eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Tetrahydrobiopterin Deficiency
Updated: Jun 5, 2008
Introduction
Background
Tetrahydrobiopterin (BH4) deficiencies are disorders that affect phenylalanine (Phe or F) homeostasis, as well as brain biosynthesis of catecholamine, serotonin, and (occasionally) nitric oxide.
BH4 deficiencies are grouped with phenylketonuria (PKU), which is an inborn error of protein metabolism that results from an impaired ability to metabolize the essential amino acid Phe. Similar to PKU, BH4 deficiencies negatively affect developmental function; however, BH4 deficiencies also affect neurologic functioning, depending on the variant. Some, but not all, BH4 deficiencies may be detected with PKU screening tests used in Western countries, depending on the variant.
BH4 deficiencies are heterogeneous. They range from mild forms that do not require treatment to severe cases that are difficult to ameliorate even with therapy.
Pathophysiology
Enzymatic reactions and defects
BH4 deficiencies fall into 4 main categories, depending on the enzymatic defect that leads to a lack of BH4. Through September 2006, 193 different mutant alleles or molecular lesions identified in the guanosine triphosphate cyclohydrolase I (GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR), carbinolamine-4a-dehydratase (PCD), or dihydropteridine reductase (DHPR) genes had been identified.1
The most well-established human function of BH4 is as the cofactor for Phe-4-hydroxylase (PAH), tyrosine-3-hydroxylase, and tryptophan-5-hydroxylase. The last 2 are key enzymes in biogenic amine biosynthesis, that is, aromatic amino acid synthesis. In addition to hydroxylating aromatic amino acids, BH4 serves as the cofactor for nitric oxide synthase and glyceryl-ether mono-oxygenase.
These reactions are based on the ability of BH4 to react with molecular oxygen to form an active oxygen intermediate that can hydroxylate substrates. Although BH4 is absolutely essential for nitric oxide synthase activity, its exact function with different forms of the enzyme and its mechanism of action remain to be defined.
BH4 is synthesized from guanosine triphosphate (GTP) in at least 4 enzymatic steps by the action of 3 enzymes. GTP cyclohydrolase I (GTPCH), the first enzyme in BH4 biosynthesis, catalyzes the formation of 7,8-dihydroneopterin triphosphate from GTP in a single reaction step. GTPCH is subject to feedback inhibition by BH4. A single-copy gene, GCH1, located on chromosome band 14q22.1-q22.2 encodes GTPCH.
In the next step, 6-pyruvoyl-tetrahydropterin synthase (PTPS) catalyzes the conversion of 7,8-dihydroneopterin triphosphate to 6-pyruvoyl-tetrahydropterin. The PTS gene on chromosome band 11q22.3-q23.3 encodes PTPS.
Sepiapterin reductase (SR) is a nicotinamide adenine dinucleotide phosphate (NADP), reduced form, (NADPH) oxidoreductase. It is required for the final 2-step reduction of the dike to intermediate 6-pyruvoyl-tetrahydropterin to BH4. The SPR gene on chromosome band 2p14-p12 encodes SR.
During the enzymatic hydroxylation of aromatic amino acids, molecular oxygen is consumed and BH4 is peroxidated and oxidized. The pterin intermediate is subsequently reduced back to BH4 by 2 enzymes and a reduced pyridine nucleotide (ie, NADH) in a complex recycling reaction.
Molecular oxygen is first bound to BH4 to form an unstable 4-alpha--peroxy-BH4. The mono-oxygenation of aromatic amino acids is thus concomitant with oxidation of BH4 to 4-alpha--hydroxy-BH4 (pterin-4-alpha-carbinolamine). Pterin-4-alpha-carbinolamine is subsequently dehydrated to quinonoid-dihydrobiopterin (q-dihydrobiopterin) and water by the specific and highly efficient pterin-4-alpha-carbinolamine dehydratase (PCD). The PCBD gene on chromosome band 10q22 encodes PCD.
In the last step of BH4 recycling, q-dihydrobiopterin is reduced back to BH4 by the NADH-DHPR. Folate inhibitors, such as methotrexate, inhibit the activity of the enzyme both in vivo and in vitro. The QHPR gene on chromosome band 4p15.3 encodes DHPR.
