CLINICAL CASES
345
[37.3]
Which treatment regimen would be most beneficial to this patient in
Question 37.2?
A. A low-Phe diet with biopterin supplementation
B. A low-Phe diet with cobalamin (vitamin B12) supplementation
C.
A low-Phe diet +
L
-dopa (3,4-dihydroxyphenylalanine)
D. A low-Phe diet +
L
-dopa and 5-hydroxytryptophan
E. A diet completely free of Phe
A nsw ers
[37.1]
E. The patient exhibits signs of a defect in the urea cycle. The pres-
ence of elevated uracil in addition to ammonia and glutamine points
to an accumulation of carbamoyl phosphate. If ornithine transcar-
bamoylase is deficient, carbamoyl phosphate will accumulate in the
mitochondria and leak into the cytosol, providing the starting com-
pound for the synthesis of uracil.
[37.2]
A. The patient, despite being put on a low-Phe diet, exhibits neuro-
logic problems resulting from an inability to synthesize catecholamine
and indoleamine neurotransmitters. This is caused by a deficiency in
dihydropteridine reductase (DHPR). DHPR regenerates tetrahydro-
biopterin (BH4), which is oxidized to dihydrobiopterin by phenylala-
nine hydroxylase, as well as tyrosine hydroxylase and tryptophan
hydroxylase (tryptophan 5-monooxygenase). If phenylalanine hydroxy-
lase were deficient, a diet low in Phe would alleviate the effects.
Since the urinary biopterin concentration is elevated, a deficiency in
GTP cyclohydrolase I is eliminated because that is an enzyme in the
biosynthetic pathway of BH4. Phe hydroxylase, Tyr hydroxylase, and
Trp hydroxylase activities are low because of a lack of BH4.
[37.3]
D. Because of the DHPR deficiency, the activities of Phe hydroxylase
and Tyr hydroxylase are low, hence the synthesis of catecholamine neu-
rotransmitters are depressed. The synthesis of the indoleamine neuro-
transmitter serotonin is also depressed because BH
4
is required for the
hydroxylation of tryptophan. The best treatment is to decrease the
Phe load by a low-Phe diet and provide the precursors for the cate-
cholamine and indoleamine neurotransmitters that occur after the
enzymes affected by the deficiency of BH4, which would be
L
-dopa
and 5-hydroxytryptophan.
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