bubble_chart Overview

Phenylketonuria is a congenital metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH) in the liver due to chromosomal gene mutations, leading to impaired phenylalanine (PA) metabolism and resulting in injury to the central nervous system.

bubble_chart Etiology

Phenylketonuria (PKU) is a type of inborn metabolic disorder first reported in 1934 by Dr. Folling from Norway. This condition is caused by a chromosomal gene mutation leading to a deficiency of phenylalanine hydroxylase (PAH) in the liver, which results in impaired phenylalanine (PA) metabolism. Phenylalanine is one of the essential amino acids for the human body. After ingestion through food, part of it is utilized for protein synthesis, while the rest is converted into tyrosine by the action of hepatic phenylalanine hydroxylase, which is further transformed into important physiological substances such as dopamine, adrenaline, and melanin.

Due to the lack of phenylalanine hydroxylase in the liver of patients with this disorder, phenylalanine cannot be converted into tyrosine and accumulates in the body, causing injury to the central nervous system. At the same time, it leads to impaired synthesis of physiological substances such as tyrosine, dopamine, adrenaline, and melanin, resulting in a series of pathological changes.

bubble_chart Pathological Changes

The brain exhibits progressive, diffuse sexually transmitted disease changes, involving both gray and white matter. Firstly, there is a disturbance in brain maturation, characterized by incomplete cortical differentiation, gray matter heterotopia, and a reduction in dendritic branching and synaptic spines. Secondly, there is impaired myelination accompanied by glial cell proliferation and spongiform degeneration. Additionally, there is a reduction in pigment in the substantia nigra and locus coeruleus.

bubble_chart Clinical Manifestations

The primary harm of PKU is damage to the nervous system. Untreated infants appear normal at birth but may exhibit early symptoms such as vomiting, dysphoria, irritability, and varying degrees of developmental delays within the first few months. Significant intellectual developmental delays become apparent between 4 to 9 months, with language development being particularly affected. Nearly half of the cases are accompanied by epileptic seizures, about one-third of which are infantile spasms, mostly occurring before 18 months of age. Approximately 80% show abnormal EEG results, which may include hypsarrhythmia or focal spikes. The form of epileptic seizures may change with age. The majority of affected children exhibit psychiatric and behavioral abnormalities such as depression, hyperactivity, and autistic tendencies. Without timely and appropriate treatment, this will ultimately lead to grade II to severe grade III intellectual disability.

Neurological signs are less common but may include microcephaly, increased muscle tone, abnormal gait, hyperreflexia, fine hand tremors, and repetitive limb movements. Due to a lack of melanin, affected children often have blond hair, light skin, and pale irises. The phenylalanine accumulated in the blood is metabolized via alternative pathways into phenylpyruvic acid and phenylacetic acid, which are excreted in large quantities in the urine, giving it an unpleasant "mousy" odor. Additionally, affected children are prone to complications such as eczema, vomiting, and diarrhea.

bubble_chart Diagnosis

Phenylketonuria is one of the earliest proposed treatable inherited metabolic sexually transmitted diseases. If diagnosed and treated early, it can prevent intellectual injury in affected children, allowing them to live a normal life. The diagnosis of affected children is mainly based on the measurement of blood phenylalanine levels, which are typically above 20mg/dl in these children.