Genetic factors
BH4 deficiency comprises heterogeneous autosomal recessive disorders caused by mutations in the PTS (most common), SPR, QHPR, and GCH1 genes. Defects in the SPR gene cause neurotransmitter deficiency without hyperphenylalaninemia (HPA); defects in the GTPCH gene (ie, GCH1) may also cause autosomal dominant dopa-responsive dystonia (DRD).
BH4 deficiency without HPA occurs in 6,10-methylenetetrahydrofolate reductase deficiency and vitiligo or DRD.
Fiori et al (2005) noted that HPA is an inherited metabolic disorder due to deficiency of the enzyme PAH or its cofactor BH4.2 BH4 -responsiveness in PAH-deficient HPA is a recently described characteristic of most mild phenotypes. BH4 -responsive patients have reduced plasma Phe levels after the oral administration of BH4.
The investigators determined the incidence of BH4-responsiveness among a nonselected cohort of patients with PAH-deficient HPA and evaluated the phenotype-genotype correlations. They evaluated 11 patients born in Lombardy, Italy, between January 2000 and December 2004. HPA (107 patients) was classified after BH4 -loading test, an analysis of urinary pterin levels, and a determination of DHPR activity in the blood. The researchers assessed the patients for BH4 -responsiveness.
Patients were given 6R-BH4 20mg/kg orally as a single dose, and plasma samples were obtained at 0, 4, 8, and 24 hours after administration. In patients with basal plasma Phe levels of 360 mmol/L, a combined Phe (100 mg Phe/kg) and BH4 (20 mg/kg) loading test was performed. Patients were considered responsive to BH4 when their plasma Phe levels decreased by 30% at 8 hours after oral administration of BH4.
The investigators found that BH4 significantly lowered blood Phe levels in 91 (85%) of 107 patients with PAH-deficient HPA. Most of the responsive patients had mild HPA (77%), although some had mild (7%) or moderate (7%) PKU. One patient with classical PKU was responsive to BH BH4. Eighteen mutations were associated to the BH4 -responsive phenotype.
The authors concluded that a consistent number of patients with PAH-deficient HPA responded to BH4 and that BH4 responsiveness seemed to be common in mild phenotypes. Genotype was not the only factor that determined BH BH4 responsiveness.
Frequency
United States
The incidence of classic PKU is approximately 1 case in 15,000 births. The incidence of BH4 deficiency is approximately 1 case per 1 million births, or 1.5-2% of cases of PKU.
International
In Taiwan, 2-30% of cases of PKU are attributed to BH4 deficiency.3 In Turkey, which has the highest incidence of PKU in the world with approximately 1 case per 2600 births, 15% of cases are due to BH4 deficiency. In Saudi Arabia, 66% of PKU cases are due to BH4 deficiency. The incidence also appears to be increased in southern Brazil. Such increased incidences are thought to be related to consanguinity.
Pangkanon et al reported the first 2 cases of PTPS deficiency in Thailand.4 Both cases were males with phenylalanine levels of 25.23 mg/dL and 23.4 mg/dL, respectively. The urinary pterins analysis showed low biopterin levels, low percentages of urinary biopterin, and high neopterin levels. The mutation analysis of the patient with a phenylalanine level of 25.23 mg/dL revealed a point mutation in exon 4 and a homozygous C-to-T transition at nucleotide 200 in codon 67 (T67M). The other patient demonstrated a compound heterozygous in exon 4, C-to-A transition at nucleotide 200 and exon 5, and C-to-T transition at nucleotide 259 of the PTS gene, confirming PTPS deficiency.
Farrugia et al (2007) noted that the deficient activity of the DHPR enzyme is due to mutations in the quinoid dihydropteridine reductase (QDPR) gene on 4p15.3.5 Deficient activity of the DHPR enzyme results in defective recycling of BH 4 , and homozygotes have a rare form of atypical HPA and PKU. The heterozygote frequency in the Maltese population is high (3.3%).
Mortality/Morbidity
- Patients with severe of BH4 deficiency present with mental retardation and neurologic impairment. Early death may result.
- Patients with mild cases can have mild degrees of mental retardation and neurologic impairment.
