GTPCH deficiency

A Fig. 6.1.7a- HPLC of pterins using a column-switching system a standard mixture b control urine c urine guanosine triphosphate cyclohydrolase I (GTPCH) deficiency d urine 6-pyru-voyl-tetrahydropterin synthase (PTPS) deficiency e urine pterin-4a-carbinolamine dehydratase (PCD) deficiency f urine dihydropteridine reductase (DHPR) deficiency g urine phenylketonuria 4-8 h after tetrahydrobiopterin (BH4) administration h-k see next page... 

A Fig. 6.1.7a-k (continued) h control blood i blood PTPS deficiency j blood DHPR deficiency blood GTPCH deficiency. Neo Neopterin, Pri primapterin... 

GTP cyclohydrolase I (GTPCH) deficiency liver, brain, kidney, lymphocytes 14q22,l-22.2 233910... 

Therapy Age Doses/day PTPS/GTPCH deficiency DHPR deficiency... 

BH4 deficiency can be caused by mutations in genes encoding the enzymes involved in its biosynthesis (GTPCH, PTPS, and SR) or regeneration (PCD/DCoH and DHPR). BH4 deficiency due to autosomal recessive mutations in BH4-metabo-lizing enzymes (except SR) has been described as a cause of hyperphenylalaninemia (HPA) [6]. Biochemical, clinical, and DNA data of patients with BH4 deficiencies are tabulated in the BIODEF and BIOMDB databases and are available on the Internet (www.bh4.org) [7]. Depending on the enzyme defect and the mode of inheritance,... 

Fig. 12.1 Tetrahydrobiopterin synthesis and recirculation left side) and enzyme reactions requiting BH4 as a cofactor right side). Each enzyme that has the potential to create a deficiency is noted with a corresponding number (i) GTP cyclohydrolase 1 (GTPCH) (2) 6-pyruvoyltetra-...

IWo disorders of BH4 metabolism may present without hyperphenylalaninemia. These are Dopa-responsive dystonia (DRD Segawa disease) and sepiapterin reductase (SR) deficiency. While DRD is caused by a mutation in the GTPCH gene and is inherited in an autosomal dominant manner, SR deficiency is an autosomal recessive trait. Both diseases evidence severe biogenic amines deficiencies. DRD usually presents with a dystonic gait and diurnal variation. At least two reports describe heteroallelic patients with DRD suggesting a wide spectrum of GTPCH variants. 

The goals of treatment are to control hyperphenylalaninemia by dietary restriction of phenylalanine (in PAH deficiency) or BH4 administration (in GTPCH and PTPS deficiency), and to restore neurotransmitter homeostasis by the oral administration of dopamine and serotonin precursors (l-Dopa and 5-hydroxytryptophan, respectively) in BH4 deficiencies. Late detection and introduction of treatment leads to irreversible brain damage. In contrast to patients with classical PKU, patients with BH4 deficiencies show progressive neurological deterioration despite treatment with phenylalanine-restricted diets. DRD and SR patients benefit from L-Dopa/Carbidopa substitution (for the relevant literature see [1-18]). 

Table 1.6. Dopa-responsive dystonia (DRD) autosomal dominant GTPCH 1 deficiency (>400 patients)...

Fig. 1.2. Typical results of a BH4 loading test (20 mg/kg body weight) in patients with hyperphenylalaninemia. Tablets of synthetic cofactor (BH4 supplied by Dr. Schircks Laboratories, Jona, Switzerland) were dissolved in 20 ml of water in dim light and administered at least 30 min before a meal. Blood was drawn before, and 4 and 8 hours after BH4 loading. Patients with GTPCH and PTPS deficiencies show a rapid normalization of blood phenylalanine. Simultaneously, there is a transient increase in tyrosine levels 4 hours after the administration of BH4. Basal plasma Phe should be >400 pmol/1...

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