1. Guthrie Method: This is the earliest, most economical, and practical semi-quantitative method for measuring blood phenylalanine. The principle is as follows: the growth of Bacillus subtilis (ATCC-6633) requires phenylalanine. On a medium containing β-2-thienylalanine (an inhibitor), Bacillus subtilis cannot grow. When a blood filter paper specimen is placed on the medium, the phenylalanine in the blood antagonizes the inhibitor in the medium, resulting in a distinct bacterial growth ring around the blood filter paper. The concentration of phenylalanine in the blood filter paper can be determined based on the size of the bacterial growth ring.
2. Fluorometric Method: A quantitative method for measuring phenylalanine.
3. Amino Acid Chromatography: A relatively simple quantitative method for phenylalanine using finger or heel blood.
4. Amino Acid Analysis: A quantitative method that employs an amino acid analyzer for automated blood amino acid analysis. It can differentiate amino acid metabolic disorders based on the quantitative levels of phenylalanine, tyrosine, and other amino acids, as well as the ratio of branched-chain to aromatic amino acids. Amino acid analysis plays a crucial role in distinguishing between types of phenylketonuria and identifying hyperphenylalaninemia.
5. Phenylalanine Tolerance Test: Oral administration of 100mg/kg phenylalanine, followed by blood tests for phenylalanine levels 1-4 hours later. If phenylalanine levels increase while tyrosine levels decrease, the diagnosis can be confirmed.

Classic cases show positive results in urine ferric chloride and 2,4-dinitrophenylhydrazine tests. However, urine tests are easily influenced by other factors, have poor stability, and a high false-positive rate, which can lead to fistula disease misdiagnosis. Therefore, they should only be used as a reference. Classic PKU should be differentiated from various forms of hyperphenylalaninemia caused by different gene mutations.

bubble_chart Treatment Measures

Low-phenylalanine dietary therapeutics is currently the only method for treating classical PKU, with the aim of preventing brain injury. The principle of dietary therapeutics is to ensure that phenylalanine intake meets the minimum requirements for growth and metabolism. Due to the deficiency of phenylalanine hydroxylase in the patient's liver, phenylalanine cannot be metabolized normally into tyrosine, leading to its accumulation in the blood and causing neurological damage. Additionally, phenylalanine is metabolized through alternative pathways to produce phenylpyruvic acid and phenylacetic acid, which are excreted in large quantities in the urine, giving the child's urine a mouse-like odor. Phenylalanine is an essential amino acid, and insufficient supply can lead to growth retardation and, in severe cases, death. Therefore, phenylalanine intake must neither be too high nor too low. Since natural proteins contain 4–6% phenylalanine, the intake of natural proteins must be strictly controlled, and low- or phenylalanine-free milk powder and protein powder should be used as the primary protein sources for PKU children. Of the total protein intake, 80% should come from artificial proteins and 20% from natural proteins, while ensuring sufficient caloric intake. Treatment must strictly limit phenylalanine intake to prevent abnormal accumulation of phenylalanine and its metabolites, while also meeting the body's needs to ensure the child's normal development. For infants, breast milk remains the best diet, and providing calculated amounts of breast milk is highly beneficial for the child's development, so stopping breastfeeding should be avoided.

Dietary treatment must also consider individual differences. Since the degree of phenylalanine hydroxylase deficiency varies greatly among children, dietary treatment must adhere to individualized principles. Additionally, due to differences in protein, caloric, phenylalanine requirements, and tolerance levels across age groups, dietary plans should be formulated and adjusted based on each child's age, weight, and blood Phe concentration to maintain phenylalanine levels within an appropriate range. Generally, dietary plans for children under one year old should be adjusted monthly, those over one year old every two months, and school-aged children every 3–4 months.

When formulating a dietary plan, first calculate the daily requirements for protein, phenylalanine, and calories based on the child's condition, then arrange the specific diet.

Regarding the duration of dietary treatment, it was previously believed that treatment could stop after brain development matured (i.e., around age 8). However, recent clinical practice has shown that stopping treatment too early can lead to intellectual regression in children, and adult patients may exhibit various degrees of psychiatric and behavioral abnormalities. Particularly in female patients, high blood phenylalanine levels during pregnancy can cause fetal brain damage. Therefore, the current international consensus advocates continuing treatment at least until the child reaches puberty, with lifelong treatment being ideal. Dietary restrictions can be appropriately relaxed in adulthood.