Race
Children of Chinese, Turkish, and Saudi Arabian descent are most often affected.
Sex
No sex predilection is reported. The mode of inheritance is autosomal recessive.
Age
- BH4 deficiency is most commonly diagnosed in newborns by means of newborn screening programs.
- Consider BH4 deficiency in patients of any age who have PKU and developmental delay or mental retardation with neurologic impairment. Newborn screening does not always detect the disease. Patients who are symptomatic usually present by age 4 months.
Clinical
History
- Most neonates with tetrahydrobiopterin (BH4) deficiencies appear healthy at birth.
- In severe PTPS deficiency, the incidence of prematurity and low birth weight is increased.
- In severe PTPS deficiency, lead-pipe or cogwheel rigidity and stiff-baby syndrome have been reported.
- BH4 deficiency converts neuronal nitric oxide synthases (NOSs) into an efficient peroxynitrite synthase, which is responsible for the increase in neuronal vulnerability to hypoxia-induced mitochondrial damage and necrosis.
- Endothelial BH4 availability is essential for maintaining pulmonary vascular homeostasis, and it is a critical mediator in the pathogenesis of pulmonary hypertension. It is also a novel therapeutic target.
- BH4 restores utilization of the flow reserve in the coronary microcirculation in subjects with hypercholesterolemia. This finding suggests that BH4 deficiency may contribute to dysfunction of the coronary microcirculatory n in hypercholesterolemia.
Physical
At birth, neonates with BH4 deficiencies often appear healthy. Pigmentary dilution can be noted. Physical findings manifest as the neonate matures.
- Patients may have red hair.
- They may have poor suckling, decreased spontaneous movements, and a floppy-baby appearance.
- If the disease is not detected on newborn screening, affected children develop progressive developmental delay and neurologic impairment that manifests as psychomotor retardation, progressive neurologic deterioration, convulsions, abnormal movements, hypersalivation, and swallowing difficulties.
Causes
See Pathophysiology.
More on Tetrahydrobiopterin Deficiency |
 Overview: Tetrahydrobiopterin Deficiency |
| Differential Diagnoses & Workup: Tetrahydrobiopterin Deficiency |
| Treatment & Medication: Tetrahydrobiopterin Deficiency |
| Follow-up: Tetrahydrobiopterin Deficiency |
| References |
| Next Page » |
References
Thony B, Blau N. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Hum Mutat. Sep 2006;27(9):870-8. [Medline].
Fiori L, Fiege B, Riva E, Giovannini M. Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. Mol Genet Metab. Dec 2005;86 Suppl 1:S67-74. [Medline].
Liu TT, Chiang SH, Wu SJ, Hsiao KJ. Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese. Clin Chim Acta. Nov 2001;313(1-2):157-69. [Medline].
Pangkanon S, Charoensiriwatanamsc W, Liamsuwanmd S. 6-pyruvoyltetrahydropterin synthase deficiency two-case report. J Med Assoc Thai. Jun 2006;89(6):872-7. [Medline].
Farrugia R, Scerri CA, Montalto SA, Parascandolo R, Neville BG, Felice AE. Molecular genetics of tetrahydrobiopterin (BH4) deficiency in the Maltese population. Mol Genet Metab. Mar 2007;90(3):277-83. [Medline].
Mikami H, Matsubara Y, Hayasaka K, Narisawa K, Obinata M, Watanabe A, et al. Molecular analysis of dihydropteridine reductase deficiency and restoration of the enzyme activity by gene transfer. J Inherit Metab Dis. 1990;13(5):787-91. [Medline].
Thony B, Leimbacher W, Stuhlmann H, Heizmann CW, Blau N. Retrovirus-mediated gene transfer of 6-pyruvoyl-tetrahydropterin synthase corrects tetrahydrobiopterin deficiency in fibroblasts from hyperphenylalaninemic patients. Hum Gene Ther. Aug 20 1996;7(13):1587-93. [Medline].
Laufs S, Blau N, Thony B. Retrovirus-mediated double transduction of the GTPCH and PTPS genes allows 6-pyruvoyltetrahydropterin synthase-deficient human fibroblasts to synthesize and release tetrahydrobiopterin. J Neurochem. Jul 1998;71(1):33-40. [Medline].
