Phenylketonuria (PKU) is an inherited disorder caused by a deficiency of the enzyme phenylalanine hydroxylase, resulting in an inability to metabolize the essential amino acid phenylalanine. Left untreated, it can cause severe intellectual disability. It is diagnosed through newborn screening and treated with a phenylalanine-restricted diet. For pregnant women with PKU, careful control of phenylalanine levels through diet is needed to prevent complications in the fetus like intellectual disability and birth defects. The case study describes a woman with mild PKU who was able to deliver a healthy infant by maintaining her phenylalanine-restricted diet during pregnancy.

1. Inherited and Congenital Disorders
Phenylketonuria (PKU)

2. Introduction
• PKU is an inborn error of protein metabolism that results from an impaired
ability to metabolise the essential amino acid phenylalanine.
• Incidence:

UK 1/14,000 births.

High frequency: northern and eastern Europe, Italy, China.
• Morbidity:

Untreated: severe mental retardation.

3. Pheynlalanine

Essential amino acid

Normal biosynthetic route;

Main route (oxidation to tyrosine by
phenylalanine hydroxylase (PAH) enzyme and
the reduced cofactor tetrahydrobiopterin (BH4).

Minor route (transamination to phenylpyruvate
and subsequent further metabolism).

Two main reasons for a lack of PAH activity;

Genetic defect in PAH gene.

Generation of inadequate amounts of the BH4.
Fig.1:Hydroxylation of phenylalanine to form
tyrosine

4. Genetics of PKU
• PKU is an autosomal recessive
disorder and is the result of
mutations in the PAH gene,
located in 12q24.1.
• Deficiency of PAH leads to
hyperphenylalaninaemia.
Fig. 2: Ideogram of chromosome 12 depicting approximate location
of PAH on the long portion.

5. Classification of PKU
• There are certain variations in the severity of the condition amongst those
with PKU. These variations depend upon the various mutations on the gene
responsible for PKU.

Classic.
• Rare forms of Hyperphenylalaninaemia:

Reductase deficiency.

Other enzymes involved in BH4 biosynthesis.

6. Clinical Manifestations

Most appear normal at birth.

Progressive developmental delay.

Later infancy and childhood: vomiting, mousy odour, seizures, and severe
behavioural disorders.

Failure of dietary treatment may deteriorate:
 Motor function.

Cognitive ability.

Neuropsychological function.
• Physical

Mental retardation.

Hypopigmentation of hair and skin.

Eczema.

7. Laboratory Investigation
• PAH deficiency can be diagnosed by newborn
screening based upon detection of
hyperphenylalaninaemia using heel prick.
• Samples are tested by Tandem mass spectrometry
• Normal phenylalanine level of infants in the first week
of life is <200 umol /L.
• Tyrosine is measured in the same blood sample to
identify 0.2-0.3% of infants with secondary
hyperphenylalaninaemia due to prematurity,
intravenous feeding, sepsis, liver disease, tyrosinaemia,
or galactosaemia.
• In 1–2% the tetrahydrobiopterin is deficient. It is tested
for in all infants with raised phenylalanine.
• Molecular genetic testing of the PAH gene is used
primarily for genetic counselling purposes.
Fig. 3: Heelprick samples for PKU
analysis

8. Maternal PKU
• Pregnant mothers with untreated PKU can give birth to children with
severe defects;

congenital malformations.

microcephaly.

severe mental retardation.
• Careful treatment with diet is compatible with normal outcome for
foetus.

9. Management
• Treatment of manifestations:

a low-protein diet and use of a Phe -free diet.
• Surveillance:

regular monitoring of Phe and Tyr concentrations in individuals with classic PKU.
• Agents/circumstances to avoid:

aspartame, an artificial sweetener that contains phenylalanine.
• Testing of relatives at risk.
• Treatment alternatives:

Gene therapy (not yet applicable).

Enzyme replacement therapy.

10. Case Study
 A 2 month pregnant, 20 year old female.
 Mild to moderate PKU.
 Diagnosed with PKU shortly after birth (700 umol/L) and was immediately placed
on a Phe-restricted medical diet.
 Blood Phe relatively stable during course of pregnancy.
 7 months later, a male infant, with expected size and weight, normal Phe levels and
no obvious birth defects, was delivered.
 Genetic testing showed that he had heterozygosity of the PAH gene with one
normal allele..