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

Tetrahydrobiopterin Deficiency

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
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

Updated: Feb 1, 2010

Introduction

Background

Tetrahydrobiopterin (BH₄) deficiencies are disorders that affect phenylalanine (Phe or F) homeostasis, as well as brain biosynthesis of catecholamine, serotonin, and (occasionally) nitric oxide.^{[1 ]}

BH₄ deficiencies are grouped with phenylketonuria (PKU), which is an inborn error of protein metabolism that results from an impaired ability to metabolize the essential amino acid Phe. Similar to PKU, BH₄ deficiencies negatively affect developmental function; however, BH₄ deficiencies also affect neurologic functioning, depending on the variant. Some, but not all, BH₄ deficiencies may be detected with PKU screening tests used in Western countries, depending on the variant.

BH₄ deficiencies are heterogeneous. They range from mild forms that do not require treatment to severe cases that are difficult to ameliorate even with therapy.

Pathophysiology

Enzymatic reactions and defects

BH₄ deficiencies fall into 4 main categories, depending on the enzymatic defect that leads to a lack of BH₄. Through September 2006, 193 different mutant alleles or molecular lesions identified in the guanosine triphosphate cyclohydrolase I (GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR), carbinolamine-4a-dehydratase (PCD), or dihydropteridine reductase (DHPR) genes had been identified.^{[2 ]}

The most well-established human function of BH₄ is as the cofactor for Phe-4-hydroxylase (PAH), tyrosine-3-hydroxylase, and tryptophan-5-hydroxylase. The last 2 are key enzymes in biogenic amine biosynthesis, that is, aromatic amino acid synthesis. In addition to hydroxylating aromatic amino acids, BH₄ serves as the cofactor for nitric oxide synthase and glyceryl-ether mono-oxygenase.

These reactions are based on the ability of BH₄ to react with molecular oxygen to form an active oxygen intermediate that can hydroxylate substrates. Although BH₄ is absolutely essential for nitric oxide synthase activity, its exact function with different forms of the enzyme and its mechanism of action remain to be defined.

BH₄ is synthesized from guanosine triphosphate (GTP) in at least 4 enzymatic steps by the action of 3 enzymes. GTP cyclohydrolase I (GTPCH), the first enzyme in BH₄ biosynthesis, catalyzes the formation of 7,8-dihydroneopterin triphosphate from GTP in a single reaction step. GTPCH is subject to feedback inhibition by BH₄. A single-copy gene, GCH1, located on chromosome band 14q22.1-q22.2 encodes GTPCH.

In the next step, 6-pyruvoyl-tetrahydropterin synthase (PTPS) catalyzes the conversion of 7,8-dihydroneopterin triphosphate to 6-pyruvoyl-tetrahydropterin. The PTS gene on chromosome band 11q22.3-q23.3 encodes PTPS.

Sepiapterin reductase (SR) is a nicotinamide adenine dinucleotide phosphate (NADP), reduced form, (NADPH) oxidoreductase. It is required for the final 2-step reduction of the dike to intermediate 6-pyruvoyl-tetrahydropterin to BH₄. The SPR gene on chromosome band 2p14-p12 encodes SR.

During the enzymatic hydroxylation of aromatic amino acids, molecular oxygen is consumed and BH₄ is peroxidated and oxidized. The pterin intermediate is subsequently reduced back to BH₄ by 2 enzymes and a reduced pyridine nucleotide (ie, NADH) in a complex recycling reaction.

Molecular oxygen is first bound to BH₄ to form an unstable 4-alpha--peroxy-BH₄. The mono-oxygenation of aromatic amino acids is thus concomitant with oxidation of BH₄ to 4-alpha--hydroxy-BH₄ (pterin-4-alpha-carbinolamine). Pterin-4-alpha-carbinolamine is subsequently dehydrated to quinonoid-dihydrobiopterin (q-dihydrobiopterin) and water by the specific and highly efficient pterin-4-alpha-carbinolamine dehydratase (PCD). The PCBD gene on chromosome band 10q22 encodes PCD.

