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

Tetrahydrobiopterin Deficiency: Treatment & Medication

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: Feb 1, 2010

Treatment

Medical Care

  • Most patients are treated in a specialty metabolic clinic, usually under the direction of a geneticist or a pediatric endocrinologist.
  • Treatment of tetrahydrobiopterin (BH4) deficiencies consists of BH4 supplementation or dietary changes to control blood Phe concentration and replacement therapy with neurotransmitter precursors (eg, levodopa and carbidopa, 5-hydroxytryptophan [5HT]). In dihydropteridine reductase (DHPR) deficiency, folinic acid is supplemented.
  • In patients with BH4 deficiency, levodopa replacement therapy (to increase dopamine levels) should be started in the first weeks or months of life. Patients diagnosed before age 2 years and 6 months can obtain normal executive functions and prevent development of motor and cognitive symptoms with levodopa supplementation.12 This finding suggests dopamine may play a critical role in ensuring stable development of executive functions in early life.
  • Depending on the variant, levels of the relevant enzymes are checked.
  • In DHPR, some positive reports have documented the use of monoamine oxidase (MAO) B inhibitor.
  • Treatment is determined on the basis of enzyme-defect phenotype, as follows:
    • Severe guanosine triphosphate (GTP) cyclohydrolase I (GTPCH) - Levodopa, 5HT, BH4
    • Severe 6-pyruvoyl-tetrahydropterin synthase (PTPS) - Levodopa, 5HT, BH4
    • Mild PTPS - BH4
    • Transient PTPS - BH4 in the neonatal period
    • Severe DHPR - Levodopa, 5HT, low-Phe diet, folinic acid
    • Mild DHPR - Low-Phe diet
    • Transient carbinolamine-4a-dehydratase (PCD) - BH4 in the neonatal period

Consultations

  • A psychologist should perform developmental testing at regular intervals.
  • Whenever possible, the patient and his or her parents should work with a nutritionist and a geneticist experienced in BH4 deficiency.

Diet

  • Treatment of BH4 deficiencies consists of BH4 supplementation (2-20 mg/kg/d) or diet to control blood Phe and, in DHPR deficiency, supplements of folinic acid (10-20 mg/d).

Activity

  • BH4 deficiencies are heterogeneous. They range from mild forms that require only marginal, if any, treatment to severe forms that are sometimes difficult to treat. In many cases, normal activity can be expected if the patient adheres to treatment.

Medication

Treatment of tetrahydrobiopterin (BH4) deficiencies consists of BH4 supplementation or diet to control blood Phe and supplements of folinic acid (10-20 mg/d) in dihydropteridine reductase (DHPR) deficiency.

Pteridines

These replace the missing essential cofactor in the enzymatic hydroxylation of the 3 aromatic amino acids. Synthetic BH 4 (sapropterin) is now approved as an orphan drug by the US Food and Drug Administration (FDA).13  Additional information can be viewed at the Tetrahydrobiopterin Web site.


Sapropterin (Kuvan)

PO active synthetic form of (6R)-L-erythro-5,6,7,8-BH4 (a cofactor for PAH) that has received orphan drug status and fast track designation for the treatment of PKU. PAH hydroxylates phenylalanine through an oxidative reaction to form tyrosine. Treatment with BH 4 can activate residual PAH enzyme, improve normal oxidative metabolism of phenylalanine, and decrease phenylalanine levels in some patients.
Essential for hydroxylation of aromatic amino acids. Replaces missing cofactor. Dose based on specific phenotypic enzyme defect. Indicated to reduce blood phenylalanine levels in patients with HPA. Used in conjunction with a phenylalanine-restricted diet.

Adult

10 mg/kg PO qd initially; dosage ranges from 5-20 mg/kg/d; dissolve tab in 4-8 oz of water or apple juice and drink contents within 15 min of dissolving (tab may not dissolve completely, but swallowing small pieces floating on top of water or juice is normal and safe); administer with food to increase absorption

Pediatric

<4 years: Not established
>4 years: Administer as in adults
PTPS or GTPCH: 2-10 mg/kg/d PO qd or divided bid
DHPR: 12-20 mg/kg/d PO qd or divided bid

Use caution with coadministration of drugs known to affect folate metabolism (eg, methotrexate, sulfamethoxazole) and their derivatives because these drugs can decrease BH 4 levels by inhibiting the enzyme DHPR; coadministration with drugs that affect nitric oxide[en dash]mediated vasorelaxation (eg, PDE-5 inhibitors such as sildenafil, vardenafil, and tadalafil) may increase risk of hypotension; a 10-year postmarketing safety surveillance program for a non-PKU indication using another formulation of sapropterin resulted in 3 patients with underlying neurologic disorders experiencing convulsions, exacerbation of convulsions, overstimulation, or irritability during coadministration with levodopa

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Regularly monitor blood phenylalanine levels to avoid HPA and resulting neurologic impairment and mental retardation; use does not eliminate need for ongoing dietary management (ie, phenylalanine-restricted diet); common adverse effects include headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, diarrhea, abdominal pain, vomiting, nausea, upper respiratory tract infection, and pharyngolaryngeal pain

Neurotransmitter precursors

These are used to supply necessary catecholamine replacement in the neurotransmitter pathway.


