Laboratory Studies

Pterins (eg, neopterin, monapterin, isoxanthopterin, biopterin, primapterin, pterin) are measured in urine. Typical urinary pterin profiles are detailed below.

In guanosine triphosphate (GTP) cyclohydrolase I (GTPCH) deficiency, neopterin and biopterin levels are low.

In 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, the neopterin level is high and the biopterin level is low.

In dihydropteridine reductase (DHPR) deficiency, the neopterin level is in the reference range or slightly increased, and the biopterin level is high. DHPR activity in RBCs can be measured via Guthrie card. In DHPR deficiency, prolactin levels may be elevated, and they can be evaluated to monitor therapy.

In carbinolamine-4a-dehydratase (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.

In a loading test with tetrahydrobiopterin (BH4),^[39]the blood Phe level was lowered to the reference range value (20 mg/dL) 4-8 hours after an oral loading dose of BH4 was 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 phenylketonuria (PKU) due to Phe-4-hydroxylase (PAH) deficiency, the change in blood Phe is minimal. Combined Phe and BH4 loading can also be performed.

Levels of neurotransmitter metabolites (eg, 5-hydroxyindoleacetic acid [5HIAA], homovanillic acid [HVA]) and pterins can be determined in cerebrospinal fluid (CSF). In addition, levels of folates (eg, 5-methyltetrahydrofolate [5MTHF]) can be measured in the CSF. Enzyme activity (ie, PTPS, GTPCH, DHPR, sepiapterin reductase [SR]) in RBCs, WBCs, or fibroblasts (FBs) can be measured.

A Phe-loading test can be used in patients with dopa-responsive dystonia (DRD), which is also termed Segawa disease.

DNA analysis is used to evaluate for mutations in the affected genes: Sanger sequencing, next generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), and quantitative real-time PCR (qRT-PCR).^{[33, 31, 32]}

Investigating the presence of deficiencies in iron, vitamins, selenium, protein, essential fatty acids, and other nutrients that have been reported in treated PKU can be considered. However, investigating these deficiencies is not part of the standard evaluation of BH4 deficiencies.

When dopamine levels are monitored to assess the treatment and disease, the measurement of serum prolactin levels instead of CSF homovanillic acid (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.

Since 1980, BH4 metabolism had been screened in 2,186 babies with hyperphenylalaninemia, using measurement of pteridines in urine to recognize BH4 synthesis deficiency (GTPCH and PTPS deficiency) and direct DHPR assay in dried blood samples to recognize DHPR deficiency.^[40]Seventy three babies with BH4 deficiency were identified. This screening demonstrated that tests on blood and urine collected on filter paper cards were convenient and simple to assemble and evaluate. In half of the babies with BH4 deficiency, the blood phenylalanine level was less than 10 mg/dL (0.6 mmol/L).

A 5-year experience of diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots examination has been reported.^[41]

Imaging Studies

In one study from Taiwan, MRI showed fewer white-matter changes but MR spectroscopy showed more in white-matter changes patients with BH4 deficiency than in patients with classic PKU.^[34]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 deficiency 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.

In another study,^[42]CT scanning in 31 patient with PTPS deficiency revealed calcification in lentiform nuclei in one patient, and MRI showed delayed myelination and abnormal high intensity signal in cerebral white matter in all of them. Most abnormalities were reversible, but small patchy or spotted areas were still present in these regions after 10-46 months of treatment.

Treatment & Management

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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.

Sections BH4 Deficiency (Tetrahydrobiopterin Deficiency)
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