How to diagnose phenylketonuria?

Written by Yan Xin Liang

Pediatrics

Updated on April 03, 2025

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Phenylketonuria is a treatable hereditary metabolic disease, where our primary goal is early diagnosis and treatment. Currently, a universal newborn screening system has been widely implemented. The standard procedure requires that after three days of breastfeeding, peripheral blood is collected from the newborn's heel, dropped onto specialized blood collection filter paper, and, once dried, sent to a screening laboratory to measure the phenylalanine concentration. If the phenylalanine concentration exceeds the cutoff value, further differential diagnosis and confirmation are conducted. Treatment typically starts two to three weeks after birth, and the prognosis is good. Additionally, diagnostic tests for phenylketonuria include urine ferric chloride, 2,4-dinitrophenylhydrazine tests, urinary purine profile analysis, and tetrahydrobiopterin loading test. Another method is through DNA analysis.

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Written by Hu Qi Feng

Pediatrics

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Mechanism of phenylketonuria

Phenylketonuria is characterized by reduced activity of phenylalanine hydroxylase, which fails to convert phenylalanine to tyrosine, causing extremely elevated levels of phenylalanine in the blood, cerebrospinal fluid, and tissues. This leads to the production of large amounts of phenylpyruvic acid, phenylacetic acid, phenyllactic acid, and p-hydroxyphenylacetic acid via alternative pathways. High concentrations of phenylalanine and its metabolic products can cause brain damage, which manifests as developmental intellectual disabilities, changes in skin and hair pigmentation, and a mousy urine odor, all part of a clinical syndrome.

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Written by Yan Xin Liang

Pediatrics

1min 2sec

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Causes of Phenylketonuria

The cause of phenylketonuria is that phenylalanine is an essential amino acid for the human body. Some of the phenylalanine ingested is used for protein synthesis, while another part is converted into tyrosine by the action of phenylalanine hydroxylase. Only a small amount of phenylalanine undergoes a secondary metabolic pathway and is converted into phenylpyruvate under the action of transaminase. Due to the reduced activity of phenylalanine hydroxylase in affected children, phenylalanine cannot be converted into tyrosine, leading to an extremely high concentration of phenylalanine in blood, cerebrospinal fluid, and tissues. This, through a bypass metabolic pathway, results in the production of a large amount of phenylpyruvate, phenylacetate, phenyllactate, and p-hydroxyphenylacetate. The high concentration of phenylalanine and its metabolic products then leads to brain damage, which is the cause of the disease.

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Written by Hu Qi Feng

Pediatrics

45sec

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Phenylketonuria Clinical Symptoms

Phenylketonuria may appear normal at birth, but symptoms usually start to appear between three to six months, with the symptoms becoming most evident at one year old. These are often manifestations of the nervous system, with prominent developmental delays in intelligence. The IQ is often lower than normal, and there may be abnormal behaviors, minor epileptic seizures, and, in a few children, increased muscle tone and hyperactive tendon reflexes. Due to insufficient melanin synthesis a few months after birth, affected children’s hair color changes from black to yellow, their skin is fair, and skin eczema is relatively common. Due to the elevated excretion of phenylacetic acid in urine and sweat, there is a distinct mouse-like urine smell.

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Written by Zeng Hai Jiang

Pediatrics

1min 1sec

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Does phenylketonuria require chromosome testing?

Phenylketonuria is usually screened during the neonatal period through routine blood testing, where the level of phenylalanine in the blood is measured to screen each newborn. This enables early diagnosis and treatment, hence reducing the occurrence of intellectual disabilities. Phenylketonuria can also be screened prenatally before the birth of the newborn. It is an autosomal recessive genetic disorder, closely related to chromosomal abnormalities. Therefore, prenatal screening can be conducted by amniocentesis between the 16th to 20th weeks of pregnancy. Chromosomal abnormalities detected through the amniocentesis indicate that the fetus carries the pathogenic gene, meaning the child will be born with phenylketonuria. If both parents carry related genes, it is crucial to undergo prenatal screening and chromosomal analysis to eliminate the risk of the fetus developing the condition.

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Written by Yan Xin Liang

Pediatrics

40sec

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Phenylketonuria patients lack phenylalanine hydroxylase.

Phenylketonuria is an autosomal recessive genetic disorder caused by mutations in the phenylalanine hydroxylase gene, leading to reduced enzyme activity and resulting in the accumulation of phenylalanine and its metabolic products in the body, causing the disease. Phenylketonuria is the most common congenital amino acid metabolism disorder, clinically presenting with intellectual developmental delays, lighter skin and hair pigmentation, and a musty urine odor. The disease is mainly caused by mutations in the phenylalanine hydroxylase gene, leading to reduced enzyme activity.