Clinical characteristics.

The phenotypic spectrum of sepiapterin reductase deficiency (SRD), which ranges from significant motor and cognitive deficits to only minimal findings, has not been completely elucidated. Clinical features in the majority of affected individuals include motor and speech delay, axial hypotonia, dystonia, weakness, and oculogyric crises; symptoms show diurnal fluctuation and sleep benefit. Other common features include parkinsonian signs (tremor, bradykinesia, masked facies, rigidity), limb hypertonia, hyperreflexia, intellectual disability, psychiatric and/or behavioral abnormalities, autonomic dysfunction, and sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, and drowsiness). Most affected individuals have nonspecific features in infancy including developmental delays and axial hypotonia; other features develop over time.

Diagnosis/testing.

The diagnosis of sepiapterin reductase deficiency is established in a proband by detection of biallelic pathogenic variants in SPR on molecular genetic testing or characteristic abnormalities of CSF neurotransmitters and pterins.

Management.

Treatment of manifestations: L-dopa in combination with carbidopa (or another peripheral decarboxylase inhibitor) is the main therapy used to correct CNS dopamine deficiency; 5-hydroxytryptophan (5-HTP), also in combination with carbidopa, has shown additional clinical benefit in some. When L-dopa/5HTP/carbidopa are not tolerated or sufficiently effective some individuals may benefit from use of other agents such as monoamine oxidase inhibitors, serotonin reuptake inhibitors, melatonin, dopamine agonists, anticholinergics, and methylphenidate. These medications most consistently correct motor abnormalities; however, in some individuals cognitive manifestations remain more refractory.

Prevention of secondary complications: Physical, occupational, and speech therapy may improve or maintain motor function.

Surveillance: Data are insufficient to determine how frequently CSF levels of dopamine and serotonin metabolites should be evaluated and whether these levels should be used to adjust medication doses.

Agents/circumstances to avoid: Although adverse events with specific agents have not been reported in persons with SRD, the following should be avoided on a theoretic basis: sulfa drugs, methotrexate, nitrous oxide, neuroleptics, and other dopamine antagonists (e.g., metoclopramide).

Evaluation of relatives at risk: Although no data on outcomes are available, it is appropriate to use molecular genetic testing for the SPR pathogenic variants identified in the proband and/or analysis of CSF neurotransmitter metabolites and pterins to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as soon as possible those who would benefit from early initiation of treatment to correct CNS dopamine and serotonin deficiency.

Genetic counseling.

SRD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the SPR pathogenic variants in the family are known.

Suggestive Findings

Sepiapterin reductase deficiency (SRD) should be suspected in individuals with characteristic clinical findings. The phenotypic spectrum is broad and suggestive signs are often nonspecific.

Core clinical features present in more than 65% of affected individuals:

• Motor and speech delay
• Axial hypotonia
• Dystonia
• Weakness
• Oculogyric crises
• Diurnal fluctuation and symptom improvement with sleep

Other common features:

• Intellectual disability
• Limb hypertonia and hyperreflexia
• Parkinsonian signs (tremor, bradykinesia, masked facies, rigidity)
• Psychiatric and/or behavioral abnormalities
• Sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, drowsiness)
• Autonomic dysfunction (excessive sweating, ptosis, nasal congestion, temperature instability)

Individuals with any of the following three broad sets of findings should be considered to possibly have SRD [Friedman et al 2012]:

• Developmental delays with axial hypotonia
• Unexplained "cerebral palsy," especially if dystonia is present
• An L-dopa-responsive motor disorder that may include dystonia. L-dopa responsiveness is evaluated in the following manner: L-dopa (in combination with 10%-25% carbidopa) may be introduced at 1 mg/kg/day and advanced slowly by 1 mg/kg/day over days/weeks monitoring for symptomatic improvement and side effects as the dose is raised. Although data are insufficient to provide precise dosing guidelines, benefit is most often achieved at low dose and is dramatic and rapid (hours to days). Because the response may be delayed or require a high dose (≥10 mg/kg/d) (as has been observed in cyclohydrolase 1-deficient dopa-responsive dystonia [DYT-GCH1]), the dose should be increased and maintained for two to four weeks – barring side effects – to fully assess efficacy of L-dopa [Author, personal observation].

