Post on 12-Jan-2016
Phe Tyr
PAH
BH4 BH2GTP
BH4-dependent HPA(atypical/malignant PKU)• Usually mild PKU/HPA• Early CNS symptomsFe
O2
PAH deficiency
Classic PKU Mild PKUMild 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
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
• 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
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
• 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
BH4 test
NEGATIVE
BH4 non-responsive
Classic PKU / Mild HPA
BH4-responsive
PKU
BH4-dependent
(atypical) PKU
Hyperhenylalaninemia differential diagnoses
POSITIVE
BH4 responsive
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
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
BH4
20 mg/kg
blood Phe, Phe/Tyr (MS/MS)
Day 1: -3 0 4 8 12 24
hours
1400
1200
1000
800
600
400
200
0
Blo
od
Ph
e
(um
ol/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
Day 1: -3 0 4 8 12 24
hours
Blo
od
Ph
e
(um
ol/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
• 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
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)
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
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
Patient education