BH4 Deficiency (Tetrahydrobiopterin Deficiency) Clinical Presentation

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

2. Li H, Förstermann U. Pharmacological Prevention of eNOS Uncoupling. Curr Pharm Des. 2013 Oct 29. [Medline].

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

4. Tobias S, Habermeier A, Siuda D, Reifenberg G, Xia N, Closs EI, et al. Dexamethasone, tetrahydrobiopterin and uncoupling of endothelial nitric oxide synthase. J Geriatr Cardiol. 2015 Sep;. 12(5):528-39. [Medline].

5. Chuaiphichai S, Crabtree MJ, Mcneill E, Hale AB, Trelfa L, Channon KM, et al. A key role for tetrahydrobiopterin-dependent endothelial NOS regulation in resistance arteries: studies in endothelial cell tetrahydrobiopterin-deficient mice. Br J Pharmacol. 2017. 174(8):657-671. [Medline]. [Full Text].

6. Douglas G, Hale AB, Crabtree MJ, Ryan BJ, Hansler A, Watschinger K, et al. A requirement for Gch1 and tetrahydrobiopterin in embryonic development. Dev Biol. 2014 Dec 31. [Medline].

7. Adlam D, Herring N, Douglas G, et al. Regulation of ß-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin. Cardiovasc Res. 2012 Mar 15. 93(4):694-701. [Medline]. [Full Text].

8. Vasquez-Vivar J, Shi Z, Luo K,Thirugnanam K, Tan S. Tetrahydrobiopterin in antenatal brain hypoxia-ischemia-induced motor impairments and cerebral palsy. Redox Biol. 2017. 13:594-599. [Medline]. [Full Text].

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

10. Blau N, Bonafe, Blaskovics ME. Disorders of phenylalanine and tetrahydrobiopterin metabolism. Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases. 2nd ed. Berlin, Germany: Springer; 2002. 89-106.

11. Blau N, Thony B, Cotton RGH. Disorders of tetrahydrobiopterin and related biogenic amines. 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.

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

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

14. Douglas G, Hale AB, Patel J, Chuaiphichai S, Al Haj Zen A, Rashbrook VS, et al. Roles for Endothelial Cell and Macrophage Gch1 and Tetrahydrobiopterin in Atherosclerosis Progression. Cardiovasc Res. 2018. doi: 10.1093/cvr/cvy078:[Medline]. [Full Text].

15. Chuaiphichai S, Rashbrook VS, Hale AB, Trelfa L, Patel J, McNeill E, et al. Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II–Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm. Hypertension. 2018. 72(1):128-138. [Medline]. [Full Text].

16. Shen J-S, Arning E, West ML, Day TS, Chen S, Meng X-L, et al. Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease. Hum. Mol. Genet. 2017. 26(6):1182–1192. [Medline]. [Full Text].

17. Rivera JC, Noueihed B, Madaan A, Lahaie I, Pan J, Belik J, et al. Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina. J Neuroinflammation. 2017. 14(1):181. [Medline]. [Full Text].

18. Mascaro I, Ceravolo F, Ferraro S, Procopio D, Falvo F, Grisolia M, et al. Neurological Involvement in Tetrahydrobiopterin Deficiency. J Pediatr Biochem. 2016. 6:19-24. [Full Text].

19. Nasser A, Moller LB, Olesen JH, Konradsen LS, Andreasen JT. Anxiety- and depression-like phenotype of hph-1 mice deficient in tetrahydrobiopterin. Neurosci Res. 2014 Dec. 89:44-53. [Medline].

20. Han B, Zou H, Han B, Zhu W, Cao Z, Liu Y. Diagnosis, treatment and follow-up of patients with tetrahydrobiopterin deficiency in Shandong province, China. Brain and Dev. 2015. 37(6):592-598. [Medline]. [Full Text].

21. de Souza CAA, Alves MRA, Soares RDL, Kanufre VDC, Rodrigues VDM, Norton RDC, et al. BH4 deficiency identified in a neonatal screening program for hyperphenylalaninemia. Jornal de Pediatria. 2018. 94(2):170-176. [Full Text].

22. Fiori L, Fiege B, Riva E, Giovannini M. Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. Mol Genet Metab. 2005 Dec. 86 Suppl 1:S67-74. [Medline].