Note: Given the broad range of neurologic manifestations (from asymptomatic to severe global developmental delay) and dramatic response to L-dopa, clinicians should maintain a high index of suspicion for SRD or other monoamine neurotransmitter disorders (see Differential Diagnosis) in individuals with unexplained neurologic dysfunction.

Establishing the Diagnosis

The diagnosis of sepiapterin reductase deficiency is established in a proband by detection of biallelic pathogenic (or likely pathogenic) variants in SPR on molecular genetic testing (see Table 1) or characteristic abnormalities of CSF neurotransmitters and pterins.

Note: Note: (1) Per ACMG/AMP 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 SPR variants of uncertain significance (or of one known SPR pathogenic variant and one SPR variant of uncertain significance) does not establish or rule out the diagnosis. (3) While analysis of either sepiapterin reductase enzyme activity in fibroblasts or pterin levels in cytokine stimulated fibroblasts could be considered [Bonafé et al 2001a], neither test is widely available or commonly used. (4) A phenylalanine load test [Hyland et al 1997], which is not commonly used, could be considered when molecular testing and analysis of CSF neurotransmitters are not available. While an abnormal phenylalanine load is suggestive, it is not diagnostic of SRD, as abnormal results are observed in other BH₄ deficiencies (including DYT-GCH1).

Molecular genetic testing approaches may include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis is performed first, followed by consideration of gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found in an individual with characteristic clinical findings and/or abnormalities of CSF metabolites. Note: To date no SPR deletions or duplications requiring gene-targeted deletion/duplication analysis have been reported.
• A multigene panel that includes SPR and other genes of interest (see Differential Diagnosis) may also be considered. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.

Characteristic CSF abnormalities of neurotransmitters and pterins include:

• Decreased levels of homovanillic acid (HVA) and 5-hyroxyindolacetic acid (5-HIAA);
• Normal to slightly increased levels of neopterin;
• Increased levels of total biopterin, dihydrobiopterin (BH2), and sepiapterin [Bonafé et al 2001b, Friedman et al 2012, Bonafé 2006].
  Note: (1) CSF should be collected using standardized protocols and analyzed by a laboratory with appropriate age-related reference ranges [Hyland et al 1993, Bräutigam et al 2002]. (2) Normal values vary by lab and by age.

Clinical Description

The phenotypic spectrum of sepiapterin reductase deficiency (SRD) has not been completely elucidated due to the small number of affected individuals reported to date, lack of systematic diagnostic evaluation and long-term follow up, and the absence of data on the prevalence and natural history of findings in untreated individuals. Of particular note, severity varies: some individuals manifest significant motor and cognitive deficits and others only minimal findings. Those with minimal findings may present at an older age or be identified because of the diagnosis of SRD in a sib [Arrabal et al 2011, Friedman et al 2012].

Clinical features in 38 individuals with SRD are summarized by Friedman et al [2012]. A few affected individuals not included in this review and described elsewhere have additional features [Steinberger et al 2004, Clot et al 2009, Lohmann et al 2012, Leuzzi et al 2013, Koht et al 2014].

Clinical features present in more than 65% of affected individuals include motor and speech delay, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit. Other common features include parkinsonian signs (tremor, bradykinesia, masked facies, rigidity), limb hypertonia, hyperreflexia, intellectual disability, psychiatric and/or behavioral abnormalities, autonomic dysfunction, and sleep disturbances (hypersomnolence, drowsiness, difficulty initiating or maintaining sleep related to alteration of the sleep-wake circadian rhythm).

Most affected individuals have nonspecific features in infancy including developmental delays and axial hypotonia. In the next few years other features that may develop include limb hypertonia, hyperreflexia, dystonia, and more apparent diurnal fluctuation and sleep disturbance.

In some instances, dystonia may present as paroxysmal stiffening of limbs and/or trunk with gaze deviation and tremor of the tongue, limbs, and/ or head [Dill et al 2012, Leuzzi et al 2013].

Numerous rarely reported findings overlap with those typical of other disorders of monoamine neurotransmitter biosynthesis (see Differential Diagnosis).