Levodopa and carbidopa (Sinemet)

First-line treatment in conjunction with 5-HTP. Combination helps levodopa cross blood-brain barrier. Ratio prescribed for BH4 is 10:1 (levodopa 100 mg with carbidopa 10 mg).

Adult

Not established

Pediatric

1-3 mg/kg/d (based on levodopa component) PO divided tid-qid initially; may gradually titrate up to 5-15 mg/kg/d PO divided tid-qid; optimal dose typically 8-10 mg/kg/d

Hydantoins, pyridoxine, and hypotensive agents may decrease levodopa effects; MAOIs may increase levodopa serum level

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with history of coronary artery disease, arrhythmias, asthma, or peptic ulcer disease; sudden discontinuation of levodopa may worsen symptoms; high-protein diets should be distributed throughout day to avoid fluctuation in levodopa absorption


5-Hydroxytryptophan (5-HTP)

First-line therapy used in conjunction with levodopa. Aromatic amino acid and immediate precursor of serotonin. Orphan drug in United States (available from Circa Pharmaceuticals or Watson Laboratories).

Adult

Not established

Pediatric

4-10 mg/kg/d PO divided tid-qid; optimal dosage is 6-8 mg/kg/d
Coadministration with levodopa: 6-8 mg/kg/d PO divided tid-qid

Coadministration with carbidopa enhances absorption and increases blood and brain levels; may increase risk of serotonin syndrome when coadministered with MAOIs, TCAs, reserpine, fenfluramine, or SSRIs

Documented hypersensitivity; peptic ulcer disease; platelet disorders; renal disease

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Anorexia, nausea, diarrhea, or vomiting common adverse effects; eosinophilia myalgia syndrome linked to tryptophan

Vitamins

These increase levels of factors necessary in the amino acid pathways.


Leucovorin (Wellcovorin)

Folinic acid (reduced form of folic acid that does not require enzymatic reduction for activation). First-line therapy in DHPR variant.

Adult

Not established

Pediatric

10-20 mg/kg/d PO as a single daily dose in DHPR

Decreases effect of methotrexate, phenytoin, phenobarbital, and sulfamethoxazole and trimethoprim combinations; increases toxicity of fluorouracil

Documented hypersensitivity; pernicious anemia; vitamin-deficient megaloblastic anemias

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Allergic sensitization reported

Selective MAO B inhibitors

When high doses of neurotransmitters are necessary, the concurrent use of selective MAO B inhibitors is recommended because such use reduces the required dosage of administered precursors.


Selegiline (Eldepryl)

Also known as L-deprenyl. Irreversible inhibitor of MAO. Possesses greater affinity for type B than for type A active sites. Can selectively inhibit MAO type B. Blocks breakdown of dopamine and extends duration of action of each dose of levodopa.

Adult

Not established

Pediatric

Not established; limited data suggest 0.1-0.3 mg/kg/d PO divided bid-tid

Allow at least 5 wk between discontinuation of fluoxetine and initiation of MAOIs to prevent fatal interactions reported with MAO type A inhibitors; data regarding tyramine-containing foods (eg, aged cheese, yeast extracts, beer) with selegiline limited; avoid administering MAOIs concomitantly with opioids; severe agitation, hallucinations, and death have occurred with concomitant administration with meperidine

Documented hypersensitivity; concomitant meperidine or other opioids; concomitant TCAs or SSRIs (relative contraindication)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use carefully in children because usage and risks not determined; in adults, daily doses exceeding recommended dose (10 mg/d) increases risk of nonselective inhibition of MAO and risk of hypertensive crisis when used concomitantly with tyramine-containing foods and other indirectly acting sympathomimetics

More on Tetrahydrobiopterin Deficiency

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

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Further Reading

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Keywords

tetrahydrobiopterin deficiency, BH4 deficiency, BH4D, malignant phenylketonuria, malignant PKU, atypical phenylketonuria, atypical PKU, malignant hyperphenylalaninemia, nonphenylketonuria hyperphenylalaninemia, non-phenylketonuria hyperphenylalaninemia, non-PKU hyperphenylalaninemia, HPA, phenylalanine, Phe, treatment, symptoms

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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, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, 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
Disclosure: Nothing to disclose.

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 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.

 
 
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