Alternative titles; symbols
SNOMEDCT: 58256000; ORPHA: 226, 238583; DO: 0081130;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
4p15.32 | Hyperphenylalaninemia, BH4-deficient, C | 261630 | Autosomal recessive | 3 | QDPR | 612676 |
A number sign (#) is used with this entry because tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) due to dihydropteridine reductase deficiency (HPABH4C) is caused by homozygous or compound heterozygous mutation in the QDPR gene (612676), which encodes an enzyme involved in the salvage pathway for BH4, on chromosome 4p15.
For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (261640).
Smith et al. (1975) described 3 children, 2 of them sibs, with an unusual type of phenylketonuria. All 3 (2 of them observed from the neonatal period) had a progressive neurologic illness that did not respond to a low phenylalanine diet, unlike classic PKU (261600). The biochemical features suggested that the block in conversion of phenylalanine to tyrosine was less severe than in classic PKU. Phenylalanine hydroxylase (PAH; 612349), measured in 1 patient, was normal. Smith et al. (1975) suggested that the patients had a disorder of biopterin metabolism possibly due to a defect in the enzyme dihydropteridine reductase.
Butler et al. (1975) reported dihydropteridine reductase deficiency in a patient unresponsive to dietary treatment. Biopterin is the natural cofactor for phenylalanine hydroxylase. In its active tetra-hydro form (BH4), biopterin donates hydrogen ions during the hydroxylation reaction. The same cofactor system is active in neural tissue for hydroxylation of tyrosine to dihydroxyphenylalanine (levodopa) in the synthesis of amine transmitters (dopaminine, noradrenaline, and adrenaline) and serotonin. Phenylalanine restriction would not be expected to help the neurologic problem. Basal ganglion symptoms can be related to the importance of levodopa and dopamine to that part of the brain.
Kaufman et al. (1975) demonstrated absence of dihydropteridine reductase in liver, brain, and cultured skin fibroblasts of a patient with elevated blood phenylalanine and no response to diet despite good control of blood levels.
Watts et al. (1979) reported a patient with hyperphenylalaninemia who had better tolerance of phenylalanine compared to patients with classic PKU. However, unlike patients with classic PKU, treatment with trimethoprim reduced the phenylalanine tolerance in this patient. Since trimethoprim inhibits 7,8-dihydrobiopterin reduction, Watts et al. (1979) speculated that the causative defect may involve the gene for dihydropteridine reductase such that it is sensitive to the reduced availability of tetrahydrobiopterin produced by trimethoprim.
Woody et al. (1989) pointed out that without folinic acid therapy as a source of tetrahydrofolate, patients with DHPR deficiency show progressive basal ganglia and other subcortical calcification. The pattern of calcification resembled that seen in CNS folate deficiency, both that in the congenital form (229050) and that in the methotrexate-induced form.
Larnaout et al. (1998) described 2 brothers with juvenile-onset DHPR deficiency. Both were considered normal until 6 years of age when they developed a fluctuating and progressive encephalopathy combining mental retardation, epilepsy, and pyramidal, cerebellar, and extrapyramidal signs.
Prenatal Diagnosis
Dahl et al. (1987, 1988) showed that RFLPs of the DHPR locus could be used for prenatal diagnosis.
Danks et al. (1975) found that intravenous tetrahydrobiopterin (BH4) treatment was effective and resulted in a fall in serum phenylalanine. Oral therapy had no effect.
In a patient with dihydropteridine reductase deficiency, the offspring of consanguineous parents, Howells et al. (1990) identified homozygosity for a mutation in the QDPR gene (612676.0001).
Smooker and Cotton (1995) reviewed 12 point mutations that had been described in DHPR cDNA, all of which resulted in dihydropteridine reductase deficiency. The mutations resulted in amino acid substitutions, insertions, or premature terminations. A further 2 mutations resulted in aberrant splicing of QDPR transcripts.