23. Blau N, Erlandsen H. The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab. 2004 Jun. 82(2):101-11. [Medline].

24. Gramer G, Burgard P, Garbade SF, Lindner M. Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase-deficient hyperphenylalaninaemia. J Inherit Metab Dis. 2007 Aug. 30(4):556-62. [Medline].

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

26. 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. 2006 Sep. 27(9):870-8. [Medline].

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

28. 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. 2007 Mar. 90(3):277-83. [Medline].

29. Ponzone A, Spada M, Ferraris S, Dianzani I, de Sanctis L. Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev. 2004 Mar. 24(2):127-50. [Medline].

30. Ye J, Yang Y, Yu W, Zou H, Jiang J, Yang R, et al. Demographics, diagnosis and treatment of 256 patients with tetrahydrobiopterin deficiency in mainland China: results of a retrospective, multicentre study. J Inherit Metab Dis. 2012 Nov 9. [Medline].

31. Wang R, Shen N, Ye J, Han L, Qiu W, Zhang H, et al. Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population. Clin. Chim. Acta. 2018. 481:132-138. [Full Text].

32. Fernández-Lainez C, Ibarra-González I, Alcántara-Ortigoza MÁ, Fernández-Hernández L, Enríquez-Flores S, González-Del Ángel A, et al. Mutational spectrum of PTS gene and in silico pathological assessment of a novel variant in Mexico. Brain Dev. 2018. 40(7):530-536. [Medline]. [Full Text].

33. Chaiyasap P, Ittiwut C, Srichomthong C, Sangsin A, Suphapeetiporn K, Shotelersuk V. Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand. BMC Med. Genet. 2017. 18:102. [Full Text].

34. Liu TT, Chiang SH, Wu SJ, Hsiao KJ. Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese. Clin Chim Acta. 2001 Nov. 313(1-2):157-69. [Medline].

35. Nalin T, Perry ID, Sitta A, et al. Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency. Mol Genet Metab. 2011. 104 Suppl:S80-5. [Medline].

36. Stojiljkovic M, Klaassen K, Djordjevic M, Sarajlija A, Kecman B, Ugrin M, et al. Tetrahydrobiopterin deficiency among Serbian patients presenting with hyperphenylalaninemia. J Pediatr Endocrinol Metab. 2015. 28(3-4):477-80. [Medline]. [Full Text].

37. Shintaku H, Ohwada M. Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan. Brain Dev. 2012 Jul 23. [Medline].

38. Opladen T, Hoffmann GF, Blau N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis. 2012 Nov. 35:963-73. [Medline].

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

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

41. 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. 2011 Jun. 3:819-26. [Medline].

42. 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. 2006 Feb. 29(1):127-34. [Medline].

43. 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].

44. 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. 1996 Aug 20. 7(13):1587-93. [Medline].

45. 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. 1998 Jul. 71(1):33-40. [Medline].

46. 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. 2000 Jan-Feb. 2(1):22-31. [Medline].

47. 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. 2009 Jul. 97(3):165-71. [Medline].

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

49. 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. 2006 Dec. 29(6):725-31. [Medline].

50. 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. 2007 May. 49(5):372-6. [Medline].

51. Porta F, Ponzone A, Spada M. Target Prolactin Range in Treatment of Tetrahydrobiopterin Deficiency. J Pediatr. 2016 Jan. 168:236-239. [Medline].

52. Porta F, Ponzone A, Spada M. Long-term safety and effectiveness of pramipexole in tetrahydrobiopterin deficiency. Eur J Paediatr Neurol. 2016. 20(6):839-842. [Medline]. [Full Text].

53. Burnett JR. Sapropterin dihydrochloride (Kuvan/phenoptin), an orally active synthetic form of BH4 for the treatment of phenylketonuria. IDrugs. 2007 Nov. 10(11):805-13. [Medline].

Anna V Blenda, PhD Clinical Associate Professor, Department of Biomedical Sciences, University of South Carolina School of Medicine, Greenville

Anna V Blenda, PhD is a member of the following medical societies: American Association for Cancer Research, American College of Medical Genetics and Genomics, American Society for Microbiology

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.

Luis O Rohena, MD, MS, FAAP, FACMG Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

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 Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Noah S Scheinfeld, JD, MD, FAAD † Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

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

Disclosure: Nothing to disclose.

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.

• Print this section
• Print the entire contents of
• Print the entire contents of article