Medical Care

Most patients are treated in a specialty metabolic clinic, usually under the direction of a geneticist or a pediatric endocrinologist.

In some cases, gene therapy has been used, with a possible effect.^{[43, 44, 45, 46]}Gene therapy is not widely used, and its use is purely experimental.

Treatment of tetrahydrobiopterin (BH4) deficiencies consists of BH4 supplementation^{[47, 48, 49]}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 Japan, sapropterin dihydrochloride is used as a treatment.^[37]

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.^[50]This finding suggests dopamine may play a critical role in ensuring stable development of executive functions in early life. While treating BH4 deficiency, there is a target prolactin range.^[51]

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.

A 2016 report described safe and clinically effective long-term use of low-dose pramipexole (~0.010 mg/kg/day) for the most common causes of BH4 deficiency, which are PTPS and DHPR deficiencies.^[52]

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.

Prevention

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

Medication

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Media Gallery

Autosomal recessive inheritance.

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Author

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.

Specialty Editor Board

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.

Chief Editor

Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, 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, PhD, 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.

Additional Contributors

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.