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Phenylketonuria (NORD)



Patient care

Information for patients and families

The Primary School
Glut1 Deficiency Foundation
The National Organization for Rare Disorders (NORD)

Phenylketonuria (NORD)


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High Yield Notes
7 pages

Phenylketonuria (NORD)

12 flashcards

USMLE® Step 1 style questions USMLE

4 questions

A 22-year-old primigravida at 26 weeks gestation comes to the office for routine prenatal care. The patient reports good fetal movement and has no complaints. She has been inconsistent with prenatal care following her initial visit at 12 weeks. An ultrasound for gestational dating at the time was consistent with her last menstrual period. The mother’s blood group is B-negative while the father’s is O-negative. The patient’s past medical history is significant for phenylketonuria. Prior to conceiving, she followed a phenylalanine-restricted diet. Temperature is 37.0°C (98.6°F), pulse is 92/min, respirations are 20/min, and blood pressure is 105/75 mmHg. An ultrasound reveals a fetus at 26 weeks with an estimated weight <10 percentile for gestational age. Laboratory evaluation reveals elevated phenylalanine levels. Which of the following pathologies is the fetus likely to suffer from based on the maternal history? 

External References

Content Reviewers:

Rishi Desai, MD, MPH

In Phenylketonuria, “Phenylketone" is a product of the amino acid phenylalanine, and “uria” means a substance present in urine. So people with phenylketonuria have phenylketones in their urine, and they develop symptoms like intellectual disability, psychiatric disorders, and seizures.

Now, amino acids are the basic building blocks that make up proteins. Phenylalanine is one of the essential amino acids, meaning our bodies can't make but must be acquired through food that contains protein. Since the body can’t store amino acids, any excess amino acids are converted into glucose or ketones and used for energy.

Phenylalanine is converted to tyrosine by phenylalanine hydroxylase enzyme, which needs the co-factor tetrahydrobiopterin to work. Tyrosine is then used to synthesize various molecules. It is turned into dopamine, which is a neurotransmitter that neurons use to communicate, norepinephrine and epinephrine, which are also neurotransmitters and hormones used by the sympathetic nervous system, and the pigment melanin, which gives color to the skin, hair, and eyes.

Alternatively, when phenylalanine levels in the blood are high, it gets converted by the enzyme phenylalanine transaminase into phenylketones such as phenylpyruvate, phenyllactate, and phenylacetate.

There are three types of Phenylketonuria. Classic, Tetrahydrobiopterin deficient, and maternal. Classic Phenylketonuria, which can be mild or severe, and Tetrahydrobiopterin deficient Phenylketonuria are both autosomal recessive genetic disorders which affect the phenylalanine hydroxylase enzyme.

In the Classic form, there’s a deficiency in the enzyme and individuals with the mild form have a more functional enzyme than those with the severe form so they can tolerate some phenylalanine in their diet.

In the Tetrahydrobiopterin deficient form, the co-factor Tetrahydrobiopterin is deficient and as a result the enzyme can’t work. Without phenylalanine hydroxylase, phenylalanine cannot be converted into tyrosine which causes phenylalanine levels to rise and tyrosine levels to fall. Without tyrosine in the body there’s no melanin so the skin, eyes, and hair lose their color.

Also, it turns out that phenylalanine uses the same transporters to get across the blood brain barrier to other amino acids, tyrosine and tryptophan. Tyrosine is needed to synthesize dopamine and norepinephrine, and tryptophan is needed to synthesize neurotransmitter serotonin. As phenylalanine levels rise, it occupies all the transporters, making it hard for tyrosine and tryptophan to get across the blood brain barrier. As a result, dopamine, norepinephrine, and serotonin levels in the brain all begin to fall, and that leads to problems in brain development and intellectual disability.

In phenylketonuria, lipoproteins which are used to transport fat through blood and cholesterol are also affected. It’s thought that phenylalanine impairs cholesterol synthesis which leads to low levels of cholesterol, both low density lipoproteins (LDLs) and high density lipoproteins (HDLs). These are all important components of myelin which is the outer insulating layer of neurons that helps facilitate rapid impulses. The lack of myelin further contributes to problems with brain development.


Phenylketonuria (PKU) is an autosomal recessive amino acid metabolism disorder involving impaired metabolism of the amino acid phenylalanine, caused by the absence or reduced activity of phenylalanine hydroxylase. In PKU toxic levels of phenylalanine and phenylketone build up in the body and tyrosine levels drop.

Symptoms include a musty odor of sweat and urine, intellectual disability, seizures, behavioral problems, and other neurological symptoms. In pregnant females, PKU can affect the fetus - causing heart disease, growth problems, intellectual disability, and microcephaly. Treatment is based on a diet with low levels of phenylalanine and supplementing with tyrosine and tetrahydrobiopterin.