In the last step of BH₄ recycling, q-dihydrobiopterin is reduced back to BH₄ by the NADH-DHPR. Folate inhibitors, such as methotrexate, inhibit the activity of the enzyme both in vivo and in vitro. The QHPR gene on chromosome band 4p15.3 encodes DHPR.

Genetic factors

BH₄ deficiency comprises heterogeneous autosomal recessive disorders caused by mutations in the PTS (most common), SPR, QHPR, and GCH1 genes. See the image below for an illustration of autosomal recessive inheritance patterns.

Autosomal recessive inheritance.

BH₄ deficiency without HPA occurs in 6,10-methylenetetrahydrofolate reductase deficiency and vitiligo or DRD.

Fiori et al noted that HPA is an inherited metabolic disorder due to deficiency of the enzyme PAH or its cofactor BH₄.^{[3 ]}BH₄ -responsiveness in PAH-deficient HPA is a recently described characteristic of most mild phenotypes. BH₄ -responsive patients have reduced plasma Phe levels after the oral administration of BH₄.

The investigators determined the incidence of BH4-responsiveness among a nonselected cohort of patients with PAH-deficient HPA and evaluated the phenotype-genotype correlations. They evaluated 11 patients born in Lombardy, Italy, between January 2000 and December 2004. HPA (107 patients) was classified after BH₄ -loading test, an analysis of urinary pterin levels, and a determination of DHPR activity in the blood. The researchers assessed the patients for BH₄ -responsiveness.

Patients were given 6R-BH₄ 20mg/kg orally as a single dose, and plasma samples were obtained at 0, 4, 8, and 24 hours after administration. In patients with basal plasma Phe levels of 360 mmol/L, a combined Phe (100 mg Phe/kg) and BH₄ (20 mg/kg) loading test was performed. Patients were considered responsive to BH₄ when their plasma Phe levels decreased by 30% at 8 hours after oral administration of BH₄.

The investigators found that BH₄ significantly lowered blood Phe levels in 91 (85%) of 107 patients with PAH-deficient HPA. Most of the responsive patients had mild HPA (77%), although some had mild (7%) or moderate (7%) PKU. One patient with classical PKU was responsive to BH BH₄. Eighteen mutations were associated to the BH₄ -responsive phenotype.

The authors concluded that a consistent number of patients with PAH-deficient HPA responded to BH₄ and that BH₄ responsiveness seemed to be common in mild phenotypes. Genotype was not the only factor that determined BH BH₄ responsiveness.

Frequency

United States

The incidence of classic PKU is approximately 1 case in 15,000 births. The incidence of BH₄ deficiency is approximately 1 case per 1 million births, or 1.5-2% of cases of PKU.

International

In Taiwan, 2-30% of cases of PKU are attributed to BH₄ deficiency.^{[4 ]}In Turkey, which has the highest incidence of PKU in the world with approximately 1 case per 2600 births, 15% of cases are due to BH₄ deficiency. In Saudi Arabia, 66% of PKU cases are due to BH₄ deficiency. The incidence also appears to be increased in southern Brazil. Such increased incidences are thought to be related to consanguinity.

Pangkanon et al reported the first 2 cases of PTPS deficiency in Thailand.^{[5 ]}Both cases were males with phenylalanine levels of 25.23 mg/dL and 23.4 mg/dL, respectively. The urinary pterins analysis showed low biopterin levels, low percentages of urinary biopterin, and high neopterin levels. The mutation analysis of the patient with a phenylalanine level of 25.23 mg/dL revealed a point mutation in exon 4 and a homozygous C-to-T transition at nucleotide 200 in codon 67 (T67M). The other patient demonstrated a compound heterozygous in exon 4, C-to-A transition at nucleotide 200 and exon 5, and C-to-T transition at nucleotide 259 of the PTS gene, confirming PTPS deficiency.

