U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

PTS-Related Tetrahydrobiopterin Deficiency (PTPSD)

Synonyms: 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency, PTS Deficiency

, MD, , MD, PhD, and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Revision: March 5, 2026.

Estimated reading time: 35 minutes

Summary

Clinical characteristics.

PTS-related tetrahydrobiopterin deficiency (PTPSD) results in a lack of tetrahydropterin, an important cofactor for phenylalanine hydroxylase (PAH), tyrosine hydroxylase, and tryptophan hydroxylase. Deficiency can thus lead to neurotransmitter and neuropsychiatric disorders. The clinical spectrum of PTPSD is broad and differs according to age of onset, severity of disease, and whether preventative therapies were initiated and maintained from an early age. In the severe form, clinical symptoms may become apparent in the neonatal period and can include hypotonia, movement disorders, abnormal eye movements, autonomic dysregulation, and impaired development. Without treatment, developmental delays become more marked. Neurologic symptoms (dysarthria, dystonia, tremors, abnormal gait, parkinsonism, oculogyric crises, motor tics) may be ameliorated by treatment with sapropterin dihydrochloride and neurotransmitter precursors. Other features of the condition can include psychiatric comorbidities (ADHD, anxiety, depression), infant feeding difficulties leading to early growth failure, hyperprolactinemia, growth hormone deficiency, sleep issues, and autonomic dysfunction; many of these features can be ameliorated by appropriate treatment. In treated individuals, development often improves during adolescence, with many adults having a normal IQ level.

In the mild (peripheral) form, affected individuals are usually asymptomatic apart from an increase in phenylalanine (Phe) levels. Some remain asymptomatic. However, with time, some have mild developmental delays and can develop deficiency of neurotransmitter production, such that treatment of some asymptomatic individuals may be required.

Diagnosis/testing.

The biochemical diagnosis of PTPSD is established in a proband with confirmed hyperphenylalaninemia, elevated neopterin levels, reduced biopterin levels, and a decreased biopterin-to-neopterin ratio in urine or dried blood spots (DBS) and normal dihydropteridine reductase (DHPR) activity in DBS. The molecular diagnosis of PTPSD is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in PTS by molecular genetic testing.

Management.

Targeted therapies: Immediate therapy with sapropterin (tetrahydrobiopterin dihydrochloride; BH4), a cofactor/cosubstrate of PAH, is recommended to reduce blood Phe concentrations in individuals with hyperphenylalaninemia. If sapropterin is not available, dietary Phe restriction should be implemented. Because sapropterin has limited access to the central nervous system (CNS), or rather, this access is only achieved at high doses, therapy with sapropterin does not normalize the activity of tyrosine or tryptophan hydroxylase in people with PTPSD. Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors (levodopa plus decarboxylase inhibitor (DCI), i.e., carbidopa or benserazide), 5-hydroxytryptophan, and/or dopamine (rotigotine patch, pramipexole) and/or serotonin agonists, or other medications (MAO inhibitors such as selegiline) to address specific neurotransmitter deficiencies and maintain optimal neurologic function.

Supportive care: Optimization of dosage and intervals of levodopa/DCI in those with abnormal movements/parkinsonism; growth hormone supplementation and/or optimization of neurotransmitter precursor therapy for growth hormone deficiency; optimization of neurotransmitter precursor therapy for recurrent hyperthermia; anticholinergic treatment may be considered for hypersalivation; standard treatment for developmental delay, spasticity, epilepsy, sleep disorders, and decreased bone mineral density.

Biochemical surveillance: Routine Phe monitoring in infants (age <1 year) weekly until normalized and then every three to six months once levels normalize; every six months in children younger than age 12 years; and every six to 12 months in adolescents and adults; the Phe target ranges correspond to those of PAH deficiency. Prolactin level at each visit. Routine clinical visits with a metabolic specialist (and metabolic dietician if on Phe-restricted diet) every one to three months in infants (age <1 year), every three to six months between ages one and seven years, and every six to 12 months in those age eight years and older.

General surveillance: At each visit, measure growth parameters and evaluate nutritional status; asses for new neurologic manifestations (changes in tone, seizures, movement disorders); monitor developmental progress and assess educational needs; monitor for behavioral issues (anxiety, ADHD, emotional dysregulation, depression, aggression); and assess for signs and symptoms of sleep disorders. At ages two, six, 12, and 18 years, consider neuropsychological evaluation. In adulthood, periodic parathormone levels and DXA scan. As needed, consider EEG to differentiate from movement disorder seizures.

Agents/circumstances to avoid: Persons with PTPSD on Phe-reduced diet should either avoid products containing aspartame or calculate total intake of Phe when using such products and adapt diet components accordingly.

Evaluation of relatives at risk: If prenatal genetic testing has not been performed, each at-risk newborn sib should be evaluated immediately (at or just after 24 hours) after birth for PTPSD using measurement of blood Phe concentration to allow for earliest possible diagnosis and treatment. If older sibs have not undergone NBS or genetic testing for the known familial pathogenic variants in PTS, measure blood Phe concentrations to clarify their disease status.

