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  • Tetrahydrobiopterin (BH)deficiencies are disorders affecting phenylalanine homeostasis, and catecholamine and serotonin biosynthesis. The minimum requirements for the normal reaction(s) are the apoenzymes, phenylalanine-4-hydroxylase (PAH), tyrosine-3-hydroxylase (TH), or tryptophan-5-hydroxylase (TPH), oxygen, the corresponding aromatic amino acids, phenylalanine, tyrosine, or tryptophan, and BH4. The complete hydroxylating system, in each case, consists of the two additional BH4-regenerating enzymes: pterin-4α-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR). BH4 is synthesized from guanosine triphosphate (GTP) catalyzed sequentially by GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR). The first two steps are clinically relevant.

  • BH deficiency comprises a heterogeneous group of disorders caused by mutations at one of the genes encoding enzymes involved in the biosynthesis (GTPCH or PTPS) or regeneration (PCD or DHPR) of BH4. Phenotypically, it presents mostly with hyperphenylalaninemia (HPA) and deficiency of the neurotransmitter precursors, L-dopa and 5-hydroxytryptophan, and thus may be detected through neonatal phenylketonuria (PKU)-screening programs. However, some mutant variants may present without HPA and some with normal neurotransmitter homeostasis: Brain nitric oxide synthase (NOS) may also be affected by a deficit of the essential cofactor BH4.

  • The genes of the corresponding enzymes are located and characterized in normal and mutant genomes. GTPCH (six exons) is on chromosome 14 (region 14q22.1-q22.2) and harbors 42 mutations, most of them associated with non-HPAdopa-responsive dystonia (DRD). PTPS (six exons) maps to human chromosome 11 (region 11q22.3-q23.3) and harbors over 28 mutations associated with HPA, some having a mild peripheral phenotype. PCD (four exons) is on chromosome 10 (region 10q22), with seven mutations described and associated with benign transient HPA. DHPR (seven exons) maps to chromosome 4 (region 4p15.3) and harbors 21 mutations, all associated with HPA and neurotransmitter deficiency.

  • Mutations of a single allele of the GTPCH gene or of two alleles of the tyrosine hydroxylase (TH) gene can lead to DRD. The spectrum of clinical symptoms in these disorders is wide and does not always include dystonia. Therapy with low-dose L-dopa normally alleviates most symptoms. Detection and differentiation of dominantly inherited GTPCH deficiency from recessively inherited TH deficiency requires measurement of pterins (neopterin and biopterin), and neurotransmitter metabolites in cerebrospinal fluid (CSF). Confirmation of a diagnosis requires enzymatic and molecular analysis in the case of dominantly inherited GTPCH deficiency and molecular analysis for TH deficiency as no suitable tissue is available for TH enzyme assay.

  • Treatment of BH deficiencies requires restoration of normal blood phenylalanine concentration by BH4 supplementation (2 to 10 mg/kg per day) or diet and replacement therapy with the neurotransmitter precursors L-dopa (+ carbidopa) and 5-hydroxytryptophan, and supplements of folinic acid in DHPR deficiency. Treatment should be initiated as early as possible (and perhaps continued for a lifetime).

  • Detection and differentiation of BH deficiencies among HPAs require measurement of pterins (neopterin and biopterin) in urine, DHPR activity in blood from a Guthrie card, and neurotransmitter metabolites in CSF. If requested, prenatal diagnosis is possible by ...

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