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Dihydropteridine Reductase Deficiency

Synonyms: DHPR Deficiency, DYT/PARK-QDPR, QDPR-Related Tetrahydrobiopterin Deficiency, Quinoid Dihydropteridine Reductase Deficiency

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

Author Information and Affiliations

Initial Posting: .

Estimated reading time: 25 minutes

Summary

Clinical characteristics.

Dihydropteridine reductase (DHPR) deficiency is characterized by hyperphenylalaninemia, abnormal muscle tone (trunk hypotonia and distal hypertonia), and autonomic dysfunction (hypersalivation, impaired temperature regulation, sweating). Without treatment, movement disorders, developmental delays, and intellectual disability develop. More than half of individuals have seizures. Neurobehavioral and psychiatric manifestations and microcephaly occur in some individuals. Early treatment prevents the most severe clinical manifestations but delays in neurocognitive development can still develop.

Diagnosis/testing.

The biochemical diagnosis of DHPR deficiency is established in a proband with confirmed hyperphenylalaninemia, normal (or slightly elevated) neopterin and elevated biopterin concentration in urine or dried blood spots (DBS), and low or absent DHPR activity in DBS or blood. The molecular diagnosis of DHPR deficiency is established in a proband with suggestive clinical and/or laboratory findings and biallelic pathogenic variants in QDPR identified by molecular genetic testing.

Management.

Targeted therapies: Sapropterin dihydrochloride; phenylalanine (Phe)-restricted diet; neurotransmitter precursors (levodopa/carbidopa and 5-hydroxytryptophan); folinic acid; anti-parkinsonian medications (dopamine agonists, selective monoamine oxidase inhibitors).

Supportive care: Additional supportive treatments include standard management for spasticity and seizures; developmental and educational support; melatonin for sleep impairment; care planning prior to surgeries and procedures; medical alert bracelet and care coordination documents for families and school; transitional care plan in adolescence.

Surveillance: Evaluation with experienced metabolic physician and nutritionist including measurement of blood Phe levels with frequency based on response to diet and sapropterin therapy; evaluation of nutritional status, safety of oral intake, and growth at each visit throughout childhood and adolescence; neurology evaluation to assess abnormal muscle tone, seizures, and movement disorders at each visit; EEG as needed; assess musculoskeletal issues, development and educational needs, neuropsychiatric manifestations, sleep issues, constipation, and family needs at each visit.

Agents/circumstances to avoid: Antiemetic (e.g., metoclopramide) and antipsychotic medications that act as central dopamine antagonists may worsen symptoms of dopamine deficiency; trimethoprim/sulfamethoxazole was reported to cause parkinsonian manifestations in an individual with DHPR deficiency; methotrexate may lead to hyperphenylalaninemia.

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

Genetic counseling.

DHPR deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a QDPR 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. Once the QDPR pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

Dihydropteridine reductase (DHPR) deficiency may be suspected in an infant with an out-of-range newborn screening (NBS) result of hyperphenylalaninemia prior to onset of suggestive findings or may be considered in an individual with suggestive findings of DHPR deficiency.

Infant with Out-of-Range NBS Result

Infants with DHPR deficiency often have out-of-range NBS results for phenylalanine hydroxylase deficiency (phenylketonuria), which is primarily based on use of dried blood spots (DBS) collected between 24 and 72 hours after birth to quantify phenylalanine (Phe) and tyrosine (Tyr) concentration by tandem mass spectrometry (MS/MS). In the United States (US) and European Union (EU) most NBS laboratories determine their own Phe and Tyr 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 concentration) have been reported in infants with DHPR deficiency [Kuseyri Hübschmann et al 2021a]. (2) Out-of-range NBS results are not specific to DHPR deficiency.

Immediately on receipt of out-of-range NBS results (i.e., elevated Phe concentration 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, Biochemical 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.

Proband with Suggestive Findings

A symptomatic individual can have the following clinical, laboratory, and/or imaging findings and family history.