Farrugia et al noted that the deficient activity of the DHPR enzyme is due to mutations in the quinoid dihydropteridine reductase (QDPR) gene on 4p15.3.^{[6 ]}Deficient activity of the DHPR enzyme results in defective recycling of BH ₄ , and homozygotes have a rare form of atypical HPA and PKU. The heterozygote frequency in the Maltese population is high (3.3%).

Mortality/Morbidity

Patients with severe of BH₄ deficiency present with mental retardation and neurologic impairment. Early death may result. Patients with mild cases can have mild degrees of mental retardation and neurologic impairment.

Race

Children of Chinese, Turkish, and Saudi Arabian descent are most often affected.

Sex

No sex predilection is reported. The mode of inheritance is autosomal recessive.

Age

BH₄ deficiency is most commonly diagnosed in newborns by means of newborn screening programs. Consider BH₄ deficiency in patients of any age who have PKU and developmental delay or mental retardation with neurologic impairment. Newborn screening does not always detect the disease. Patients who are symptomatic usually present by age 4 months.

Clinical

History

• Most neonates with tetrahydrobiopterin (BH₄) deficiencies appear healthy at birth.
• In severe 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, the incidence of prematurity and low birth weight is increased.
• In severe PTPS deficiency, lead-pipe or cogwheel rigidity and stiff-baby syndrome have been reported.
• BH₄ deficiency converts neuronal nitric oxide synthases (NOSs) into an efficient peroxynitrite synthase, which is responsible for the increase in neuronal vulnerability to hypoxia-induced mitochondrial damage and necrosis.
• Endothelial BH₄ availability is essential for maintaining pulmonary vascular homeostasis, and it is a critical mediator in the pathogenesis of pulmonary hypertension. It is also a novel therapeutic target.
• BH₄ restores use of the flow reserve in the coronary microcirculation in subjects with hypercholesterolemia. This finding suggests that BH₄ deficiency may contribute to dysfunction of the coronary microcirculatory in hypercholesterolemia.

Physical

At birth, neonates with BH₄ deficiencies often appear healthy. Pigmentary dilution can be noted. Physical findings manifest as the neonate matures.

• Patients may have red hair.
• They may have poor suckling, decreased spontaneous movements, and a floppy-baby appearance.
• If the disease is not detected on newborn screening, affected children develop progressive developmental delay and neurologic impairment that manifests as psychomotor retardation, progressive neurologic deterioration, convulsions, abnormal movements, hypersalivation, and swallowing difficulties.

Causes

• See Pathophysiology.

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 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.
  • 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.
• DHPR activity in RBCs can be measured on Guthrie card.
• In a loading test with tetrahydrobiopterin (BH₄),^{[7 ]}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 phenylketonuria (PKU) due to Phe-4-hydroxylase (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 cerebrospinal fluid (CSF).
• Determine levels of folates (eg, 5-methyltetrahydrofolate [5MTHF]) 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 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 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.

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.^{[4 ]}
  • 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.^{[8,9,10,11 ]}
• Gene therapy is not widely used, and its use is purely experimental.

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.

Dosing

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

Interactions

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

Contraindications

None known

Precautions

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).

Dosing

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

Interactions

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

Contraindications

Documented hypersensitivity

Precautions

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).

Dosing

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

Interactions

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

Contraindications

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

Precautions

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.

Dosing

Adult

Not established

Pediatric

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

Interactions

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

Contraindications

Documented hypersensitivity; pernicious anemia; vitamin-deficient megaloblastic anemias

Precautions

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.

Dosing

Adult

Not established

Pediatric

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

Interactions

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

Contraindications

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

Precautions

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

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 phenylketonuria (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.

Multimedia

Media file 1: Autosomal recessive inheritance.

References

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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

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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