Currently, China has low- or phenylalanine-free formulations, with the most widely used being government-approved special nutritional diets for PKU—such as the Visdol series of low- or phenylalanine-free milk powder, protein powder, starch, and beverages. Other domestic manufacturers have also developed similar products. The quality of these formulations significantly impacts treatment efficacy, so careful selection is essential.

To ensure therapeutic efficacy, blood phenylalanine concentration should be regularly monitored (see Table 4). The normal blood phenylalanine concentration is 1-2 mg/dl, while untreated classic PKU typically shows blood phenylalanine levels >20 mg/dl, mostly ranging between 20-50 mg/dl, with >50 mg/dl being rare. During dietary treatment, blood Phe concentration should be monitored 1-2 times per week in the first month, then monthly thereafter. The key to dietary treatment lies in controlling the blood phenylalanine concentration in PKU children and ensuring adequate protein and calorie intake. Insufficient protein and calorie supply can lead to nutritional deficiencies, causing protein breakdown in the body, which similarly elevates blood Phe levels. Additionally, regular follow-up tests should include hemoglobin, albumin, electroencephalogram (EEG), physical and intellectual development assessments. When necessary, blood amino acid analysis should be performed to measure tyrosine levels and the ratio of branched-chain amino acids to aromatic amino acids.

In addition to dietary therapy, the treatment of atypical phenylketonuria should also include supplementation with various neurotransmitters, such as BH4, dopamine, serotonin, folic acid, etc.

For children with other complications, symptomatic treatment should be provided. For example, children with epileptic seizures should start regular anti-epileptic drug treatment as early as possible. Children with eczema may recover spontaneously after satisfactory control of blood Phe levels. If the eczema is severe, topical Yaodui treatment can be administered.

Intellectual disability caused by brain injury is irreversible, but with cognitive rehabilitation, varying degrees of improvement can be achieved, and some may even show significant progress. For families with the means, cognitive rehabilitation training for the child can be considered. For children with grade III intellectual disability, the goal of training is to develop basic self-care abilities, while for those with mild grade II disability, survival skills training should also be provided in addition to life skills.

Early detection and early treatment yield the best outcomes for PKU children. Some can achieve normal intellectual levels, but no treatable child should be overlooked. Previous textbooks suggested that treatment was unnecessary for children over six months old, but our experience shows that children of any age can achieve varying degrees of intellectual improvement and self-care abilities with treatment.

For suspected cases in outpatient clinics, screening and diagnosis should still be conducted, followed by treatment to reduce the population with intellectual disabilities.

bubble_chart Prevention

Avoid consanguineous marriages, and heterozygous individuals should not marry. Conduct newborn screening to detect PKU children early and initiate treatment promptly to prevent intellectual disabilities. For families with a history of PKU, prenatal diagnosis can be performed during subsequent pregnancies. This involves collecting fetal chorionic villi or amniotic fluid in the early or intermediate stage [second stage] of pregnancy and using genetic diagnosis to determine whether the fetus is normal, a carrier, or affected, thereby making a decision to continue or terminate the pregnancy.

Currently, about 80% of gene mutations in PKU children in China have been identified, while approximately 20% remain unclear. Each PKU family carries two mutant genes, so genetic diagnosis can yield three possible results:

1. Both mutant genes can be clearly diagnosed.
2. One mutant gene can be clearly diagnosed, while the other remains unclear.
3. Neither mutant gene can be clearly diagnosed.

The first two outcomes allow for prenatal diagnosis, while the third, under the premise of excluding non-classical PKU, may also permit prenatal diagnosis through linkage analysis for indirect genetic diagnosis.

Since PKU is a genetic disorder, genetic diagnosis requires blood samples from both the child and parents. Additionally, due to the vast variety and complexity of mutant genes, genetic diagnosis should be conducted six months to a year before attempting another pregnancy. This ensures that targeted prenatal diagnosis can be performed during pregnancy based on the genetic diagnosis results.