Clinical findings

  • Abnormal muscle tone (trunk hypotonia and distal hypertonia)
  • Autonomic dysfunction (hypersalivation, impaired temperature regulation, sweating)
  • Dystonia / extrapyramidal movement disorder
  • Developmental delay without regression
  • Seizures
  • Neurobehavioral and psychiatric manifestations
  • Microcephaly

Laboratory findings

  • Elevated plasma Phe concentration
  • Quantitative assay of urine (or DBS) pterins. Normal (or slightly elevated) neopterin and elevated biopterin
  • Cerebrospinal fluid (CSF). Low neurotransmitter metabolites 5-hydroxyindoleacetic acid and homovanillic acid; low 5-methyltetrahydrofolate
  • Elevated plasma prolactin concentration

Imaging findings. Abnormalities on brain MRI have been reported in some untreated individuals [Kuseyri Hübschmann et al 2021b, Ribeiro et al 2023, Jarrah et al 2025] and can include the following:

  • Brain atrophy
  • Hyperintensity T2/FLAIR in basal ganglia
  • Basal ganglia calcifications
  • Incomplete hippocampal inversion

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

Biochemical Diagnosis

The biochemical diagnosis of DHPR deficiency is established in a proband with confirmed hyperphenylalaninemia (see Table 1), normal (or slightly elevated) neopterin and elevated biopterin concentration in urine or DBS, and low or absent DHPR activity in DBS or blood.

Molecular Diagnosis

The molecular diagnosis of DHPR deficiency is established in a proband with suggestive clinical and/or laboratory findings and biallelic pathogenic (or likely pathogenic) variants in QDPR identified by molecular genetic testing (see 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 QDPR variants of uncertain significance (or of one known QDPR pathogenic variant and one QDPR variant of uncertain significance) does not establish or rule out 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 clinical and/or laboratory findings suggest the diagnosis of DHPR deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of QDPR is 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.
  • A multigene panel that includes QDPR 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 rapid-turnaround exome or genome sequencing is necessary in critically ill infants. To date, most QDPR 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.

Dihydropteridine Reductase Deficiency: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
QDPR 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.

Clinical Characteristics

Clinical Description

The clinical spectrum of dihydropteridine reductase (DHPR) deficiency is broad and differs according to age of onset, severity of disease, and whether targeted therapies were initiated and maintained from any early age.

Onset. Most infants with DHPR deficiency are identified due to elevated phenylalanine (Phe) concentration on newborn screening (NBS). In those not identified by NBS, neurologic manifestations (axial hypotonia, limb hypertonia) frequently appear at a few months of life.

Abnormal muscle tone. Infants typically have axial hypotonia with limb hypertonia even when placed on a Phe-restricted diet. Unlike phenylalanine hydroxylase (PAH) deficiency, treatment with a low-Phe diet alone does not prevent disease progression in individuals with DHPR deficiency if the production of neurotransmitters is severely impacted. Abnormal muscle tone may be ameliorated but not completely resolved in those also treated with sapropterin (synthetic tetrahydrobiopterin [BH4]), folinic acid, and neurotransmitter precursors.

Autonomic dysfunction can be seen in neonates, and includes hypersalivation, temperature regulation impairment, and sweating, which typically improves with targeted therapies.

Movement disorders. Extrapyramidal movement disorders are most frequently seen after age three months in untreated individuals and primarily involve dystonia and tremors. Movement disorders, including relevant gait disorder and dystonia in the extremities or neck, become more prominent during childhood.

Developmental delay and intellectual disability. Infants appear normal at birth but can fall behind in motor and cognitive development if they are not treated with neurotransmitter precursors, even if therapeutic Phe levels are maintained with a Phe-restricted diet. Developmental delays are usually noted around age two months. 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.

Most individuals with DHPR deficiency develop mild-to-moderate intellectual disability. With treatment and developmental and educational support, independence (or partial independence) in adulthood is often possible, with some affected individuals able to pursue higher education.

Epilepsy. More than half of individuals with DHPR deficiency have seizures [Opladen et al 2020]. Various types of seizures can occur. Abnormal EEG patterns are seen in the majority of individuals with DHPR deficiency, but findings are nonspecific. Intractable seizures can develop without treatment.

Neurobehavioral/psychiatric manifestations. Individuals with DHPR deficiency can develop behavioral disturbances and significant psychiatric manifestations, even with dietary treatment and other targeted therapies. Findings can include attention-deficit/hyperactivity disorder, anxiety, depression, emotional dysregulation, and irritability. To date, prevalence of behavioral disturbances and psychiatric manifestations in those with DHPR deficiency is unknown.

Growth. Up to 25% of individuals with DHPR deficiency were reported to be microcephalic. To date, it is unclear if feeding, difficulty with weight gain, or linear growth are affected.

Neuroimaging. Abnormalities on brain MRI have been reported in some untreated individuals and can include brain atrophy, hyperintensity T2/FLAIR in the basal ganglia, basal ganglia calcifications, and incomplete hippocampal inversion [Kuseyri Hübschmann et al 2021b, Ribeiro et al 2023, Jarrah et al 2025].

