Phenylketonuria: Symptoms, Risks, and Dietary Restrictions - Urology

Dr. Li Yilun reply Urology

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Due to network issues, I apologize for the delayed response.
Phenylketonuria (PKU) is a rare inherited metabolic disorder.
1.
Causes and Symptoms of Phenylketonuria
In 1934, Dr.
Folling from Norway discovered a distinct musty odor in the urine of patients with familial intellectual disabilities, later identified as phenylpyruvic acid.
In 1937, it was officially named phenylketonuria (PKU).
PKU is an autosomal recessive disorder primarily caused by a metabolic defect in the hydroxylation of phenylalanine (Phe) to tyrosine (Tyr).
Currently, five different enzyme deficiencies are known to cause this metabolic defect: phenylalanine hydroxylase (PAH), GTP cyclohydrolase I (GTPCHI), 6-pyruvoyl tetrahydropterin synthase (PTPS), dihydropteridine reductase (DHPR), and pterin-4α-carbinolamine dehydratase (PCD).
The clinical symptoms and diagnostic methods vary depending on the specific enzyme deficiency, leading to different treatment approaches.
The deficiency of phenylalanine hydroxylase (PAH) results in the most common form of PKU, characterized by yellow hair, pale dry skin, and intellectual disabilities.
Literature reports indicate that approximately 98-99% of PKU patients in Europe and the United States have this type, with an incidence of about 1 in 10,000, although there are significant regional and ethnic differences.
In Taiwan, screening of 870,000 newborns shows an incidence of about 1 in 34,000, with only about 70-80% of patients having classic PKU.
The second to fourth enzyme deficiencies lead to a lack of the cofactor tetrahydrobiopterin (BH4) necessary for the conversion of phenylalanine to tyrosine.
Clinical symptoms include those of classic PKU, along with severe neurological symptoms (such as seizures), growth retardation, and increased susceptibility to infections.
The fifth deficiency also results in insufficient BH4, but the clinical symptoms are mild and may not require treatment.
Approximately 20-30% of PKU patients in Taiwan have BH4 deficiency, which differs significantly from results in Western countries, highlighting the need for differential diagnosis to ensure appropriate treatment.
2.
Treatment of Phenylketonuria
To prevent the sequelae of PKU, it is crucial to treat the condition as early as possible.
According to foreign literature, patients treated within one month have an average IQ of 95, while those treated at one to two months have an average IQ of 85; late or untreated patients have an average IQ of 53-45.
Based on domestic experience and international literature, the prognosis for BH4 deficiency is very good, especially regarding the control of neurological symptoms and growth development.
If treated during the neonatal period, patients can achieve IQ levels within the normal range.
Treatment approaches for different types of PKU are as follows:
(1) Classic PKU: A low-phenylalanine diet is implemented to maintain blood phenylalanine levels between 4-8 mg/dL, while also ensuring a balanced intake of protein and calories for normal growth.
The dietary control should be maintained as long as possible, at least until the age of six.
Female patients should continue this diet until after their reproductive years to prevent maternal PKU, which can lead to congenital disabilities in the next generation.
(2) BH4 synthesis deficiency (GTPCHI, PTPS): BH4 supplementation (1-5 mg/kg/day) is provided to maintain blood phenylalanine levels below 4 mg/dL.
Due to neurological symptoms, supplementation with central nervous system precursors such as L-dopa (5-15 mg/kg/day), 5-hydroxytryptophan (4-10 mg/kg/day), and carbidopa (1-2 mg/kg/day) is necessary.
Neurotransmitter medications should be gradually increased in small doses to reach the maximum tolerated dose for the patient.
(3) DHPR deficiency: Dietary control is similar to that of classic PKU, with BH4 and central nervous system precursor supplementation as in BH4 synthesis deficiency, along with folinic acid supplementation.
3.
Confirmation and Differential Diagnosis of Phenylketonuria
Newborn screening is the best method for early diagnosis of PKU.
The most effective screening method is measuring the phenylalanine levels in dried blood spots; if the concentration exceeds 2 mg/dL, further testing is warranted.
If phenylalanine levels continue to rise, confirmation and differential diagnosis should be performed.
When screening for amino acid metabolic disorders in newborns, it is essential to ensure that the infant has consumed adequate protein (breastfeeding for more than 48 hours) to avoid false negatives.
Confirmation of PKU should include:
(1) Clinical assessment by a pediatrician with specialized training.
(2) Blood amino acid analysis.
(3) Gas chromatography-mass spectrometry (GC/MS) analysis of urinary organic acids.
(4) High-performance liquid chromatography (HPLC) quantification of neopterin (N) and biopterin (B) in urine, calculating the proportion of biopterin as B% = [B/(B+N)] × 100%.
(5) Quantification of red blood cell DHPR activity.
(6) BH4 oral loading test: If blood phenylalanine levels drop below 2 mg/dL four to six hours after oral BH4 (7.5 mg/kg), the patient is considered responsive; if there is no decrease in phenylalanine levels, the patient is nonresponsive.

Differential diagnosis of PKU can be inferred if blood phenylalanine is elevated while tyrosine is normal or low, and abnormal metabolites of phenylketones are present in urine.
Further differentiation can be made as follows:
(1) Classic PKU: Normal (or slightly elevated) B%, unresponsive to BH4 oral loading test, normal DHPR activity.
(2) GTPCHI deficiency PKU: Normal B%, very low N and B levels, responsive to BH4 oral loading test, normal DHPR activity.
(3) PTPS or SR deficiency PKU: B% < 5%, responsive to BH4 oral loading test, normal DHPR activity.
(4) DHPR deficiency PKU: B% > 80%, partial response to BH4 oral loading test, very low DHPR activity.
(5) PCD deficiency PKU: Presence of a large amount of 7-biopterin in urine HPLC chromatograms.

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Reply Date: 2007/12/29