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