Sleep impairment can include hypersomnolence or insomnia, fatigue, and/or sleep disorders. Sleep impairment is reported in approximately 10% of individuals and typically responds to treatment with melatonin.

Prognosis. Early treatment prevents the most severe clinical manifestations but delays in neurocognitive development can still develop. With continuation of therapy, the disease becomes relatively stable in adults. 5-methyltetrahydrofolate (5-MTHF) can become depleted in the brain due to the possible inhibition of folic acid recycling by dihydrobiopterin (BH2), which accumulates in individuals with DHPR deficiency. This is treated with administration of folinic acid that is brain penetrant. Discontinuation of folinic acid therapy can result in an acute encephalopathy [Pappalardo et al 2022].

Genotype-Phenotype Correlations

With the exception of two individuals with mild DHPR deficiency who were compound heterozygous for c.635T>G (p.Phe212Cys) and c.451G>A (p.Gly151Ser) [Blau et al 1992], 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 GCH1, PCBD, PTS, or QDPR (see Differential Diagnosis).

Prevalence

BH4 deficiencies are less common than PAH deficiency (phenylketonuria). The incidence of BH4 deficiencies is ~1%-2% of all individuals with hyperphenylalaninemia, or ~1:500,000 newborns, and about 27% of BH4 deficiency is due to DHPR deficiency. Approximately 47% of all reported individuals with DHPR deficiency are from the Middle East [Blau 2016].

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, 6-pyruvoyl-tetrahydropterin synthase deficiency is the most common.

Inherited cochaperone DNAJC12 deficiency has been identified as a potential differential diagnosis for primary hyperphenylalaninemia, alongside PAH deficiency and disorders of BH4 metabolism (see Table 3). 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 resembling BH4 deficiency, but with normal BH4 metabolites, similar to PAH deficiency.

Table 3.

Disorders Known to Cause Hyperphenylalaninemia

Disease MechanismGeneDisorderMOI
Name / ReferenceAbbreviation
Phenylalanine hydroxylase deficiency PAH Phenylalanine hydroxylase deficiency PAH deficiencyAR
BH4 deficiency disorders assoc w/hyperphenylalaninemia GCH1 GTP cyclohydrolase 1 deficiency, autosomal recessive (OMIM 233910)AR GTPCH deficiencyAR
PCBD1 Pterin-4-alpha-carbinolamine dehydratase deficiency (OMIM 264070)PCD deficiencyAR
PTS 6-pyruvoyl-tetrahydropterin synthase deficiency (PTS-Related Tetrahydrobiopterin Deficiency)PTS deficiency, PTPSDAR
QDPR Dihydropteridine reductase deficiency (topic of this GeneReview)DHPR deficiency, DHPRDAR
Cochaperone deficiency 1 DNAJC12 DNAJC12-related mild hyperphenylalaninemia (OMIM 617384)DNAJC12 deficiencyAR

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

1.

DNAJC12 encodes a cochaperone of HSP70, which interacts with phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase.

Management

Consensus guidelines for the diagnosis and treatment of tetrahydrobiopterin deficiencies, including dihydropteridine reductase (DHPR) deficiency, have been published [Opladen et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DHPR deficiency, the evaluations summarized Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Dihydropteridine Reductase Deficiency: Recommended Evaluations Initial Diagnosis

System/ConcernEvaluationComment
Biochemical Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian 1
  • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
  • Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance, & prognosis).
Neurologic Neurologic eval to obtain CSF studies & assess for abnormal muscle tone, autonomic dysfunction, & movement disordersConsider EEG if seizures are a concern.
Development Developmental assessmentConsider referral to developmental pediatrician.
Genetic counseling By genetics professionals 2To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of DHPR deficiency to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

CSF = cerebrospinal fluid; DHPR = dihydropteridine reductase; MOI = mode of inheritance

1.

After a new diagnosis of DHPR deficiency in a child, the closest hospital and local pediatrician should also be informed.

2.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Targeted Therapies

The general concepts of immediate care for children with confirmed DHPR deficiency include supplementation of the missing neurotransmitter precursors (in those who have low neurotransmitter levels in cerebrospinal fluid [CSF]), reduction of elevated phenylalanine (Phe), and supplementation of folinic acid [Lourenço et al 2021]. Treatment of hyperphenylalaninemia typically involves the administration of oral sapropterin dihydrochloride (a synthetic form of BH4). Not all individuals with DHPR deficiency respond to BH4 therapy, and even those who respond to BH4 therapy may still need a long-term Phe-restricted diet.