Pregnancy management: Women with PTPSD who have received appropriate treatment throughout childhood and adolescence and during pregnancy may have offspring with normal intellectual and behavioral development, particularly if levels of Phe are kept in the normal range during pregnancy. Intensive clinical and biochemical supervision by a multidisciplinary team before, during, and after pregnancy in a woman with PTPSD is essential to control the symptoms of the disease, adjust the treatment if needed, and monitor the development of the fetus. If the affected woman has elevated blood Phe concentrations during pregnancy, the fetus is at high risk for maternal phenylketonuria (MPKU) syndrome (reported specifically in women who have PAH deficiency as the primary cause of their elevated Phe levels), including malformations and intellectual disability, since Phe is a potent teratogen.

Genetic counseling.

PTPSD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PTS pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial PTS pathogenic variants. Children born of one parent with PTPSD and one parent with two normal PTS alleles are obligate heterozygotes. If the mother is the affected parent, MPKU syndrome is a critical issue. Females with PTPSD should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (i.e., MPKU syndrome) when they reach childbearing age. Once the PTS pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for PTPSD are possible.

Diagnosis

Deficiency of tetrahydrobiopterin (BH4), a cofactor for the enzyme phenylalanine hydroxylase (PAH), can lead to accumulation of phenylalanine (Phe) in the blood (hyperphenylalaninemia). In addition, it impairs activity of tyrosine (Tyr) and tryptophan hydroxylase, leading to defective synthesis of neurotransmitters; this, together with hyperphenylalaninemia, can cause central nervous system (CNS) dysfunction. BH4 can be synthesized directly from guanosine triphosphate (GTP) by GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase, or it can be produced through a salvage pathway by sepiapterin reductase and dihyropteridine reductase. This chapter focuses on deficiency of BH4 due to reduced or absent PTPS (PTPSD).

Suggestive Findings

A diagnosis of PTPSD may be suspected due to an abnormal newborn screening (NBS) result of hyperphenylalaninemia prior to onset of suggestive findings or may be considered because of symptoms of PTPSD.

Abnormal NBS Result

NBS for PTPSD is primarily based on use of dried blood spots (DBS) collected between 24 hours and 72 hours after birth to quantify Phe and Tyr concentrations by tandem mass spectrometry (MS/MS). In the United States (US) and European Union (EU) most NBS laboratories determine their own levels for results that are considered out of range. For information on NBS by state in the US, see www.newbornscreening.hrsa.gov/your-state. Note: (1) False negative results (i.e., normal blood Phe value) for PTPSD have been reported in several individuals whose NBS was collected prior to 24 hours of life; these individuals were subsequently detected on the second NBS done one week later [Manzoni et al 2020]. (2) Out-of-range NBS results are not specific to PTPSD.

Immediately on receipt of out-of-range NBS results (i.e., elevated Phe levels and/or elevated Phe:Tyr ratio), further evaluation to establish a diagnosis is required and presumptive management should be considered. It is recommended that plasma amino acids be obtained in all children with an elevated Phe level on NBS.

Recommended types of diagnostic testing for infants with elevated Phe levels on NBS are reviewed in Table 1. See also Establishing the Diagnosis, Analyte Diagnosis and Molecular Diagnosis to make an analyte diagnosis or confirm a diagnosis molecularly, respectively.

  • For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
  • If a metabolic specialist is not available, the treatments suggested in Management should be considered.

Symptomatic Individual

A symptomatic individual can have either typical findings associated with later-diagnosed PTPSD or untreated PTPSD resulting from any of the following: NBS not performed, false negative NBS result, symptom onset prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Supportive – but nonspecific – clinical findings, brain MRI findings, and preliminary laboratory findings are listed here.

Clinical findings

  • Microcephaly
  • Intellectual disability
  • Seizures or epilepsy
  • Disturbance of muscle tone and posture
  • Drowsiness
  • Irritability
  • Oculogyric crises
  • Abnormal movements
  • Temperature instability
  • Hypersalivation
  • Swallowing difficulties

Brain MRI findings. Nonspecific findings have been reported in some untreated individuals and can include the following [Wang et al 2006]:

  • Brain atrophy
  • Isolated central tegmental tract hyperintensity
  • White matter abnormalities

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Analyte Diagnosis

The biochemical diagnosis of PTPSD is established in a proband with confirmed hyperphenylalaninemia (see Table 1), elevated neopterin levels, reduced biopterin levels, and a decreased biopterin-to-neopterin ratio in urine or dried blood spots (DBS) and normal dihydropteridine reductase (DHPR) activity in DBS.

Note: A sapropterin dihydrochloride (BH4) loading test, in which an individual is given 20 mg/kg of sapropterin with subsequent serial measurements of serum Phe levels at baseline (prior to the sapropterin load), four hours, eight hours, 24 hours, 32 hours, and 48 hours after the loading dose is positive in people with PTPSD; however, with the availability of pterin analysis and genetic testing, this loading test is rather outdated.

