Case report
Late diagnosis of classical phenylketonuria in our patient (infant)


The case of a 9.5-month-old girl who was investigated for unexplained psychomotor retardation
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History:
•Family history: without interest
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•A girl from 4th pregnancy, 2 x spontaneous abortion, healthy brother, oligohydramnion, prenatal
ultrasound in pregnancy 2x (12th and 38th week), biochemical screening of M. Down, all in the norm,
childbirth in 40th week by caesarean section for non-advancing birth, 3600g/ 51 cm, breastfed 6
months, then mixed baby food, parents observed a difference from older healthy brother – the girl
did not smile, did not make contact, family doctor advised to wait
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•At 8.5 months – eye examination, finding in the norm
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•In 9.5 months was admitted to the hospital, at the Deparment of Neurology – delay of psychomotor
development, does not sit, does not climb, she rolls over on the tummy and back, on the tummy is on
the elbows, sometimes on the palms, says the syllables
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•age-appropriate nutrition, head frontooccipital circumference 41 cm ↓, other anthropometric
parameters in the standard
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Examination
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•Differential diagnosis:
•MRI of the brain: myelinization of white matter corresponds to 6-8 months of age, delayed, further
finding in the norm
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•metabolic screening was performed to rule out inborn error of metabolism (IEM)
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•Phenylalanine (Phe) in the blood was found to be significantly increased and reached 1768μmol/l
(standard up to 120μmol/l), corresponding to classical phenylketonuria (PKU)
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•molecular-genetic examination of PAH gene for PKU/HPA: genotype
p.(Gly272*)/p.(Thr328Ala),mutations are described causal, listed in the HGMD database
(www.hgmd.org)
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Phenylketonuria - PKU
•IEM of amino acid Phe caused by deficiency of phenylalanin hydroxylase enzyme (PAH) in the liver
(EC 1.14.16.1), PAH gen 12q23.2
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•Heredity: autosomal recessive, incidence in the Czech Republic 1: 5,250 live birth
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•r.1954 - prof. Bickel – therapy: low-protein diet, low in phenylalanine
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•Early postnatal, sufficiently intense and long-term low protein diet allows normal or almost
normal development of cognitive functions
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•The diet is compiled individually according to sex, weight, age, protein, carbohydrate and fat
needs and Phe tolerance in the diet
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•Other treatment options: GMP-glycomacropeptide, cofactor BH4-Kuvan, enzyme replacement
therypy-ERT-Pegvaliasa® (BIOMARINE)
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Phenylketonuria-screening
•Introduced by Prof. Robert Guthrie (1916-1995), University of Buffalo, USA, NY
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•PKU - bacterial inhibitory test (B. subtilis)
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•In 1963 introduced - neonatal screening in the Czech Republic, by law only in 1975
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•Since 2009 in the Czech Republic screening is provided using MS/MS (tandem mass spectrometry)

Newborn screening in the Czech
Republic - IEM
•Disturbances of amino acid metabolism:
•Phenylketonuria – PKU
•Maple sirup urine disease – MSUD
•urea cycle defects: Argininemia, Citrullinemia
•Homocystinuria from CBS deficiency, pyridoxine non-responsive
•Homocystinuria from MTHFR deficiency
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•Organic acidurias
•Glutaric aciduria type 1, Isovaleric aciduria (IVA)
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•Disorders of fatty acid oxidation
•Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
•Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
•Very long-chain acyl-CoA dehydrogenase (VLCHAD) deficiency
•Carnitine palmitoytransferase I (CPT1) deficiency
•Carnitine palmitoytransferase II (CPT2) deficiency
•Carnitin acylcarnitine translocase (CACT) deficiency
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•biotinidase deficiency
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•How could that happen?






•The child was born in Thailand, his parents worked here in tourism
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•Parents had health insurance
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•Screening was conducted: 2nd day after birth, blood Phe level 3.4 mg/ dl, i.e. 204μmol/l, standard
up to 2 mg/dl or 120μmol/l
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•Parents were communicated that the blood Phe up to 4 mg/ dl, i.e. 240μmol/l, is normal in
Thailand, within this range, no further control was performed !!!!!!!!!!!???????
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Thailand and inborn errors of metabolism (IEM)
•Incidence of IEM in Europe and North America 29-40/100,000, in Asia 16-26/100,000 live births
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•In Thailand provided PKU screening since 1996, incidence of PKU 2.22/ 100,000 live births (180,000
newborns examined in 2012 at Siriraj Hospital Bangkok)
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•Method: Guthrie test for low price and simple examination
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•In 2015, a pilot study on selected IEM using MS/MS – a highly costly method for Thailand, yet the
introductions recommend for PKU, IVA, MSUD, MCD (Thiboonboon K et al.: An Economic Evaluation of
Neonatal Screening fo Inborn Errors of Metabolism Using Tandem Mass Spectrometers in Thailand, Plos
One, August 2015)
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•the diet of our patients with PKU is vegetarian and vegan
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Our patient at the age of 24 months:
•Anthropometric parameters: weight 12.1 kg, length 86.5 cm, head frontooccipital circumference 46.7
cm
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•Laboratory tests: Phe in the blood 60-150μmol/l (60-360); Zn in the blood 10.5μmol/l (11.5-15.3);
Se in the blood 0.67μmol/l (0.7-1.24); other laboratory parameters in the standard
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•Neurological examination: pathological EEG in the sense of epilepsy, but the finding improved,
clinically free of seizures, antiepileptics is not used
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•NMR of the brain now not done due to progress in psychomotor development and improved EEG
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•psychological examination: the level of motor functions ranged from 12 months, the overall level
of mental functions corresponded to about 10 months of age. Prediction for the future: IQ 44,
impairment of neurocognostic functions is irreversible
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