Romstad et al. (2000) studied 17 patients belonging to 16 Turkish families with DHPR deficiency. The patients were detected at neonatal screening for hyperphenylalaninemia or upon the development of neurologic symptoms. A mutation screen of the entire open reading frame and all splice sites of the QDPR gene identified 10 different mutations, 7 of which were novel (e.g., 612676.0007). Six of the mutations were missense, 2 were nonsense, and 2 were frameshift mutations. All patients had homoallelic genotypes, which allowed the establishment of genotype-phenotype associations.
Butler, I. J., Holtzman, N. A., Kaufman, S., Koslow, S. H., Krumholz, A., Milstien, S. Phenylketonuria due to deficiency of dihydropteridine reductase. (Abstract) Pediat. Res. 9: 348, 1975.
Dahl, H.-H. M., Hutchinson, W., McAdam, W., Wake, S., Morgan, F. J., Cotton, R. G. H. Human dihydropteridine reductase: characterisation of a cDNA clone and its use in analysis of patients with dihydropteridine reductase deficiency. Nucleic Acids Res. 15: 1921-1932, 1987. [PubMed: 3031582] [Full Text: https://doi.org/10.1093/nar/15.5.1921]
Dahl, H.-H. M., Wake, S., Cotton, R. G. H., Danks, D. M. The use of restriction fragment length polymorphisms in prenatal diagnosis of dihydropteridine reductase deficiency. J. Med. Genet. 25: 25-28, 1988. [PubMed: 2895188] [Full Text: https://doi.org/10.1136/jmg.25.1.25]
Danks, D. M., Bartholome, K., Clayton, B. E., Curtius, H., Grobe, H., Lemming, R., Pfleiderer, W., Rembold, H., Rey, F. Malignant hyperphenylalaninaemia--current status (June 1977). J. Inherit. Metab. Dis. 1: 49-53, 1978. [PubMed: 117241] [Full Text: https://doi.org/10.1007/BF01801843]
Danks, D. M., Cotton, R. G. H., Schlesinger, P. Tetrahydrobiopterin treatment of variant form of phenylketonuria. (Letter) Lancet 306: 1043 only, 1975. Note: Originally Volume II. [PubMed: 53532] [Full Text: https://doi.org/10.1016/s0140-6736(75)90335-9]
Danks, D. M., Schlesinger, P., Firgaira, F., Cotton, R. G. H., Watson, B. M., Rembold, H., Hennings, G. Malignant hyperphenylalaninemia--clinical features, biochemical findings, and experience with administration of biopterins. Pediat. Res. 13: 1150-1155, 1979. [PubMed: 503643] [Full Text: https://doi.org/10.1203/00006450-197910000-00014]
Dianzani, I., de Sanctis, L., Smooker, P. M., Gough, T. J., Alliaudi, C., Brusco, A., Spada, M., Blau, N., Dobos, M., Zhang, H.-P., Yang, N., Ponzone, A., Armarego, W. L. F., Cotton, R. G. H. Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations. Hum. Mutat. 12: 267-273, 1998. [PubMed: 9744478] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)12:4<267::AID-HUMU8>3.0.CO;2-C]
Firgaira, F. A., Cotton, R. G. H., Danks, D. M. Dihydropteridine reductase deficiency: diagnosis by assay on peripheral blood cells. (Letter) Lancet 315: 160 only, 1980. Note: Originally Volume I. [PubMed: 6101503] [Full Text: https://doi.org/10.1016/s0140-6736(80)90648-0]
Firgaira, F. A., Cotton, R. G. H., Danks, D. M. Dihydropteridine reductase deficiency: diagnosis by assays on peripheral blood-cells. Lancet 314: 1260-1263, 1979. Note: Originally Volume II. [PubMed: 93181] [Full Text: https://doi.org/10.1016/s0140-6736(79)92279-7]