Molecular Diagnosis

The molecular diagnosis of PTPSD is established in a proband with consistent analyte findings and/or suggestive clinical features by identification of biallelic pathogenic (or likely pathogenic) variants in PTS by molecular genetic testing (Table 2).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic PTS variants of uncertain significance (or of one known PTS pathogenic variant and one PTS variant of uncertain significance) does not establish or rule out the diagnosis in the absence of biochemical testing. In this scenario, analyte testing can aid in the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of PTPSD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel, the advantage of which is that it includes assessment for the more common PAH deficiency, DNAJC12 deficiency, and the various other genes associated with BH4-related causes of elevated Phe concentrations (see Differential Diagnosis).

  • Single-gene testing. Sequence analysis of PTS can be performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; several such deletions have been previously identified [Blau et al 2000, Wang et al 2018]. Note: Pathogenic variants outside the coding region can be missed by exome sequencing and have also been reported [Stenson et al 2020].
  • A multigene panel that includes PTS and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2

Exome or genome sequencing can be used. Ordering a rapid turnaround time exome or genome sequencing is recommended when newborns or infants are critically ill. To date, most PTS pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing [Stenson et al 2020].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in PTPSD

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
PTS Sequence analysis 387% 4
Gene-targeted deletion/duplication analysis 5Rare 4
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from Himmelreich et al [2021] and the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Blau et al [2000]) may not be detected by these methods.

Clinical Characteristics

Clinical Description

The clinical spectrum of PTPSD is broad and differs according to age of onset, severity of disease, and whether preventative therapies were initiated and maintained from an early age. In general, this condition can be divided into two forms [Manzoni et al 2020]: severe and mild (or peripheral). Infants are usually identified due to elevated phenylalanine (Phe) levels on newborn screening (NBS) and started on a low-Phe diet while confirmatory testing is still pending. However, unlike phenylalanine hydroxylase (PAH) deficiency, a low-Phe diet may not prevent symptom onset and progression (see Management) in people with PTPSD, particularly if they have the severe form that impacts the production of neurotransmitters.

  • Severe form. Affected individuals have decreased levels of cerebrospinal fluid (CSF) monoamine neurotransmitter metabolites, including 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA). Those who are treated with sapropterin dihydrochloride (BH4) and neurotransmitter precursors prior to age two months have a better prognosis and frequently experience progressive improvements in neurologic and developmental symptoms. However, most affected individuals still have some signs and symptoms, even on such therapy.
  • Mild (or peripheral) form. The mild form does not impact CSF neurotransmitter levels. Affected individuals may have either milder developmental issues or, less commonly, a normal neurologic outcome with BH4 therapy alone or in combination with neurotransmitter precursors (see Management).

Severe PTPSD

Affected individuals can experience symptoms as early as the neonatal period. Clinical signs can include hypotonia, movement disorders, abnormal eye movements, autonomic dysregulation, and impaired development. However, affected infants who are diagnosed through NBS are usually asymptomatic, although there is an increased risk of prematurity and low birth weight (even without prematurity).

Once results of confirmatory testing are available, these children are started on BH4 therapy and can revert to a totally normal diet without the need of Phe or protein restriction.

Table 3.

Select Features of Severe PTPSD

Feature% of Persons w/FeatureComment
Developmental delays>95%About 75% of untreated persons have cognitive impairment, w/smaller proportion of treated persons experiencing developmental delays or permanent cognitive impairment
Axial hypotonia90%
Prematurity60%Typically mild, w/average gestational age of affected persons being 37.8 ± 2.4 weeks [Manzoni et al 2020]
Low birth weight60%Average z score −1.14 ± 0.97 SD 1 [Manzoni et al 2020]
Distal hypertonia60%
Cognitive impairment75%
Oculogyric crises60%
Dystonia / involuntary movements40%
Swallowing problems35%

SD = standard deviation

1.

After correcting for sex and gestational age

Developmental delay (DD) and intellectual disability (ID). People with PTPSD may have no suggestive findings at birth, although those with the most severe forms tend to be born prematurely with low birth weight.

  • Developmental delays are usually noted around age one month.
  • Without treatment, developmental delays become more marked.
  • With treatment, affected individuals might still require additional help in school.
    • Speech is typically the most affected developmental parameter.
    • Development frequently improves during adolescence, with many adults having a normal IQ level [Manzoni et al 2020]. This may be true even for those who experienced speech or more global developmental delays when they were younger.
    • Independent or partially independent living is often attainable, with some affected individuals attending college.

Other neurodevelopmental features. Neurologic symptoms frequently appear at a few months of life and may be ameliorated, but not completely eliminated, by treatment with BH4 and neurotransmitter precursors. These include the following:

  • Axial hypotonia with limb hypertonia
  • Movement disorders, most frequently seen after age three months:
    • Dysarthria
    • Dystonia
    • Tremors
    • Abnormal gait
    • Parkinsonism, including bradykinesia or cogwheeling
    • Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
    • Motor tics

Epilepsy. Epilepsy is not a common finding in affected individuals, although on occasion abnormal movements can be confused with epilepsy. However, a small number of affected individuals have experienced seizures, including absence seizures, focal seizures, or generalized seizures [Manti et al 2020].

