SUMMARY There is a defect in tetrahydrobiopterin metabolism in brains from subjects with senile dementia of Alzheimer type compared to age-matched controls. This defect results in lowered total biopterin concentrations in brain. Brains from subjects with senile dementia of Alzheimer type retain their ability to synthesis neopterin and have normal dihydropteridine reductase activity, indicating a specific loss of ability to convert dihydroneopterin triphosphate to tetrahydrobiopterin.The synthesis of dopamine and noradrenaline in the brain is dependent upon the activity of tyrosine hydroxylase, and this in tum is regulated by the concentration of the hydroxylase cofactor, 5,6, 7, Protein was measured by the biuret method. Each brain sample was assayed for dihydropteridine reductase, BH4 synthesis activity, total neopterin and total biopterin.

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The retention of radioactivity after doses of 14C- and 3H-labelled folic acid is described. Radioactivity was retained in liver, kidney and gut of rats for some time after administration of the dose. The retained radioactivity could not be displaced by large doses of unlabelled folic acid or unlabelled 5-methyltetrahydrofolate. 14C- and 3H-labbelled folates showed similar chromatographic behaviour onion-exchange chromatography to 5-methyltetrahydrofolate, and on ion-exchange and gel-permeation chromatography to synthetic pteroylhepta-gamma-glutamate.

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SUMMARY We describe a method of screening for dihydropteridine reductase deficiency and dihydrobiopterin synthesis deficiency-the two inherited defects that cause tetrahydrobiopterin deficiency-using blood spots on Guthrie cards. Dihydropteridine reductase deficiency may be identified positively, and a biopterin value of <6-0 [ig/l in the presence of hyperphenylalaninaemia indicates further investigation for dihydrobiopterin synthesis deficiency.Tetrahydropbiopterin deficiency can arise from defective synthesis of dihydrobiopterin,' 2 or from lack of dihydropteridine reductase activity,23 and is a cause of neonatal hyperphenylalaninaemia. Routine screening for phenylketonuria depends upon detection of raised phenylalanine values but does not distinguish hyperphenylalaninaemia arising from tetrahydrobiopterin deficiency from the far more common cause of hyperphenylalaninaemia, phenylalanine hydroxylase deficiency. Tetrahydrobiopterin is the cofactor for the hydroxylation of tyrosine4 and tryptophan5 as well as phenylalanine.Patients with cofactor deficiency develop gross lack of serotonin, dopamine, and noradrenaline. Phenylalanine restriction alone is not the appropriate treatment for these patients who require additional treatment with L-dopa, carbidopa and 5-hydroxytryptophan.