Table 5.

Dihydropteridine Reductase Deficiency: Targeted Therapies

TypeTreatmentDosageConsideration
PAH cofactorSapropterin dihydrochloride 1 (synthetic form of BH4)5-20 mg/kg/day 2
  • Adjust dose to aim for blood Phe concentration comparable to PAH deficiency (phenylketonuria).
  • Some persons may be unresponsive to sapropterin.
DietaryPhe-restricted diet
  • Primarily in persons nonresponsive to BH4 therapy
  • Infants: Phe-free metabolic infant formula in combination w/breastmilk &/or infant formula
Neurotransmitter precursorsLevodopa/
carbidopa		Gradually increase to 5-10 mg/kg/day divided 3x/day 2Requires stepwise dose increase to reach maximal dose
5-hydroxytryptophanUp to 5 mg/kg/day 2Always w/levodopa/carbidopa
Vitamin replacementFolinic acid3-15 mg/day 2
Anti-parkinsonian medicationDopamine agonistsDose per experienced neurologistIn those w/extrapyramidal movement disorders despite adequate dosages of levodopa/carbidopa
Selective MAO inhibitors

BH4 = tetrahydrobiopterin; MAO = monoamine oxidase; PAH = phenylalanine hydroxylase; Phe = phenylalanine

1.

Sepiapterin, a precursor for BH4, was recently established as a therapeutic option for individuals with phenylalanine hydroxylase deficiency (phenylketonuria). Initial clinical studies have shown positive results with use of sepiapterin in those with primary pterin deficiencies.

2.

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Outpatient Routine Treatment of Manifestations

Table 6.

Dihydropteridine Reductase Deficiency: Outpatient Routine Treatment of Manifestations

ManifestationTreatmentConsiderations/Other
Abnormal muscle tone Physical medicine & rehab / PT & OT treatment as neededConsider need for positioning & mobility devices & disability parking placard.
Movement disorders See Targeted Therapies, Anti-parkinsonian medication.
Developmental delay /
Intellectual disability /
Neurobehavioral issues 		See Developmental Delay / Intellectual Disability Management Issues.
Seizures Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Sleep impairment Consider treatment w/melatonin
Planning for surgery or procedure
(incl dental procedures)
  • Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. 2
  • Following surgery or fasting due to surgery, oral medication, particularly levodopa/DCI, should be resumed promptly to prevent movement disorders.
  • Consider placing flag in affected person's medical record such that all care providers are aware of diagnosis.
  • Note: Special IV fluids are not required for this metabolic condition.
Care coordination
  • Encourage medical alert bracelet.
  • Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors.
  • Provide families w/letter to optimize social & school services.
Invaluable for coordinating treatment at centers w/o expertise in biochemical disorders
Transition to adult care As a lifelong disorder w/varying implications according to age, a smooth transition of care from pediatric setting to adult setting for long-term mgmt is ideal. 3

ASM = anti-seizure medication; DCI = dopa-decarboxylase inhibitor; IV = intravenous; OT = occupational therapy; PT = physical therapy

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.

2.

Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected individuals deemed to be high risk for perioperative complications.

3.

Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with DHPR deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.

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.
    • PT, 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

  • Physical therapy is recommended to maximize mobility and to reduce mainly in late-treated individuals the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).
  • Consider in late-treated individuals use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

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.

Speech, language, and communication issues. Speech-language evaluation should be considered early in development for children who have delayed communication milestones or who are not yet talking. Evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) is appropriate for individuals who have speech or receptive and expressive language difficulties. An AAC evaluation should be completed by a speech-language pathologist who has expertise in the area. This evaluation typically accounts for cognitive abilities, sensory impairments, and motor skills 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. Many children will continue to require AAC into later childhood and adulthood, while some may use their AAC for a shorter time to help aid 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 DHPR deficiency 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. Although standardized procedures for transitional care do not exist for DHPR deficiency due to the absence of multidisciplinary outpatient departments and lack of adult-specific metabolic centers in most locations, transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with DHPR deficiency 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