Neurobehavioral/psychiatric manifestations. People with PTPSD can develop behavioral disturbances and significant psychiatric comorbidities, even when they are treated. Findings can include:

  • Attention-deficit/hyperactivity disorder (ADHD)
  • Anxiety
  • Depression
  • Aggression
  • Oppositional defiant disorder (ODD)
  • Emotional dysregulation
  • Irritability

Growth/feeding. Individuals with PTPSD have the highest rate of symmetrical intrauterine growth restriction (sIUGR) and infants who are small for their gestational age among the group of BH4 deficiencies (see Differential Diagnosis). They also have an increased risk of prematurity.

Infant feeding difficulties can lead to growth failure early in life. This usually resolves with time and appropriate medical therapy. Supplementation with neurotransmitter precursors can improve feeding issues, such as swallowing problems and gastroesophageal reflux disease.

Weight and height often improve over time, such that they approach typical values [Manzoni et al 2020].

Endocrinologic. Defective dopamine production can lead to levodopa-refractory hyperprolactinemia, pituitary gland abnormalities, and growth hormone deficiency; appropriate neurotransmitter precursor therapy can reduce the risk of these complications [Yıldız et al 2024]. There is an inverse correlation between prolactin levels and growth [Manzoni et al 2020].

  • Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see Management).
  • Some affected individuals have true growth hormone deficiency (see Management) [Opladen et al 2020].
  • Currently there is no evidence that individuals with PTPSD have issues with bone health; however, as there are recommendations for maintaining bone health in individuals with PAH deficiency, this has also been recommended for individuals with PTPSD (see Management).

Other associated features

  • Sleep issues can include hypersomnolence or insomnia, fatigue, and/or sleep disorders.
  • Autonomic dysfunction can include hypersalivation and sweating, which typically improves with therapy (see Management).
  • Brain MRI findings, which are found in about 50% of affected individuals who have undergone brain imaging, can include the following [Manti et al 2020, Manzoni et al 2020]:
    • Periventricular hyperintensities
    • Delayed myelination
    • Brain calcifications
    • Brain atrophy
    • Pituitary gland hyperplasia or adenoma

Mild (Peripheral) PTPSD

In the mild (peripheral) form, affected individuals are usually asymptomatic apart from an increase in Phe levels. With time, they can have mild developmental delays and can develop deficiency of neurotransmitter production. Some remain asymptomatic.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Nomenclature

BH4-deficient hyperphenylalaninemia is an umbrella term encompassing all types of hyperphenylalaninemia caused by BH4 deficiency, i.e., hyperphenylalaninemia associated with pathogenic variants in PTS, GCH1, PCBD, or QDPR (see Differential Diagnosis).

Hyperphenylalaninemia type III is an outdated term previously used to denote PTPSD.

Prevalence

The exact global prevalence of PTPSD is still unknown. However, it is estimated that BH4 deficiencies (all forms) account for about 1%-2% of hyperphenylalaninemias, which have a prevalence of approximately one in 15,000 individuals. Additionally, PTPSD specifically accounts for around 54% of all BH4 deficiencies [Opladen et al 2020].

Differential Diagnosis

The most common genetic cause of hyperphenylalaninemia is phenylalanine hydroxylase (PAH) deficiency. Hyperphenylalaninemia due to impaired synthesis or recycling of tetrahydrobiopterin (BH4), the cofactor in the phenylalanine (Phe), tyrosine (Tyr), and tryptophan hydroxylation reactions, accounts for approximately 1%-2% of individuals with elevated Phe concentrations in most populations. However, for individuals with an elevated Phe concentration from populations in which PAH deficiency is less common (e.g., Japan, Taiwan), the risk to the affected individual of having a disorder of pterin metabolism is much higher. Of the disorders of pterin metabolism, PTPSD is the most common.

Inherited co-chaperone DNAJC12 deficiency has been identified as a potential differential diagnosis for primary hyperphenylalaninemia, alongside PAH deficiency and disorders of BH4 metabolism (see Table 4). DNAJC12 deficiency presents with a wide clinical spectrum, ranging from asymptomatic to severely disabled individuals. DNAJC12 deficiency exhibits unique biochemical characteristics, such as decreased neurotransmitter metabolites in the cerebrospinal fluid (CSF) resembling BH4 deficiency, but with normal BH4 metabolites similar to PAH deficiency.

Table 4.

Disorders Known to Cause Hyperphenylalaninemia

Disease MechanismGeneDisorderMOI
Name / ReferenceAbbreviation
Phenylalanine hydroxylase deficiency PAH Phenylalanine hydroxylase deficiencyPAH deficiencyAR
BH4 deficiency disorders assoc w/
hyperphenylalaninemia		 GCH1 Autosomal recessive GTP cyclohydrolase I deficiency (OMIM 233910)AR GTPCH deficiencyAR
PCBD1 Pterin-4-alpha-carbinolamine dehydratase deficiency (OMIM 264070)PCD deficiencyAR
PTS 6-pyruvoyl-tetrahydropterin synthase deficiency (topic of this GeneReview)PTS deficiency, PTPSDAR
QDPR Q-dihydropteridine reductase deficiency (OMIM 261630)DHPR deficiencyAR
Co-chaperone deficiency 1 DNAJC12 DNAJC12 deficiency (OMIM 617384)DNAJC12 deficiencyAR

AR = autosomal recessive; BH4 = tetrahydrobiopterin; MOI = mode of inheritance

1.

