Tetrahydrobiopterin Deficiency Clinical Presentation

  • Author: Noah S Scheinfeld, MD, JD, FAAD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Aug 3, 2011
 

History

Most neonates with tetrahydrobiopterin (BH4) deficiencies appear healthy at birth.

In severe 6-pyruvoyl-tetrahydropterin synthase (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 use 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 in hypercholesterolemia.

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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.

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Causes

See Pathophysiology.

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Contributor Information and Disclosures
Author

Noah S Scheinfeld, MD, JD, FAAD  Assistant Clinical Professor, Department of Dermatology, Columbia University College of Physicians and Surgeons; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, and New York Eye and Ear Infirmary; Private Practice

Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Optigenex Consulting fee Independent contractor

Coauthor(s)

Elena L Jones, MD  Clinical Assistant Professor of Dermatology, Columbia University College of Physicians and Surgeons; Clinic Chief, Department of Dermatology, St Luke's-Roosevelt Hospital Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Erawati V Bawle, MD, FAAP, FACMG  Retired Professor, Department of Pediatrics, Wayne State University School of Medicine

Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American College of Medical Genetics and American Society of Human Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert Anthony Saul, MD  Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center

Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Shintaku H. Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab. Apr 2002;3(2):123-31. [Medline].

  2. Kim HK, Ha SH, Han J. Potential therapeutic applications of tetrahydrobiopterin: from inherited hyperphenylalaninemia to mitochondrial diseases. Ann N Y Acad Sci. Jul 2010;1201:177-82. [Medline].

  3. Crabtree MJ, Hale AB, Channon KM. Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling intetrahydrobiopterin deficiency. Free Radic Biol Med. Jun 1 2011;11:1639-46. [Medline].

  4. 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].

  5. 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].

  6. 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].

  7. Pangkanon S, Charoensiriwatanamsc W, Liamsuwanmd S. 6-pyruvoyltetrahydropterin synthase deficiency two-case report. J Med Assoc Thai. Jun 2006;89(6):872-7. [Medline].

  8. 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].

  9. Feillet F, Chery C, Namour F, et al. Evaluation of neonatal BH4 loading test in neonates screened for hyperphenylalaninemia. Early Hum Dev. Sep 2008;84(9):561-7. [Medline].

  10. Dhondt JL. Lessons from 30 years of selective screening for tetrahydrobiopterin deficiency. J Inherit Metab Dis. May 11 2010;[Medline].

  11. Opladen T, Abu Seda B, Rassi A, Thöny B, Hoffmann GF, Blau N. Diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots: further development of the method and 5 years experience. J Inherit Metab Dis. Jun 2011;3:819-26. [Medline].

  12. 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].

  13. 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].

  14. 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].

  15. 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].

  16. Tanaka Y, Kato M, Muramatsu T, 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].

  17. 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].

  18. Blau N. The Hyperphenyalaninemias. In: A Differential Diagnosis and International Database of Tetrahydrobiopterin Deficiencies. Tectum Verlag; 1996.

  19. 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.

  20. 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].

  21. Blau N, Thony B. Tetrahydrobiopterin in biomedical research. J Inherit Metab Dis. Feb 2009;1:1-2. [Medline].

  22. 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.

  23. Blau N, Thony B, eds. Pterins, Folates, and Neurotransmitters in Molecular Medicine. Heilbronn, Germany: SPS; 2003.

  24. Boveda MD, Couce ML, Castineiras DE, 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].

  25. Delgado-Esteban M, Almeida A, Medina JM. Tetrahydrobiopterin deficiency increases neuronal vulnerability to hypoxia. J Neurochem. Sep 2002;82(5):1148-59. [Medline].

  26. Demos MK, Waters PJ, Vallance HD, et al. 6-pyruvoyl-tetrahydropterin synthase deficiency with mild hyperphenylalaninemia. Ann Neurol. Jul 2005;58(1):164-7. [Medline].

  27. 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].

  28. Jaggi L, Zurfluh MR, Schuler A, et al. Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab. Mar 2008;3:295-305. [Medline].

  29. Karacic I, Meili D, Sarnavka V, et al. Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Mol Genet Metab. Jul 2009;97(3):165-71. [Medline].

  30. Kaufman S. Tetrahydrobiopterin: Basic Biochemistry and Role in Human Disease. Baltimore, MD: Johns Hopkins University Press; 1997.

  31. Langenbeck U. Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias. J Inherit Metab Dis. Feb 2008;1:67-72. [Medline].

  32. Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis. Jun 2009;3:333-42. [Medline].

  33. 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].

  34. Wang CH, Li SH, Weisel RD, et al. Tetrahydrobiopterin deficiency exaggerates intimal hyperplasia after vascular injury. Am J Physiol Regul Integr Comp Physiol. Aug 2005;289(2):R299-304. [Medline].

  35. Wang L, Yu WM, He C, 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].

  36. 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].

 
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