eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Tetrahydrobiopterin Deficiency: Follow-up

Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Coauthor(s): Elena L Jones, MD, Clinical Assistant Professor of Dermatology, College of Physicians and Surgeons of Columbia University; Clinic Chief, Department of Dermatology, St Luke's-Roosevelt Hospital Center
Contributor Information and Disclosures

Updated: Jun 5, 2008

Follow-up

Deterrence/Prevention

  • Avoid substances containing aspartame.
  • Avoid drugs that effect folate metabolism such as methotrexate and trimethoprim-sulfamethoxazole.

Prognosis

  • The prognosis for normal intelligence is good with dietary and medical treatment.
  • Nontreatment and treatment failure are associated with neurologic and cognitive dysfunction.
  • Treatment is not always successful.

Patient Education

  • Teach parents how to administer the diet, medications, and supplements at home, and involve all caregivers.
  • Children should begin involvement in their dietary and medical planning as soon as they are developmentally ready.

Miscellaneous

Medicolegal Pitfalls

  • Misdiagnosis of the condition as PKU with subsequent neurologic impairment
  • Failure to recognize that screening may have been performed too soon (eg, before 12-24 h of life, depending on local standards), leading to a false-negative result
  • Failure to avoid drugs that affect folate metabolism, such as trimethoprim-sulfamethoxazole and methotrexate
  • Failure to provide adequate energy intake, essential amino acids, vitamins, and minerals
  • Failure to monitor for common nutritional deficiencies

Special Concerns

  • During pregnancy, levels of pterins can be evaluated in amniotic fluid and in other maternal material to determine if the fetus has a tetrahydrobiopterin (BH4) deficiency.
  • Such tests are usually performed only in women who have had children with BH4 deficiency.
 


More on Tetrahydrobiopterin Deficiency

Overview: Tetrahydrobiopterin Deficiency
Differential Diagnoses & Workup: Tetrahydrobiopterin Deficiency
Treatment & Medication: Tetrahydrobiopterin Deficiency
Follow-up: Tetrahydrobiopterin Deficiency
References
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References

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  2. 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].

  3. 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].

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

  5. 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].

  6. 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].

  7. 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].

  8. 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].

  9. 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].

  10. 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].

  11. 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].

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

  13. 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.

  14. 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].

  15. 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.

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

  17. 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].

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

  19. 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].

  20. 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].

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

  22. 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].

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

  24. 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].

  25. 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].

  26. 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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Further Reading

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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

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Contributor Information and Disclosures

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, 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, College of Physicians and Surgeons of Columbia University; Clinic Chief, Department of Dermatology, St Luke's-Roosevelt Hospital Center
Disclosure: Nothing to disclose.

Medical Editor

Erawati V Bawle, MD, FAAP, FACMG, Director, Division of Genetic and Metabolic Disorders, Department of Pediatrics, Children's Hospital of Michigan; Professor (Clinician-Educator), Wayne State University School of Medicine
Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

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.

CME Editor

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, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, 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.

 
 
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