DNAJC12 encodes co-chaperone of HSP70, which interacts with PAH, tyrosine hydroxylase, and tryptophan hydroxylase.

Management

Consensus guidelines for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies have been published [Opladen et al 2020] (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PTPSD, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The general concepts of immediate care for children with confirmed PTPSD include supplementation of the missing neurotransmitter precursors (in those who have low neurotransmitter levels in cerebrospinal fluid [CSF]) and restoring deficient cofactors to normalize hyperphenylalaninemia.

  • In individuals with hyperphenylalaninemia, immediate therapy involving dietary phenylalanine (Phe) restriction is recommended to lower Phe levels, similar to the approach taken in phenylalanine hydroxylase (PAH) deficiency.
  • For infants, Phe-free metabolic infant formula in combination with breastmilk and/or infant formula may be used.
  • However, once a diagnosis of PTPSD is confirmed, treatment typically involves the administration of oral sapropterin, which is a synthetic form of BH4, or a Phe-reduced diet, if sapropterin is not available.
  • BH4 can easily reach the liver and enable the enzyme PAH to function properly.
  • Unlike in PAH deficiency, oral sapropterin has the ability to completely normalize Phe levels, eliminating the need for a long-term restricted diet.
  • Sepiapterin, a prodrug of BH4, has been shown to lower blood Phe levels in individuals with PTPSD at lower doses compared to sapropterin [Curtius et al 1979].
    Sepiapterin is now approved in Europe and the United States for individuals with PAH deficiency [Muntau et al 2024]. In addition to lowering Phe levels, sepiapterin could potentially offer the advantage of crossing the blood-brain barrier and activating tyrosine and tryptophan hydroxylase [Smith et al 2019] (see Therapies Under Investigation).
  • Therefore, after initiating sapropterin therapy, the diet can be liberalized.

Targeted Pharmacologic Therapy

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Sapropterin has limited access to the central nervous system (CNS), and this access is only achieved at high doses, typically around 40 mg/kg/day (although this would be considered an off-label dose for this medication).

  • Due to this limitation, therapy with sapropterin does not fully normalize the activity of tyrosine (Tyr) or tryptophan hydroxylase in people with PTPSD.
  • Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors and/or dopamine and serotonin agonists, or other medications to address specific neurotransmitter deficiencies and maintain optimal neurologic function.
  • Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see Table 8).

Table 6.

PTPSD: Targeted Pharmacologic Therapy

Treatment ClassMechanism of ActionSpecific DrugDoseComments
CofactorPAH activatorSapropterin5-20 mg/kg/dayHigher doses might allow CSF penetration (this would be considered an off-label dose)
Neurotransmitter precursorsConversion to dopamine for direct activation of dopamine receptorsLevodopa + DCIUp to 10 mg/kg/day (levodopa part) 1, 2This medication requires stepwise dose increase to reach maximal dose. 1, 2
5-hydroxytryptophan (5-HTP)Up to 5 mg/kg/day
MAO inhibitorsPrevent breakdown of serotonin & dopamineSelegiline
  • Start at 0.1 mg/kg/day in 2-3 divided doses.
  • Increase every 2 weeks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day.
  • Dose at breakfast & lunch; avoid nighttime doses if insomnia is experienced.
  • Dose sublingual preparations much lower (see package insert).
Dopamine agonistsMimics dopamine effectPramipexoleAge >2 yrs:
  • Start w/2 µg/kg/day divided BID.
  • Increase by 1 µg/kg every 2 weeks, if tolerated, to max of 10 µg/kg/day
Rotigotine patchAge >12 yrs & >15 kg:
  • Start w/2 mg/day.
  • Increase weekly by 2 mg up to a max of 8 mg/day.
  • Do not cut patches.
  • Drug-induced dyskinesias require a lower dose &/or slower dose increase.
  • Skin reactions occur in about 30% of people.
CabergolineSee package insert.To address hyperprolactinemia, particularly in females after puberty

BID = twice a day; CSF = cerebrospinal fluid; DCI = decarboxylase inhibitor; PAH = phenylalanine hydroxylase; PTPSD = PTS-related tetrahydrobiopterin deficiency

1.

Levodopa treatment should be started at 0.5 to 1 mg/kg/day and be stepwise increased to a final dose of up to 10 mg/kg/day (or the individual maximally tolerated dosage) in at least four to five doses per day over a time period of five to 10 (or more) weeks.

2.

The pace of dosage increase depends on individual levodopa sensitivity.

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see Table 7).

Table 7.

