Hyperphenylalaninemia, Bh4-Deficient, C

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).

Clinical Features

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.

Diagnosis

Prenatal Diagnosis

Dahl et al. (1987, 1988) showed that RFLPs of the DHPR locus could be used for prenatal diagnosis.

Clinical Management

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.

Molecular Genetics

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.