Seizures (mostly febrile) occasionally occur, though frequency may be over-reported as oculogyric crises and paroxysmal stiffening episodes may be confused with seizures.

A few reports note low birth weight [Bonafé et al 2001b, Leuzzi et al 2013], poor somatic growth [Lohmann et al 2012, Leuzzi et al 2013], and/or microcephaly [Blau et al 1998, Bonafé et al 2001b, Leuzzi et al 2013].

During later childhood, abnormalities in behavior and cognition become more apparent. These may be under-reported due to the prominence of the motor features.

While many affected individuals have intellectual disability, others with mild learning disabilities or normal cognition have been reported.

Psychiatric and/or behavioral findings most commonly include inattention, irritability, and anxiety; however, a wide range of symptoms may occur. It is hypothesized (though not yet proven) that early treatment may mitigate cognitive or psychiatric/behavioral abnormalities.

Genotype-Phenotype Correlations

Although several possible genotype-phenotype correlations have been suggested in individuals with biallelic SPR pathogenic variants, due to the small number of affected individuals these conclusions remain uncertain [Arrabal et al 2011, Friedman et al 2012]. Phenotypic variability is broad even among family members with identical pathogenic variants.

One individual heterozygous for a SPR pathogenic variant in the 5’ untranslated region with a mild form of L-dopa-responsive dystonia and reduced SR activity in fibroblasts has been reported [Steinberger et al 2004].

Nomenclature

Two individuals originally reported as having "central" dihydropteridine reductase (DHPR) deficiency [Blau et al 1998, Blau et al 1999] were later diagnosed with SRD [Bonafé et al 2001b].

Prevalence

No data are available on the prevalence of SRD.

A total of approximately 50 probands have been reported to date [Bonafé et al 2001a, Bonafé et al 2001b, Steinberger et al 2004, Neville et al 2005, Abeling et al 2006, Echenne et al 2006, Friedman et al 2006, Verbeek et al 2008, Clot et al 2009, Kusmierska et al 2009, Leu-Semenescu et al 2010, Mazzuca et al 2010, Wali et al 2010, Arrabal et al 2011, Bainbridge et al 2011, Dill et al 2012, Friedman et al 2012, Lohmann et al 2012, Thibert et al 2012, Leuzzi et al 2013, Koht et al 2014].

SRD may be under-recognized due to lack of awareness.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with sepiapterin reductase deficiency (SRD), the following evaluations are recommended:

• Consultation with a neurologist
• Physical therapy, occupational therapy, and speech therapy evaluations depending on severity of manifestations
• Neuropsychological evaluation depending on the severity of manifestations
• Social services consultation depending on the severity of manifestations
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Therapy is aimed at correcting central nervous system (CNS) neurotransmitter deficits.

Recommended treatments are based on the few reported cases in the literature and extrapolation from strategies employed in treatment of other neurotransmitter disorders.

While the medications discussed below reduce manifestations of SRD, response can range from complete resolution to partial improvement. These medications most consistently correct motor abnormalities while in some cognitive manifestations remain more refractory.

Often, medications must be prescribed "off-label" without established pediatric dose ranges [Friedman et al 2012]:

• L-dopa (0.1-16 mg/kg/day) in combination with 10%-25% carbidopa (or another peripheral decarboxylase inhibitor) is the main therapy to correct CNS dopamine deficiency. Optimal therapeutic level is determined by clinical response.
  Note: (1) Dose-related dyskinesias may occur [Abeling et al 2006, Neville 2007, Arrabal et al 2011, Friedman et al 2012]; they can be eliminated in most instances with reduced dosage or addition of a dopamine agonist to reduce fluctuations in dopaminergic stimulation [Lohmann et al 2012]. (2) Gastrointestinal side effects such as nausea may be reduced by increasing the proportion of administered carbidopa. (3) Although not reported, it is theoretically possible that individuals with SRD receiving high-dose L-dopa could develop cerebral folate deficiency and require supplementation with folinic acid (as has been observed in aromatic L-amino acid decarboxylase deficiency [Brun et al 2010]).
• 5-hydroxytryptophan (5-HTP) (1-6 mg/kg/day) also in combination with carbidopa to correct CNS serotonin deficiency has shown additional clinical benefit in some.
• Tetrahydrobiopterin (BH₄; sapropterin dihydrocloride) may in theory be of benefit, although none was reported in four patients treated for only a short time [Friedman et al 2006, Friedman et al 2012]. Note that it is difficult to achieve adequate CNS levels of BH₄ due to limited transport across the blood brain barrier.
• Other agents used when L-dopa/5HTP/carbidopa are not tolerated or sufficiently effective which have shown benefit in single or small numbers of patients include:
  • Monoamine oxidase inhibitors (selegeline)
  • Serotonin reuptake inhibitors (sertraline)
  • Melatonin
  • Dopamine agonists (bromocriptine, pramipexole)
  • Anticholinergics
  • Methylphenidate