PTPSD: Supportive Care

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay /
Intellectual disability /
Neurobehavioral issues 		See Developmental Delay / Intellectual Disability Management Issues.
Spasticity Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & fallsConsider need for positioning & mobility devices, disability parking placard.
Abnormal movements / parkinsonism Optimize dosage & intervals of levodopa/carbidopa administration.See Table 6.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Movement disorders can be confused w/epilepsy.
  • Education of parents/caregivers 1
Swallowing difficulties / Poor growth
  • Feeding therapy may be considered.
  • Gastrostomy tube placement is usually not required.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Growth hormone deficiency Optimize neurotransmitter precursor therapy.Particularly when prolactin levels are ↑, suggesting defective dopamine production.
Consider growth hormone supplementation.In those w/true growth hormone deficiency
Recurrent hyperthermia Optimize neurotransmitter precursor therapy.
Hypersalivation Consider anticholinergic treatment.
Sleep disorders Consider melatonin supplementation.Consider referral to sleep disorders clinic.
↓ bone mineral density Standard treatment per endocrinologist
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; PTPSD = PTS-related tetrahydrobiopterin deficiency

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction

Gross motor dysfunction. For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Neurobehavioral/Psychiatric Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Transitional Care

As PTPSD is a lifelong disorder with varying implications according to age, smooth transition of care of affected individuals from a pediatric setting to an adult-centered multidisciplinary care setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because standardized procedures for transitional care do not exist for PTPSD due to the absence of multidisciplinary outpatient departments and lack of adult-specific metabolic centers in most places, the following have been observed:

  • Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
  • As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.

Surveillance

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Table 8 are recommended to monitor the individual's response to care, existing manifestations, and the emergence of new manifestations.

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 9 are recommended.

Agents/Circumstances to Avoid

Aspartame is an artificial sweetener in widespread use that is often added to soft drinks, foods, and some medications to improve their taste. It is metabolized in the gastrointestinal tract into Phe and other byproducts. Persons with PTPSD on a Phe-reduced diet should either avoid products containing aspartame or calculate total intake of Phe when using such products and adapt diet components accordingly [Maler et al 2023].

Note: Some medications (such as antibiotics) contain aspartame; thus, short treatment courses might need to be given if no alternative antibiotics are readily available.

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. If the PTS pathogenic variants in the family are known, molecular genetic prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to allow for institution of treatment at birth of an infant known to be affected.

Newborn sib of a proband with PTPSD. If prenatal testing has not been performed, each at-risk newborn sib should be evaluated immediately (at or just after 24 hours) after birth for PTPSD using measurement of blood Phe concentration to allow for earliest possible diagnosis and treatment.

  • The initial newborn screening (NBS) Phe measurement (collected when the newborn is on a normal formula / breast milk diet) should determine if the Phe concentration is elevated. If the blood Phe concentration is elevated, a Phe-free formula should be provided as soon as possible to quickly reduce the infant's blood Phe concentration (see Treatment of Manifestations). Note: False negative results for PTPSD have been reported in several individuals whose NBS was collected prior to 24 hours of life; these individuals were subsequently detected on the second NBS done one week later [Manzoni et al 2020].
  • In most circumstances, the NBS blood Phe measurement will be available before the results of molecular genetic testing, even if the familial pathogenic variants are known. Molecular genetic testing can be used to confirm the diagnosis in a newborn with a positive NBS (molecular genetic testing in this circumstance is most informative if the familial PTS pathogenic variants are known). Note that if molecular testing is performed, carrier status would also be determined, so appropriate genetic counseling when testing a minor should also be included in any discussion.

Older at-risk sibs. Because phenotypic variability may be significant, previously undiagnosed and even apparently asymptomatic sibs of an affected individual may also be affected [Vockley et al 2014].

  • Review of sib NBS results is recommended to confirm the disease status of at-risk sibs. If older sibs have not undergone NBS, it is important to measure blood Phe concentrations of at-risk sibs to clarify their disease status.
  • If the PTS pathogenic variants in the family are known, molecular genetic testing can clarify the status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with PTPSD who have received appropriate treatment throughout childhood and adolescence and during pregnancy may have offspring with normal intellectual and behavioral development, particularly if levels of Phe are kept in the normal range during pregnancy. Intensive clinical and biochemical supervision by a multidisciplinary team before, during, and after pregnancy in a woman with PTPSD is essential to control the symptoms of the disease, adjust the treatment if needed, and monitor the development of the fetus. If the affected woman has elevated blood Phe concentrations during pregnancy, the fetus is at high risk for maternal phenylketonuria (MPKU) syndrome (reported specifically in women who have PAH deficiency as the primary cause of their elevated Phe levels) including malformations and intellectual disability, since Phe is a potent teratogen (see Phenylalanine Hydroxylase Deficiency, Clinical Characteristics, MPKU Syndrome) [Rouse & Azen 2004, Prick et al 2012].

  • Sapropterin. The fetal risk of sapropterin therapy during pregnancy is generally considered lower than the risk to the fetus if the mother has elevated Phe levels during pregnancy. Studies done in animal models do not suggest an increased risk of malformations in exposed animal embryos. There is limited human data on the use of this medication during pregnancy.
  • Levodopa/DCI. Limited human data is available on the use of levodopa during pregnancy, which has primarily involved women taking this medication due to Parkinson disease; however, case reports and drug registries have not identified an increased risk of major congenital anomalies in exposed human fetuses [Kuseyri et al 2018].
  • 5-hydroxytryptophan. There is no data on the use of this medication during human pregnancy. However, in animal models, large doses (doses that lead to maternal toxicity) did interfere with embryo development.
  • Carbergoline. This medication is not expected to lead to an increased risk of birth defects in exposed human fetuses.
  • Selegiline. This medication is typically avoided in pregnancy due to concerns about possible vasoconstrictive effects.
  • Rotigotine. There is limited data on the use of this medication during human pregnancy. However, in animal models, use of this medication (often at greatly elevated doses than would be used in routine care) interfered with embryo survival.
  • Pramipexole. There is limited data on the effect of this medication on the fetus during human pregnancy. However, based on data from animal models, the rate of malformations is not expected to be increased.

