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

Tetrahydrobiopterin Deficiency: Differential Diagnoses & Workup

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

Differential Diagnoses

Hyperphenylalaninemia
Phenylketonuria

Other Problems to Be Considered

Neonatal neurologic diseases
Neonatal dystonic diseases (depending on variant of tetrahydrobiopterin deficiency)
Liver disease
Other causes of mental retardation
Tyrosinemia type II (Richner-Hanhart syndrome)
Tyrosinemia

Workup

Laboratory Studies

  • Pterins (eg, neopterin, monapterin, isoxanthopterin, biopterin, primapterin, pterin) are measured in urine. Typical urinary pterin profiles are as follows:
    • In GTPCH deficiency, neopterin and biopterin levels are low.
    • In PTPS deficiency, the neopterin level is high and the biopterin level is low.
    • In DHPR deficiency, the neopterin level is in the reference range or slightly increased, and the biopterin level is high.
    • In PCD deficiency, the neopterin level is initially high, the biopterin level is in the subnormal range, and a primapterin level (7-substituted biopterin) is present.
  • DHPR activity in RBCs can be measured on Guthrie card.
  • In a loading test with tetrahydrobiopterin (BH4), the blood Phe level is lowered to the reference range value (e2 mg/dL) 4-8 hours after an oral loading dose of BH4 is given.
    • When the preload blood Phe level is more than 20 mg/dL, the test result is positive if the level decreases less than 10 mg/dL for 4 hours, even if it does not decrease to the reference range at 4-8 hours after loading.
    • In classic PKU (due to PAH deficiency), the change in blood Phe is minimal.
  • Combined Phe and BH4 loading is performed.
  • Determine levels of neurotransmitter metabolites (eg, 5-hydroxyindoleacetic acid [5HIAA], homovanillic acid [HVA]) and pterins in CSF.
  • Determine levels of folates (eg, 5-methyltetrahydrofolate [5MTHF]) in the CSF.
  • Enzyme activity (ie, PTPS, GTPCH, DHPR, SR) in RBCs, WBCs, or fibroblasts (FBs) can be measured.
  • A Phe-loading test can be used in patients with DRD (Segawa disease).
  • DNA analysis can be used to look for mutations in the affected genes.
  • In DHPR, prolactin levels may be elevated, and they can be evaluated to monitor therapy.
  • Consider investigating the presence of deficiencies in iron, vitamins, selenium, protein, essential fatty acids, and other nutrients that have been reported in treated PKU. However, investigating these deficiencies is not part of the standard evaluation of BH4 deficiencies.
  • When dopamine levels are monitor to assess the treatment and disease, the measurement of serum prolactin levels instead of CSF HVA levels is recommended.
    • Because dopamine inhibits the secretion of prolactin, the serum prolactin concentration reflects the cerebral production of dopamine and functions as a useful indicator of dopamine creation and content in the hypothalamus.
    • Hyperprolactinemia has been documented in numerous patients with BH4 deficiencies.
  • Continued monitoring of serotonin and folate metabolism is performed by assessing 5HIAA and 5MTHF levels in the CSF.

Imaging Studies

  • In one study from Taiwan, MRI showed fewer white-matter changes but magnetic resonance (MR) spectroscopy showed more in white-matter changes patients with BH4 deficiency than in patients with classic PKU.3
    • MR spectroscopy may be useful for monitoring dosages of supplements used to treat this disorder.
    • In addition, MR spectroscopy may be helpful in understanding the neurophysiologic changes that occur in association with this disease.
  • In a study from Turkey, cranial CT scanning in 2 patients with DHPR demonstrated severe cortical and subcortical atrophy and bilateral corticomedullary and basal ganglial calcifications. These findings indicate that CT scanning has a role in monitoring such patients.

Procedures

  • In some cases, gene therapy has been used, with a possible effect.6,7,8,9
  • Gene therapy is not widely used, and its use is purely experimental.

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

  1. 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].

  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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