Hyperphenylalaninemia is caused
primarily by a deficiency of the hepatic apoenzyme phenylalanine-4- hydroxylase (PAH) or by one of the enzymes involved in its cofactor biosynthesis (GTP cyclohydrolase I, GTPCH; and 6-pyruvoyl-tetrahydropterin synthase, PTPS) or its regeneration (dihydropteridine reductase, DHPR; and pterin carbinolamine 4a-dehydratase, PCD). Tetrahydrobiopterin (BH4) is known to be the natural cofactor for PAH, tyrosine-3-hydroxylase, and tryptophan-5-hydroxylase. The latter two are key enzymes in the biosynthesis of the neurotransmitters, dopamine and serotonin.
Phenylalanine is feedback inhibitor of both tyrosine and tryptophan hydroxylases, depletion of catecholamines and serotonin occurs in untreated patients with PAH deficiency. Hyperphenylalaninemias (PAH and BH4 deficient) are heterogeneous disorders varying from severe, e.g., classical phenylketonuria (PKU), to mild, benign, and transient forms. For the pterin defects, symptoms may manifest during the first weeks of life but usually are noted at about 4 months of age.
Two disorders of BH4 metabolism may present without hyperphenylalaninemia. These are Dopa-responsive dystonia (Segawa disease) and sepiapterin reductase deficiency. While the first is caused by a mutation in the GTPCH gene and is inherited in an autosomal dominant manner, sepiapterin reductase deficiency is an autosomal recessive trait. Both diseases evidence severe biogenic amines deficiencies.
Today, the Guthrie screening test has been replaced by powerful tandem mass spectrometry techniques or by enzymatic methods. Once hyperphenylalaninemia has been detected, a sequence of quantitative tests enables the differentiation between variants, i.e. classical PKU, BH4-responsive PKU and BH4 deficiencies. Because the BH4 deficiencies are actually a group of diseases which may be detected because of hyperphenylalaninemia, but not simply and routinely identified by neonatal mass screening, selective screening for a BH4 deficiency is essential in every newborn with even slightly elevated phenylalanine levels. Screening for a BH4 deficiency should be done in all newborns with plasma phenylalanine levels greater than 120 micromol/l (2 mg/dl), as well as in older children with neurological signs and symptoms.
The goals of treatment are to control hyperphenylalaninemia by dietary
restriction of phenylalanine and to restore neurotransmitter homeostasis
by the oral administration of dopamine and serotonin precursors in BH4 deficiencies. 4 Late detection and introduction of treatment leads to irreversible brain damage. In contrast to patients with classical PKU, patients with BH4 deficiencies show progressive neurological deterioration despite treatment with phenylalanine-restricted diets.
Biosynthesis and regeneration of tetrahydrobiopterin including possible metabolic defects and catabolism of phenylalanine.
1.2/1.6=GTP cyclohydrolase I (GTPCH),
1.3=6-pyruvoyl-tetrahydropterin synthase (PTPS),
1.4=dihydropteridine reductase (DHPR),
1.5=pterin-4a-carbinolamine dehydratase (PCD),
1.7=sepiapterin reductase SR,
carbonyl reductase (CR), aldose reductase (AR),
dihydrofolate reductase (DHFR),
aromatic amino acid decarboxylase (AADC),
tyrosine hydroxylase (TH),
tryptophan hydroxylase (TPH),
nitric oxide synthase (NOS).
SIGNS AND SYMPTOMS
The classical PKU that is a phenyalanine 4- hydroxilase deficiency is accompanied with some characteristic signs and symptoms listed below:
The characterictic clinical findings in the neonatal age( not so clear) and until adulthood are odor of the urine and body, mental ritardation and lighter pigmentation in famigliar constelation.
In a routine lab and in a special lab can be tested FeCl3 that is present in tall the ages and some strumental diagnosis can be applied like MRI brain and EEG, in all ages, the test og Phe, that is high in every decade of life, 5HIAA, HVA (CSF) that decrease in all decades of life and the Phe load test the results negative in the neonate, infant, child, adolescence and adult.
In the Gastrointestinal system the most present symptom is vomiting and in the Central Nervous System we spot microcephaly( after infancy), mental ritardation ( after infancy) , irritability ( after infancy more or less) , seizures, hypotonia and autism.
The adult may have heart problems and every age can present an eczematous rash.