See MotherToBaby for further information on medication use during pregnancy.

During pregnancy

  • Co-monitor in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PTPSD.
    • Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
    • In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
  • Monitor dietary intake of pregnant women with PTPSD to ensure nutrient adequacy with proper proportion of protein, fat, and carbohydrates.
  • Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at the appropriate gestational ages.

Therapies Under Investigation

Sepiapterin, a prodrug of BH4 with enhanced brain permeability, has been studied in individuals with PTPSD (NCT03519711) and is now approved in Europe and United States for individuals with PAH deficiency [Muntau et al 2024].

In addition to lowering Phe levels, sepiapterin could potentially offer the advantage of crossing the blood-brain barrier and activating tyrosine and tryptophan hydroxylase [Smith et al 2019].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PTPSD is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for a PTS pathogenic variant.
  • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a PTS pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for a PTS pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • Unless an affected individual's reproductive partner is a carrier of a PTS pathogenic variant, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in PTS.
  • If the proband is female, fetal exposure to elevated maternal blood phenylalanine (Phe) concentrations during pregnancy is a critical issue (see Pregnancy Management). Note: Offspring of women with PTPSD who have received appropriate treatment throughout childhood and adolescence and during pregnancy can have normal intellectual and behavioral development.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a PTS pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the PTS pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • Young women of childbearing age with PTPSD should receive counseling regarding the teratogenic effects of elevated maternal blood Phe concentrations during pregnancy (see Pregnancy Management).
  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PTS pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

PTS-Related Tetrahydrobiopterin Deficiency (PTPSD): Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
PTS11q23​.16-pyruvoyl tetrahydrobiopterin synthaseBIOMDBdb : Database of Mutations Causing BH4 Deficiencies and other PND (PTS)
PTS database		PTSPTS

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for PTS-Related Tetrahydrobiopterin Deficiency (PTPSD) (View All in OMIM)

261640HYPERPHENYLALANINEMIA, BH4-DEFICIENT, A; HPABH4A
6127196-@PYRUVOYL-TETRAHYDROPTERIN SYNTHASE; PTS

Molecular Pathogenesis

Tetrahydrobiopterin (BH4) can be synthesized directly from guanosine triphosphate (GTP) by GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase, or it can be produced through a salvage pathway by sepiapterin reductase and dihyrofolate reductase.

One of the functions of BH4 is as a cofactor for the enzyme phenylalanine hydroxylase. Deficiency of this cofactor can lead to accumulation of phenylalanine in the blood, which can cause central nervous system (CNS) dysfunction.

BH4 is also a cofactor for tyrosine and tryptophan hydroxylase, enzymes involved in the synthesis of monoamine neurotransmitters whose deficiency can cause CNS dysfunction independently from hyperphenylalaninemia and for all three forms of nitric oxide synthase.

Mechanism of disease causation. Loss of function

Chapter Notes

Acknowledgments

Nicola Longo is supported in part by the Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium funded by the National Institutes of Health (U54HD100982).

Thomas Opladen is subnet coordinator with the framework of MetabERN, the European Reference Network for Hereditary Metabolic Disorders, Subnetwork NOMS (Disorders of Neuromodulators and Other Small Molecules), and coordinator of the International Working Group on Neurotransmitter-Related Disorders (iNTD).

Nenad Blau is supported by the Nenad Blau IEMbase Endowment Fund of the MCF, Marin County, California.

Revision History

  • 5 March 2026 (ma) Revision: sepiapterin approved for use in individuals with PAH deficiency
  • 10 July 2025 (ma) Review posted live
  • 21 June 2024 (nb) Original submission