Grobe, H., Bartholome, K., Milstien, S., Kaufman, S. Hyperphenylalaninaemia due to dihydropteridine reductase deficiency. Europ. J. Pediat. 129: 93-98, 1978. [PubMed: 28230] [Full Text: https://doi.org/10.1007/BF00442368]
Howells, D. W., Forrest, S. M., Dahl, H.-H. M., Cotton, R. G. H. Insertion of an extra codon for threonine is a cause of dihydropteridine reductase deficiency. Am. J. Hum. Genet. 47: 279-285, 1990. [PubMed: 2116088]
Kaufman, S., Holtzman, N. A., Milstien, S., Butler, I. J., Krumholz, A. Phenylketonuria due to a deficiency of dihydropteridine reductase. New Eng. J. Med. 293: 785-790, 1975. [PubMed: 1160969] [Full Text: https://doi.org/10.1056/NEJM197510162931601]
Larnaout, A., Belal, S., Miladi, N., Kaabachi, N., Mebazza, A., Dhondt, J. L., Hentati, F. Juvenile form of dihydropteridine reductase deficiency in 2 Tunisian patients. Neuropediatrics 29: 322-323, 1998. [PubMed: 10029353] [Full Text: https://doi.org/10.1055/s-2007-973586]
Longhi, R., Riva, E., Valsasina, R., Paccanelli, S., Giovannini, M. Phenylketonuria due to dihydropteridine reductase deficiency: presentation of two cases. J. Inherit. Metab. Dis. 8 (suppl. 2): 97-98, 1985. [PubMed: 3930875] [Full Text: https://doi.org/10.1007/BF01811476]
Milstien, S., Holtzman, N. A., O'Flynn, M. E., Thomas, G. H., Butler, I. J., Kaufman, S. Hyperphenylalaninemia due to dihydropteridine reductase deficiency: assay of the enzyme in fibroblasts from affected infants, heterozygotes, and in normal amniotic fluid cells. J. Pediat. 89: 763-766, 1976. [PubMed: 978323] [Full Text: https://doi.org/10.1016/s0022-3476(76)80798-6]
Milstien, S., Kaufman, S., Summer, G. K. Hyperphenylalaninemia due to dihydropteridine reductase deficiency: diagnosed by measurement of oxidized and reduced pterins in urine. Pediatrics 65: 806-810, 1980. [PubMed: 7367090]
Romstad, A., Kalkanoglu, H. S., Coskun, T., Demirkol, M., Tokatli, A., Dursun, A., Baykal, T., Ozalp, I., Guldberg, P., Guttler, F. Molecular analysis of 16 Turkish families with DHPR deficiency using denaturing gradient gel electrophoresis (DGGE). Hum. Genet. 107: 546-553, 2000. [PubMed: 11153907] [Full Text: https://doi.org/10.1007/s004390000407]
Smith, I., Clayton, B. E., Wolff, O. H. New variant of phenylketonuria with progressive neurological illness unresponsive to phenylalanine restriction. Lancet 305: 1108-1111, 1975. Note: Originally Volume I. [PubMed: 49470] [Full Text: https://doi.org/10.1016/s0140-6736(75)92498-8]
Smooker, P. M., Cotton, R. G. H. Molecular basis of dihydropteridine reductase deficiency. Hum. Mutat. 5: 279-284, 1995. [PubMed: 7627180] [Full Text: https://doi.org/10.1002/humu.1380050402]
Watts, R. W. E., Purkiss, P., Chalmers, R. A. A new variant form of phenylketonuria. Quart. J. Med. 48: 403-417, 1979. [PubMed: 317358]
Woody, R. C., Brewster, M. A., Glasier, C. Progressive intracranial calcification in dihydropteridine reductase deficiency prior to folinic acid therapy. Neurology 39: 673-675, 1989. [PubMed: 2785251] [Full Text: https://doi.org/10.1212/wnl.39.5.673]