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

Dihydropteridine Reductase Deficiency: Recommended Surveillance

System/ConcernEvaluationFrequency/Comment
Metabolic balance / Nutrition
  • Measure blood Phe levels in DBS.
  • Eval w/experienced metabolic physician & metabolic nutritionist; may include assessments of biochemical analytes w/adjustments in medication & dietary therapies based on age, weight, & diet.
  • Every 3 mos in those responsive to BH4 therapy
  • In those not responsive, frequency according to national PAH deficiency (phenylketonuria) guidelines
Feeding/Growth
  • Eval of nutritional status & safety of oral intake
  • Assessment of height, weight, & head circumference
At each visit throughout childhood & adolescence
Neurologic
  • Neurology eval to assess for abnormal muscle tone & seizures
  • EEG if seizures are suspected
  • Assessment for clinical manifestations of movement disorders, severity, & responses to treatment
At each visit
Musculoskeletal Physical medicine & OT/PT assessment of mobility & self-help skills
Development
  • Monitoring of developmental milestones
  • Neuropsychological testing using age-appropriate standardized assessment batteries
Neurobehavioral/
Psychiatric
  • Assessment for sleep issues
  • Assessment for anxiety, ADHD, ASD, aggression, & self-injury
Gastrointestinal Assessment for constipation
Family/Community Assessment of family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning)

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BH4 = tetrahydrobiopterin; DBS = dried blood spots; OT = occupational therapy; PAH = phenylalanine hydroxylase; Phe = phenylalanine; PT = physical therapy

Agents/Circumstances to Avoid

Antiemetic and antipsychotic medications that act as central dopamine antagonists should be avoided in individuals with DHPR deficiency because they have the potential to worsen symptoms of dopamine deficiency (e.g., metoclopramide should not be used for the treatment of nausea).

Trimethoprim/sulfamethoxazole should be avoided because it was reported to cause parkinsonian manifestations in an individual with DHPR deficiency. The interaction between trimethoprim and dihydrofolate reductase (DHFR) appears to be the causative factor.

Due to the inhibitory effect of methotrexate on DHPR and its interaction with DHFR, this treatment may lead to hyperphenylalaninemia.

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. If the QDPR 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 DHPR deficiency. If prenatal testing has not been performed, each at-risk newborn sib should be evaluated immediately after birth (at or just after 24 hours of life) for DHPR deficiency 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).
  • 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 QDPR pathogenic variants are known). Note: 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.

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

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Mode of Inheritance

Dihydropteridine reductase (DHPR) deficiency 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 QDPR 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 QDPR 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 QDPR 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 also has DHPR deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in QDPR.

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

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the QDPR pathogenic variants in the family.

Related Genetic Counseling Issues

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

Family planning

  • 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 QDPR 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

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.

Dihydropteridine Reductase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
QDPR4p15​.32Dihydropteridine reductaseBIOMDBdb : Database of Mutations Causing BH4 Deficiencies and other PND (QDPR)
QDPR database		QDPRQDPR

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 Dihydropteridine Reductase Deficiency (View All in OMIM)

261630HYPERPHENYLALANINEMIA, BH4-DEFICIENT, C; HPABH4C
612676QUINOID DIHYDROPTERIDINE REDUCTASE; QDPR

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 dihydrofolate reductase. Pterin-4-alpha-carbinolamine dehydratase and dihydropteridine reductase ensure BH4 regeneration.

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 3-monooxygenase (tyrosine hydroxylase) and tryptophan 5-hydroxylase 1 (tryptophan hydroxylase), enzymes involved in the synthesis of monoamine neurotransmitters whose deficiency can cause CNS dysfunction independently from hyperphenylalaninemia. BH4 is also a cofactor for all three forms of nitric oxide synthase.

BH4 is oxidized during the hydroxylation reaction and needs to be converted back to the active form. This requires the sequential action of two enzymes, pterin-4-alpha-carbinolamine dehydratase and the NAD(P)H-dependent dihydropteridine reductase.

QDPR pathogenic variants result in loss of function of dihydropteridine reductase, resulting in defective recycling of BH4. The lack of active BH4 causes hyperphenylalaninemia and severe depletion of all monoamine neurotransmitters.

Mechanism of disease causation. Loss of function

Table 8.

QDPR Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment
NM_000320​.3
NP_000311​.2 		c.635T>Gp.Phe212CysSee Genotype-Phenotype Correlations.
c.451G>Ap.Gly151Ser

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Thomas Opladen (ed.grebledieh-inu.dem@nedalpo.samoht) is actively involved in clinical and basic research regarding individuals with QDPR-related dihydropteridine reductase (DHPR) deficiency. Dr Opladen would be happy to communicate with persons who have any questions regarding diagnosis of DHPR deficiency or other considerations.

Revision History

  • 2 June 2026 (sw) Review posted live
  • 17 February 2026 (nb) Original submission

References

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