CASE 3: PHENYLKETUNURIA

This is a case of a 4 month old infant who was born normal but was noted to be less than
normally attentive to her surroundings in the last several weeks.

Observations:
 Psychomotor maturation seemed to be delayed
 Tremor in the extremities
 Twitching movements in the crib

Laboratory Findings:
 Musty odor urine
 Presence of excess phenyalanine in the blood (elevated to 18mg/dl)

Diagnosis:
Phenylketunuria

BIOCHEMICAL BASIS:

In Phenylketunuria, the lack of the enzyme phenylalanine hydroxylase prevents the

conversion of Phenylalanine to tyrosine which is the precursor of essential metabolites for the
development of the body such as thyroxine, DOPA and melanin. When Phenylalanine is not
converted to tyrosine, it shifts into a secondary pathway wherein it undergoes transamination and
forms Phenylpyruvate which accumulates in the body and causes other manifestations of the
disease.
QUESTIONS:
1. What is the biochemical defect in this case?
Phenylketunuria (PKU) is an autosomal recessive disorder of metabolism caused
by a deficiency of the enzyme phenylalanine hydroxylase, which is the one responsible
for processing the essential amino acid phenylalanine to be converted to tyrosine. The
lack of this liver enzyme causes a buildup of phenylalanine in the body, which over time
can lead to mental retardation, organ damage and abnormal posture. Phenylketunuria may
lead into more severe conditions such as severe mental retardation and may also cause
neurologic symptoms.

2. Why is the odor of the patient’s urine musty?

When phenylalanine is not converted to tyrosine, this essential amino acid
undergoes transamination and forms Phenylpyruvate. Together with Phenylalanine,
phenylpyruvate then accumulates in the blood causing the Phenylalanine serum level to
increase. Phenypyruvate then undergoes decarboxylation to form phenylacetate and
phenyl lactate. Phenylpyruvate is excreted in the urine and causes a musty odor which is
useful in the diagnosis of PKU.

3. Explain the neurologic manifestations of the patient.

A major clinical manifestation in PKU patients is impaired cognitive development
and function such as mental retardation. This condition is due to the accumulation of the
amino acid phenylalanine that becomes a major donor of amino groups in
aminotransferase activity and depletes neural tissue of α-ketoglutarate. This absence of α-
ketoglutarate in the brain shuts down the TCA cycle and the associated production of
aerobic energy, which is essential to normal brain development. Also, the elevated
phenylalanine levels have a direct effect on power production, protein synthesis and
neurotransmitter homeostasis in the developing brain, Phenylalanine also inhibits the
transport of neutral amino acids across the blood-brain barrier which will result to a
selective amino acid deficiency in the cerebrospinal fluid. Thus, the neurologic
manifestations of PKU are caused by the effect of substrate accumulation of
Phenylalanine on cerebral metabolism.

4. What is the mainstay of therapy for this condition?

Dietary restriction of phenylalanine is the mainstay of therapy in PKU and
treatment should be continued indefinitely. Also, supplementation of other essential
amino acids, vitamins, minerals, and energy intake, using medical foods and low-protein
foods is prescribed for this condition to prevent other nutritional deficiencies such as
protein/calorie malnutrition, osteoporosis, and catabolism. Aspartame must be avoided
because phenylalanine is one of the components of aspartame.