"Peripheral" tetrahydrobiopterin deficiency with hyperphenylalaninaemia due to incomplete 6-pyruvoyl tetrahydropterin synthase deficiency or heterozygosity.

Four patients in three families with "peripheral" tetrahydrobiopterin deficiency were investigated. They were characterized biochemically by a tetrahydrobiopterin-responsive hyperphenylalaninaemia, a high neopterin/biopterin ratio in urine and plasma, and normal or elevated concentrations of biopterin, homovanillic acid, and 5-hydroxyindole acetic acid in cerebrospinal fluid. From measurements of the activity of erythrocyte 6-pyruvoyl tetrahydropterin synthase (PTS, formerly called phosphate-eliminating enzyme) and phenylalanine loading tests in the patients and their parents, one patient was demonstrated to be heterozygous for PTS deficiency. The others were obviously genetic compounds (allelism) with incomplete PTS deficiency. Three of the children developed normally, two of them under treatment with tetrahydrobiopterin. In the latter two patients, significantly lower concentrations of biopterin, homovanillic acid, and 5-hydroxyindole acetic acid in cerebrospinal fluid were noted at age 7 months (when treatment was interrupted) than those observed at 3 and 5 weeks, respectively. The infant who is heterozygous for PTS deficiency was born small for gestational age and showed a moderately delayed psychomotor development. It is concluded that "peripheral" tetrahydrobiopterin deficiency is caused by a partial PTS deficiency with sufficient activity to cover the tetrahydrobiopterin requirement of tyrosine 3-hydroxylase and trytophan 5-hydroxylase in brain but not enough for phenylalanine 4-hydroxylase in liver. For therapy, tetrahydrobiopterin, 2-5 mg/kg in a single oral dose per day, is recommended to keep plasma phenylalanine normal. A careful observation of the mental development is indicated.