Laufs S, Kim SH, Kim S, Blau N, Thony B. Reconstitution of a metabolic pathway with triple-cistronic IRES-containing retroviral vectors for correction of tetrahydrobiopterin deficiency. J Gene Med. Jan-Feb 2000;2(1):22-31. [Medline].
Tanaka Y, Kato M, Muramatsu T, Saito F, Sato S, Matsuo N, et al. Early initiation of L-dopa therapy enables stable development of executive function in tetrahydrobiopterin (BH4) deficiency. Dev Med Child Neurol. May 2007;49(5):372-6. [Medline].
Burnett JR. Sapropterin dihydrochloride (Kuvan/phenoptin), an orally active synthetic form of BH4 for the treatment of phenylketonuria. IDrugs. Nov 2007;10(11):805-13. [Medline].
Blau N. The Hyperphenyalaninemias. In: A Differential Diagnosis and International Database of Tetrahydrobiopterin Deficiencies. Tectum Verlag; 1996.
Blau N, Bonafe, Blaskovics ME. Disorders of phenylalanine and tetrahydrobiopterin metabolism. In: Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases. 2nd ed. Berlin, Germany: Springer; 2002:89-106.
Blau N, Erlandsen H. The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab. Jun 2004;82(2):101-11. [Medline].
Blau N, Thony B, Cotton RGH. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B. The Metabolic and Molecular Bases of Inherited Diseases. McGraw-Hill; 2001:1725-76.
Blau N, Thony B, eds. Pterins, Folates, and Neurotransmitters in Molecular Medicine. Heilbronn, Germany: SPS; 2003.
Boveda MD, Couce ML, Castineiras DE, Cocho JA, Perez B, Ugarte M, et al. The tetrahydrobiopterin loading test in 36 patients with hyperphenylalaninaemia: evaluation of response and subsequent treatment. J Inherit Metab Dis. Oct 2007;30(5):812. [Medline].
Delgado-Esteban M, Almeida A, Medina JM. Tetrahydrobiopterin deficiency increases neuronal vulnerability to hypoxia. J Neurochem. Sep 2002;82(5):1148-59. [Medline].
Demos MK, Waters PJ, Vallance HD, Lillquist Y, Makhseed N, Hyland K, et al. 6-pyruvoyl-tetrahydropterin synthase deficiency with mild hyperphenylalaninemia. Ann Neurol. Jul 2005;58(1):164-7. [Medline].
Gramer G, Burgard P, Garbade SF, Lindner M. Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase-deficient hyperphenylalaninaemia. J Inherit Metab Dis. Aug 2007;30(4):556-62. [Medline].
Kaufman S. Tetrahydrobiopterin: Basic Biochemistry and Role in Human Disease. Baltimore, MD: Johns Hopkins University Press; 1997.
Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L. Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev. Mar 2004;24(2):127-50. [Medline].
Shintaku H. Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab. Apr 2002;3(2):123-31. [Medline].
Wang CH, Li SH, Weisel RD, Fedak PW, Hung A, Li RK, et al. Tetrahydrobiopterin deficiency exaggerates intimal hyperplasia after vascular injury. Am J Physiol Regul Integr Comp Physiol. Aug 2005;289(2):R299-304. [Medline].
Wang L, Yu WM, He C, Chang M, Shen M, Zhou Z, et al. Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency. J Inherit Metab Dis. Feb 2006;29(1):127-34. [Medline].
Zurfluh MR, Fiori L, Fiege B, Ozen I, Demirkol M, Gartner KH, et al. Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency. J Inherit Metab Dis. Dec 2006;29(6):725-31. [Medline].
Further Reading
Keywords
tetrahydrobiopterin deficiency, BH4 deficiency, BH4 deficiency, BH4 D, BH4D, malignant phenylketonuria, malignant PKU, atypical phenylketonuria, atypical PKU, malignant hyperphenylalaninemia, nonphenylketonuria hyperphenylalaninemia, non-phenylketonuria hyperphenylalaninemia, non-PKU hyperphenylalaninemia, HPA, phenylalanine, Phe
