Phenylketonuria- A case report

Case details

A newborn male infant was diagnosed as having phenylketonuria (PKU), and immediately placed on diet low in phenylalanine ; careful compliance with the diet and frequent monitoring of the patient’s plasma Phenyl alanine level resulted in the level being maintained at the lower limit of the normal range. The patient appeared to be developing normally until 4 months of age, when he developed truncal hypotonia and spasticity of the limbs. Despite being on a low-phenylalanine diet, at 5 months the patient had several grand mal (epileptic) seizures. After an abnormal Phenyl alanine-loading test, the patient’s urine was found to have a markedly elevated urinary biopterin concentration.

Which of the following enzymes is most likely deficient in this patient?

A. Dihydropterin reductase

B. GTP cyclohydrolase I

C. Phenylalanine hydroxylase

D. Tryptophan hydroxylase

E. Tyrosine hydroxylase

Answer- The correct answer is A- Dihydropterin reductase. This enzyme catalyzes the conversion of Dihydrobiopterin to tetrahydrobiopterin (figure). Tetrahydrobiopterin (BH4), is oxidized to dihydrobiopterin by phenylalanine hydroxylase, as well as tyrosine hydroxylase and tryptophan hydroxylase (tryptophan 5-monooxygenase).  BH4 is the cofactor for phenylalanine, tyrosine, and Tryptophan hydroxylase. The latter two hydroxylase are essential for biosynthesis of the neurotransmitters dopamine and serotonin.

Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor tetrahydrobiopterine causes accumulation of phenylalanine in body fluids and the central nervous system (CNS).

In the given case, the patient, despite being put on a low-Phenyl alanine diet, exhibits neurologic problems resulting from an inability to synthesize catecholamines. This rules out classical phenylketonuria. If phenylalanine hydroxylase were deficient, a diet low in Phenyl alanine  would have improved the effects.

The present situation is due to  deficiency of  dihydrobiopterin reductase .

In 1–2% of infants with hyperphenylalaninemia, the defect resides in one of the enzymes necessary for production or recycling of the cofactor BH4 .These infants are diagnosed as having PKU, but they deteriorate neurologically despite adequate control of plasma phenylalanine. Plasma phenylalanine levels may be as high as those in classic PKU or in the range of milder forms of hyperphenylalaninemia. Neurologic manifestations, such as loss of head control, truncal hypotonia (floppy baby), drooling, swallowing difficulties, and myoclonic seizures, develop after 3 months  of age despite adequate dietary therapy.

Phenyl alanine to tyrosine conversion

Figure- Conversion of phenyl alanine to tyrosine

As regards other options

Since the urinary biopterine concentration is elevated in the given case, a deficiency in GTP cyclohydrolase I is also ruled out because that is an enzyme in the biosynthetic pathway of BH4.

Phenyl alanine hydroxylase, Tyrosine  hydroxylase, and Tryptophan hydroxylase activities would  also be low  in this patient because of a lack of BH4.

Yet  the most possible defect in this case is deficiency of Dihydrobiopterine reductase.

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