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  1. 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.

  2. 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.

  3. 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-HPA dopa-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.

  4. 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.

  5. 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).

  6. 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 enzyme assay, measurement of metabolites in amniotic fluid, or DNA analysis in all forms of BH4 deficiency.

  7. The catecholamines [dopamine (DA), norepinephrine (NE), and epinephrine (E)], together with serotonin (5-hydroxytryptamine or 5HT), are major neurotransmitters that are involved with the control of brain homeostasis, behavior, and movement. The initial synthesis steps require hydroxylation of tyrosine to L-dopa, via the action of TH, for the catecholamines, and hydroxylation of tryptophan to 5-hydroxytryptophan (5HTP), via the action of tryptophan hydroxylase (TPH), for 5HT. L-Dopa and 5HTP are then decarboxylated by aromatic L-amino acid decarboxylase (AADC) to yield DA and 5HT, respectively. DA can then be further hydroxylated in a reaction catalyzed by dopamine β-hydroxylase (DβH) to form NE, which in turn can be methylated by phenylethanolamine N-methyltransferase to form E. Catabolism of the active neurotransmitters is completed by catechol O-methyltransferase (COMT), and monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B).

  8. Inherited disorders affecting catecholamine and 5HT metabolism have been described at the level of TH, AADC, DβH, and MAO-A. Although there is some overlap of clinical features, the main phenotypic features of each disease are different. Characteristic features are occulogyric crises, temperature instability and ptosis in AADC deficiency, parkinsonian features in early cases or dystonia in later-onset cases of TH deficiency, orthostatic hypotension in adolescence in DβH deficiency, and signs of violent, often sexual aggression, in males with MAO-A deficiency.

  9. The genes for TH, AADC, DβH, and MAO-A are located and characterized in normal and mutant genomes. TH (14 exons) is on chromosome 11 (region 11p15.5) and harbors three mutations. AADC (15 exons) maps to chromosome 7 (region 7p12.1-p12.3) and harbors six point mutations causing single amino acid substitutions. DβH (12 exons) is on chromosome 9 (region 9q34.3). No mutations on this gene have been described. MAO-A (15 exons) maps to the X chromosome (region Xp11.4-p11.3). A single mutation creating a termination codon has been described.

  10. Treatment of the neurotransmitter defects attempts restoration of normal central neurotransmitter levels. This is achieved by administration of L-dopa (+ carbidopa) in TH deficiency, or MAO inhibitors and DA agonists in AADC deficiency. Trials with vitamin B6 should also always be attempted. Dihydroxyphenylserine restores NE levels in DβH deficiency. Treatment is not available in MAO-A deficiency, but avoidance of amine-containing foods may help prevent aggressive episodes. Detection and differentiation of the defects of catecholamine and serotonin metabolism require the measurement of catecholamines, 5HT, and their metabolites in either CSF, plasma, or urine. Prenatal diagnosis is possible by fetal liver enzyme assay in AADC deficiency, and by DNA analysis where mutations in previous siblings have been described.

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