J. Inher. Metab. Dis. 9 (1986) 239-243 Tetrahydrobiopterin Non-Responsiveness in Dihydropteridine Reductase Deficiency is Associated with the Presence of Mutant Protein R. G. H. COTTON ~, I. JENNINGS 1, G. BRACCO 2, A. PONZONE 2 and O. GUARDAMAGNA2 1Olive Miller Protein Laboratory, Birth Defects Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Victoria, Australia 3052 2Clinica Pediatrica, Universita Di Torino, OspedaIe Infantile Regina Margherita, Piazza Polonia 94, 10126 Torino, Italy Correlation of the response to a load of tetrahydrobiopterin (BH4) in dihyd- ropterin reductase (DHPR) deficient patients to the type of mutation in these patients has led to the conclusion that 4 patients without mutant DHPR molecules in their cells respond to the BH 4 load, whereas 3 patients with mutant DHPR in their cells do not respond. Intravenous injection of BH 4 in 1 of the cases not responding to BH 4 again showed no response. Dihydropteridine reductase (DHPR) deficiency is one of the causes of deficiency of tetrahydrobiopterin (BH4), which manifests as malignant hyperphenylalaninaemia unresponsive to low phenylalanine dietary therapy, presumably due to a lack of the neurotransmitter products of tyrosine and tryptophan hydroxylase. We initiated the use of intravenous BH 4 as a diagnostic tool (to lower serum phenylalanine) and as an attempted therapy (Danks et al., 1975, 1979). Although the BH4 load test in an oral form (Curtius et al., 1979) has been useful, it is not absolutely necessary for diagnosis and is complicated by the lack of response of some DHPR deficient patients to the BH 4 load test (see below; Niederwieser et al., 1982). In contrast there appear to be no patients with BH 4 deficiency due to other causes (GTP cyclohydrolase deficiency and dihydrobiopterin synthetase deficiency) who have not responded to the BH 4 load test (Niederwieser et al., 1982). Heterogeneity in underlying mutations in inherited diseases is a general rule and has been demonstrated in DHPR deficiency (Firgaira et al., 1981b; Firgaira et al., 1983). In this paper we present some evidence to support a contention that the non-responding DHPR deficient patients have in their cells residual mutant DHPR molecules (CRM ÷) whereas responders have no mutant molecules detectable (CRM-). This evidence comes from consideration of results obtained from 5 MS received 15.1.86. Accepted 26.2.86 239 Journal of Inherited Metabolic Disease. ISSN 0141-8955. Copyright© SSIEM and MTP Press Limited, Queen Square, Lancaster, UK. Printed in The Netherlands.