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Phenylketonuria (PKU) is a rare, inherited, autosomal recessive disorder where the enzyme phenylalanine hydroxylase (PAH) does not work properly. This causes the amino acid phenylalanine (Phe) to build up to toxic levels, leading to brain damage and other complications if neglected and untreated. With newborn screening, early treatment, and a strict lifelong lowPhe diet (plus special medical supplements), most people with PKU can lead a normal life and independently (1).

What PKU:

PKU is by birth error of metabolism where the body fails to convert phenylalanine into tyrosine because of deficiency of the enzyme phenylalanine hydroxylase (PAH). Phenylalanine is an essential amino acid primarily present in protein-rich foods and in the artificial sweetener aspartame. Because PAH is deficient, Phe accumulates in the blood and brain, producing toxic metabolites and disrupting brain development and function. Untreated, this leads to severe, IRREVERSIBLE intellectual disability and neurological problems causing difficulties with normal life cycle of people (1).

The PAH gene and enzyme:

PAH is on chromosome 12 (region q22–24.1). More than 950 PAH variants have been identified, with the majority being missense variants that lead to enzyme misfolding or loss of function. Severity of PKU correlates with residual PAH activity and genotype:

Very low/absent activity → classic (severe) PKU

Partial activity → mild or moderate PKU / hyperphenylalaninemia

Severity types

Mayo Clinic and the guidelines distinguish types by severity:

1. Classic PKU

2. Little or no usable PAH enzyme

3. Very high untreated Phe levels and highest risk of severe brain damage.

4. Milder forms (mild or moderate PKU non-classic hyperphenylalaninemia): Some residual enzyme function. Phe levels are elevated but lower; brain damage risk is lower but still present without control.

Diagnosis and Classification

Diagnostic steps.

Positive newborn screen for elevated Phe → urgent referral to metabolic center.

Confirmatory tests:

• Quantitative plasma amino acids (Phe level)

• Assessment for BH4 (tetrahydrobiopterin) deficiencies and other causes of hyperphenylalaninemia (via pterin analysis, DHPR activity, etc.)

• Genetic testing (PAH genotyping): not strictly required for diagnosis, but valuable to:

• Predict metabolic severity

• Help predict BH4 responsiveness

Treatment Principles: Start Early, Treat for Life

Neurological damage begins early; delays in treatment significantly reduce IQ.

Guideline recommendation:

Start treatment as early as possible, and ideally before day 10 of life.

Lifelong treatment. Because there is no strong evidence that stopping diet in adults is safe, guidelines recommend treatment for life.

The PKU Diet and Nutritional Management

Core dietary strategy. The cornerstone of PKU management is a strict, low phenylalanine (low protein) diet, customized to each individual’s Phe tolerance (2).

Complications and Long-Term Issues

If untreated (or poorly controlled) complications include:

Seizures, tremors, spastic paraparesis, behavioural, emotional, and social problems, psychiatric disorders, white matter abnormalities, leukoencephalopathy, vision loss (reported in some late-treated adults), overall major developmental and functional impairment, higher rates of overweight and obesity, especially in females.

These findings strongly support lifelong structured follow-up and optimizing metabolic control.

Pharmacologic and Emerging Treatments

Sapropterin is a synthetic form of BH4, the cofactor for PAH. It acts as a pharmacological chaperone to improve residual PAH activity in some genotypes.

Only a subset of patients (BH4 responders) benefit with lower blood Phe levels for the same dietary intake, or increased natural protein (Phe) tolerance while maintaining target Phe levels Responsiveness can be: predicted partially from genotype. Confirmed with BH4 loading tests.

Pregnancy and Maternal PKU

Women with PKU who become pregnant face a special risk called maternal PKU syndrome. The fetus may not have PKU, but if maternal Phe is high, Phe crosses the placenta and is teratogenic. Universal newborn screening, very early treatment, and lifelong adherence to a low Phe diet with medical supplements prevent the profound disability once universally seen in PKU.

Despite proper care, mild neurocognitive and psychosocial problems may still arise, so maintaining strict metabolic control and ongoing multidisciplinary follow-up throughout life is advised.

Special attention to women of childbearing age is critical to prevent maternal PKU syndrome and protect future children.

Pharmacologic treatments such as sapropterin and new emerging therapies are broadening the range of options, especially for adults, but dietary management continues to be the primary treatment approach.

References:

1. Anton-Păduraru DT, Trofin F, Chis A, Sur LM, Streangă V, Mîndru DE, Dorneanu OS, Păduraru D, Nastase EV, Vulturar R. Current Insights into Nutritional Management of Phenylketonuria: An Update for Children and Adolescents. Children (Basel). 2025 Feb 7; 12(2):199. doi: 10.3390/children12020199. PMID: 40003301; PMCID: PMC11854529.

2. Phenylketonuria. Website “New World Encyclopedia (NWE)”. – URL: https://www.newworldencyclopedia.org/entry/Phenylketonuria (data accessed: 12.12.2025)

*The review article has been written under the guidance of Associate Professor ofbiology department of Orenburg State Medical University, Cand. Sc. (Biology), G.F. Kolchugina

*Данная обзорная статья написана под руководством доцента кафедры биологии Оренбургского государственного медицинского университета, кандидата биологических наук Г.Ф. Кольчугиной.