References

Literature Cited

  • Blau N, Oppliger-Scherer T, Baumer A, Riegel M, Matasovic A, Schinzel A, Jaeken J, Thony B. Isolated central form of tetrahydrobiopterin deficiency associated with hemizygosity on chromosome 11q and a mutant allele of PTPS. Hum Mut. 2000;16:54-60. [PubMed: 10874306]
  • Curtius HC, Niederwieser A, Viscontini M, Otten A, Schaub J, Scheibenreiter S, Schmidt H. Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiapterin. Clin Chim Acta. 1979;93:251-62. [PubMed: 445845]
  • Himmelreich N, Blau N, Thöny B. Molecular and metabolic bases of tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 2021;133:123-36. [PubMed: 33903016]
  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
  • Kuseyri O, Weissbach A, Bruggemann N, Klein C, Gizewska M, Karall D, Scholl-Burgi S, Romanowska H, Krzywinska-Zdeb E, Monavari AA, Knerr I, Yapici Z, Leuzzi V, Opladen T. Pregnancy management and outcome in patients with four different tetrahydrobiopterin disorders. J Inherit Metab Dis. 2018;41:849-63. [PubMed: 29594647]
  • Lowe TB, DeLuca J, Arnold GL. Similarities and differences in key diagnosis, treatment, and management approaches for PAH deficiency in the United States and Europe. Orphanet J Rare Dis. 2020;15:266. [PMC free article: PMC7519570] [PubMed: 32977849]
  • Maler V, Goetz V, Tardieu M, Khalil AE, Alili JM, Meunier P, Maillot F, Labarthe F. Aspartame and Phenylketonuria: an analysis of the daily phenylalanine intake of aspartame-containing drugs marketed in France. Orphanet J Rare Dis. 2023;18:142. [PMC free article: PMC10249154] [PubMed: 37291632]
  • Manti F, Nardecchia F, Banderali G, Burlina A, Carducci C, Carducci C, Donati MA, Gueraldi D, Paci S, Pochiero F, Porta F, Ortolano R, Rovelli V, Schiaffino MC, Spada M, Blau N, Leuzzi V. Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients. Mol Genet Metab. 2020;131:155-62. [PubMed: 32651154]
  • Manzoni F, Salvatici E, Burlina A, Andrews A, Pasquali M, Longo N. Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth. Mol Genet Metab. 2020;131:380-9. [PMC free article: PMC7749858] [PubMed: 33234470]
  • Muntau AC, Longo N, Ezgu F, Schwartz IVD, Lah M, Bratkovic D, Margvelashvili L, Kiykim E, Zori R, Campistol Plana J, Belanger-Quintana A, Lund A, Guilder L, Chakrapani A, Mungan HN, Guimas A, Cabrales Guerra IDC, MacDonald A, Ingalls K, Smith N, group As. Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2024;404:1333-45. [PubMed: 39368841]
  • Opladen T, Lopez-Laso E, Cortes-Saladelafont E, Pearson TS, Sivri HS, Yildiz Y, Assmann B, Kurian MA, Leuzzi V, Heales S, Pope S, Porta F, Garcia-Cazorla A, Honzik T, Pons R, Regal L, Goez H, Artuch R, Hoffmann GF, Horvath G, Thony B, Scholl-Burgi S, Burlina A, Verbeek MM, Mastrangelo M, Friedman J, Wassenberg T, Jeltsch K, Kulhanek J, Kuseyri Hubschmann O, International Working Group on Neurotransmitter related D. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH(4)) deficiencies. Orphanet J Rare Dis. 2020;15:126. [PMC free article: PMC7251883] [PubMed: 32456656]
  • Prick BW, Hop WC, Duvekot JJ. Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies. Am J Clin Nutr. 2012;95:374-82. [PubMed: 22205310]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Rouse B, Azen C. Effect of high maternal blood phenylalanine on offspring congenital anomalies and developmental outcome at ages 4 and 6 years: the importance of strict dietary control preconception and throughout pregnancy. J Pediatr. 2004;144:235–9. [PubMed: 14760268]
  • Smith N, Longo N, Levert K, Hyland K, Blau N. Exploratory study of the effect of one week of orally administered CNSA-001 (sepiapterin) on CNS levels of tetrahydrobiopterin, dihydrobiopterin and monoamine neurotransmitter metabolites in healthy volunteers. Mol Genet Metab Rep. 2019;21:100500. [PMC free article: PMC6700519] [PubMed: 31453106]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16:188-200. [PubMed: 24385074]
  • Wang L, Yu WM, He C, Chang M, Shen M, Zhou Z, Zhang Z, Shen S, Liu TT, Hsiao KJ. Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency. J Inherit Metab Dis. 2006;29:127-34. [PubMed: 16601879]
  • Wang R, Shen N, Ye J, Han L, Qiu W, Zhang H, Liang L, Sun Y, Fan Y, Wang L, Wang Y, Gong Z, Liu H, Wang J, Yan H, Blau N, Gu X, Yu Y. Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population. Clin Chim Acta. 2018;481:132-8. [PubMed: 29499199]
  • Yıldız Y, Kuseyri Hubschmann O, Akgoz Karaosmanoglu A, Manti F, Karaca M, Schwartz IVD, Pons R, Lopez-Laso E, Palacios NAJ, Porta F, Kavecan I, Balci MC, Dy-Hollins ME, Wong SN, Oppeboen M, Medeiros LS, de Paula LCP, Garcia-Cazorla A, Hoffmann GF, Jeltsch K, Leuzzi V, Gokcay G, Hubschmann D, Harting I, Ozon ZA, Sivri S, Opladen T. Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism. J Inherit Metab Dis. 2024;47:431-46. [PubMed: 37452721]
Copyright © 1993-2026, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. Test.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (https://www.genereviews.org) and copyright (© 1993-2026 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: addmast@wu.edu

Bookshelf ID: NBK616086PMID: 40638773
GeneReviews by Title

Views

In this GeneReview

Bulk Download

GeneReviews Links

Key Sections in This GeneReview

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

ClearTurn OffTurn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...