Clinical work-up for the suspected PKU newbornsAim: definitve diagnosis, HPA typing, starting treatment
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BH4 test
NEGATIVEBH4 non-responsive
Classic PKU / Mild HPA
BH4-responsive PKU
BH4-dependent(atypical) PKU
Hyperhenylalaninemia differential diagnoses
POSITIVEBH4 responsive
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0 4 8 12 16 24
BH420 mg/kg
normal diet diet
blood Phe, Phe/Tyr (MS/MS)
BH4 loadingPhe > 360 μM
POSITIVE (Phe ↓ >30%) → BH4-responsive/atypical PKU? measure pterins, DHPR
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normal diet diet
POSITIVE (Phe ↓ >30%) → BH4-responsive/atypical PKU? measure pterins, DHPR
Combined Phe + BH4 loadingPhe < 360 μM
0 4 8 1216 24
Phe100 mg/kg
-3 24-3
1612840
Phe100 mg/kg
BH420 mg/kg
blood Phe, Phe/Tyr (MS/MS)
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Day 1: -3 0 4 8 12 24
hours
1400
1200
1000
800
600
400
200
0
Blood Phe
(umol/l) Phe
(100 mg/kg)
1193
122
40 39 45
Interpreting the BH4 test result - Case 2
888
387
888
812
705
Phe (100 mg/kg)
BH4 (20 mg/kg)
Day 2: 24 27 31 35 39 51
BH4-dependent
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Day 1: -3 0 4 8 12 24
hours
Blood Phe
(umol/l)
Phe (100 mg/kg)
412
137
6542
35
Interpreting the BH4 test result - Case 2
96
140
BH4 (20 mg/kg)
Day 2: 24 27 31 35 39 51
BH4-responsive
1400
1200
1000
800
600
400
200
0
96
670
254
533
440
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• Send DNA sample for mutation analysis to Semmelweis University,
2nd Dept. Pediatrics
• Screen for 6 most frequent PAH mutation (R408W, R158Q, R261Q,
R252W, IVS 10nt546, IVS12 splice-site)
• Whole gene sequencing
Molecular genetical diagnoses
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Classic PKU treament, advices
• Treat immediately after diagnosis
• Gold standard: Phe-free medical food (enriched with vitamins, trace elements, additional energy)
• Breastfeeding is encouraged, ⅓ of daily protein intakeDiet overshoot: Phe-deficiency: lethargy, feeding problem, diarrhea, anaemia, anorexia
• In PKU: target Phe-level: 120-360 μmol/l
• In HPA (120-360 μmol/l): no treament is necessary (except pregnancy)
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BH4-deficiency treament, advices
• BH4 5-10 mg/kg/day
• Neurotransmitter precursors:
L-DOPA (Madopar 1-3, 4-7, 8-12 mg/kg/day)
5-hidroxi triptophan (Tript-OH 6-9 mg/kg/day)
MAO-B blocker selegiline (0.25 mg/kg/day)
• Low-Phe diet if necessary
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Follow-up
• Blood sample via mail regularly
• Control check-ups: 0-3 years: every 3 months 3-6 years: every 6 months> 6 years: yearly
Physical examination, laboratory studies
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Patient education