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F. Veyckemans

Phenylketonuria and other hyperphenylalaninemias

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Keywords Phenylketonuria; ICD 10: E70.0, E70.1 OMI: 260600, 260630 GARD 7383; Synonyms: Phenylalanine hydroxylase deficiency, BH4 deficiency (dihydropterin reductase deficiency), PKU, Fǿlling disease, Phenylpyruvic oligophrenia
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Phenylketonuria (PKU) is an inherited error of metabolism. Its prevalence is estimated at 1/50.000 but ranges from 1/2600 in Turkey, 1/50.000 in the UK and 1/100.000 in Japan. In 98% of the cases, it is caused by the autosomal recessive transmission of a mutation of the PAH gene (12q23.2) which codes for phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine to tyrosine. In all other cases, it is caused by the autosomal recessive transmission of a mutation of one of the genes responsible for the synthesis or regeneration of tetrahydrobiopterin (BH4).These are: the GCH1 gene coding for GTP cyclohydroxylase1 (14q22.2), the PTS gene coding for 6-pyruvoyl-tetrahydropterine synthase (11q23.1), the PCBD gene coding for pterin-4α-carbinolamine dehydratase (10q22.2) or the QDPR gene coding for dihydropterin reductase (4p15.32). Most of these cases are caused by a dihydropterin reductase deficiency. They are called BH4 deficiency or defects in pterin metabolism. BH4 is a cosubstrate of phenylalanine hydroxylase (see figure at the end of the text) but it is also involved in the synthesis of the amino acids tyrosine, tryptophan and arginine. A deficiency in the production of these amino acids results in a deficiency of the neurotransmitters dopamine, serotonin and nitric oxide. In addition, in rare cases, hyperphenylalaninaemia may be caused by a mutation in DNAJC12, a protein responsible for the proper folding of PHA (4). In developed countries, PKU is currently detected by a systematic screening (bloodspots 24–72 h after birth, “Guthrie’s test”). If the test is positive, the PAH deficiency is confirmed by other tests (including genetic testing). More than 950 different pathogenic variants have been described in PKU patients and they result in a reduced enzymatic activity of PAH. Depending on this residual enzymatic activity, the phenotype of PKU is highly variable. According to plasma Phe levels at diagnosis and tolerance, defined as the highest dietary Phe intake able to keep blood Phe levels within the safe range (120–360 μmol/l), PKU is classified into - classic PKU, if the patient tolerates less than 250-350 mg dietary Phe per day, - moderate PKU, if the patient tolerates 350-400 mg dietary Phe per day, - mild PKU, if the patient tolerates 400–600 mg dietary Phe per day. - mild or non-phenylketonuric hyperphenylalaninaemia: the Phe levels are persistently below 600 μmol/l on a normal diet. These patients have a normal intellectual and behavioural development without treatment: whether this is a benign anomaly that requires no treatment is a matter of controversy. According to the first European PKU guidelines, PAH deficiency is now classified into mild PAH deficiency (not needing treatment), BH4 responsive and BH4 unresponsive PKU. If PKU is left untreated, the accumulation of Phe in the brain will lead to severe global developmental delay, intellectual disability, behavioural problems, epilepsy, movement disorders, and hypomelanosis with light skin, blond hair, blue eyes, an eczematous rash. In untreated BH4 deficiency, the patients present with microcephaly, developmental delay, intellectual disability, tremor, dystonia, uncoordinated movements, hyperthermia and epilepsy. In case of untreated DNAJC12 deficiency, the patient’s phenotype varies from autistic features or hyperactivity to severe intellectual disability with dystonia and parkinsonism. PKU is treated by initiating a lifelong diet that restricts the intake of high-protein food. The aim of the classical diet is to keep Phe blood levels between 120–360 μmol/l for the first 12 years of life and in case of wish to become pregnant and during pregnancy. In other age periods the target range is 120–600 μmol/l. The classical diet is very restrictive and timeconsuming. Therefore many children, adolescence and adults struggle to adhere to the diet resulting in neuropsychological symptoms such as executive dysfunction, mood disorders, anxiety, reduced vigilance and attention deficit hyperactivity disorder. Some patients (often those with mild PKU) respond to a 48 h test with 20 mg/kg/d oral BH4 with a reduction of at least 30 % of the plasma Phe levels. In these cases, called BH4-responsive PKU, a daily intake of oral BH4 can be associated with a less restrictive diet. In case of hyperphenylalaninemia with no in PAH nor pterin metabolism abnormalities, a mutation in DNAJC12 should be looked for using molecular biology. A more “normal” and less protein restricted diet supplemented with large neutral amino acids (LNAA) is available [5]. Adherence to LNAA is typically better than to the classical diet making LNAA an excellent alternative in the treatment of PKU. The aim of this less-restricted diet is to keep Phe blood levels between 900–1500 μmol/l. The medical treatment of BH4 deficiency is more complex. In addition to the restrictive Phefree diet, it involves: sapropterin dihydrochloride (BH4) 2-20 mg/kg/d in 2–3 doses; folic acid 15 mg/d; L-dopa 1–2 mg/d in 4 doses; 5-hydroxytryptophan 1–10 mg/kg/d in 4 doses; entacapone (a COMT inhibitor) 15 μg/kg/d in 2–3 doses; selegilin (a MAO-B inhibitor) 0.1–0.25 mg/kg/d in 3–4 doses and pramipexole (a dopa receptors agonist) 6–35 μg/kg/d in 2 doses. However, some like dihydropterin reductase deficiency are a contraindication to BH4 supplementation due to the risk of conversion into BH2. Concerning anaesthesia, there are only a few concerns in patients with PKU who are under medical treatment since infancy. Patients should avoid protein catabolism (a short preanaesthetic fasting time and administration of glucose-containing IV electrolytic solutions), avoiding gelatin and aspartame-containing drugs as well as exposure to N2O because there is a risk of dietary vitamin B12 deficiency. In case of parenteral nutrition, a solution without Phe should be used. The same concerns should be kept for patients with defects of pterin metabolism and BH4 responsive PKU, but their medical treatment should be continued up to the morning of anaesthesia.