Prevention of Secondary Complications

Physical, occupational, and speech therapy may improve or maintain function.

Surveillance

Data are insufficient to determine how frequently CSF levels of dopamine and serotonin metabolites should be evaluated and whether these levels should be used to adjust medication doses. Practices range from at least annual assessment of CNS neurotransmitter metabolites to adjustment of neurotransmitter precursor therapy based solely on clinical manifestations.

Because clinical manifestations are more difficult to assess in children, it would seem prudent to evaluate CSF neurotransmitter metabolites two to four times yearly in children younger than age two years and at least yearly in children younger than age ten years.

Note: Plasma prolactin levels may inversely correlate with CNS dopamine levels but are neither a sensitive nor specific marker [Leuzzi et al 2002, Furukawa et al 2003, Concolino et al 2008].

Agents/Circumstances to Avoid

Although adverse events with specific agents have not been reported in persons with SRD, several should be avoided on a theoretic basis including:

• Sulfa drugs, which impair BH₄ biosynthesis by inhibiting sepiapterin reductase [Haruki et al 2013]
• Methotrexate, which inhibits dihydropteridine reductase, an enzyme involved in BH₄ regeneration [Woody & Brewster 1990]
• Nitrous oxide, which may impair folate metabolism [Wyatt & Gill 1999]
• Neuroleptics and other dopamine antagonists (e.g., metoclopramide)

Evaluation of Relatives at Risk

While no data on outcomes are available, it is appropriate to use molecular genetic testing for the SPR pathogenic variants identified in the proband and/or analysis of CSF neurotransmitter metabolites and pterins to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as soon as possible those who would benefit from early initiation of treatment to correct CNS dopamine and serotonin deficiency.

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

Pregnancy Management

No pregnancies have been reported to date in women with SRD.

Based on reports that suggest that L-dopa may be advantageous during pregnancy in women with GTP cyclohydrolase 1-deficient dopa-responsive dystonia (DYT-GCH1), it would seem prudent for women with SRD to continue L-dopa therapy during pregnancy [Trender-Gerhard et al 2009, Watanabe & Matsubara 2012].

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.

Mode of Inheritance

Sepiapterin reductase deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one SPR pathogenic variant).
• Heterozygotes are generally asymptomatic and are not at risk of developing the disorder. Current data are insufficient to associate clinical manifestations with heterozygosity for an SPR pathogenic variant; however, several anecdotal reports have raised this possibility, including the following:
  • An individual with a heterozygous SPR pathogenic variant in the 5’ untranslated region and a mild L-dopa-responsive dystonia phenotype [Steinberger et al 2004]
  • Fibromyalgia which segregated with carrier status in one small pedigree [Bainbridge et al 2011]
  • The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [Friedman et al 2006, Lohmann et al 2012]

Sibs of a proband

• At conception, each sib of an affected individual has 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 an at-risk sib is known to be unaffected, the risk of the sib being a carrier of a SPR pathogenic variant is 2/3.
• Heterozygotes (carriers) are asymptomatic and are usually not at risk of developing the disorder (see Parents of a proband).

Offspring of a proband. Individuals with sepiapterin reductase deficiency have not been reported to reproduce; however, only a few identified individuals are of childbearing age.

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

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SPR 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

• The optimal time for determination of genetic risk, clarification of carrier status, 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 have or are at risk of having one or more SPR pathogenic variants.

Prenatal Testing and Preimplantation Genetic Testing

Once the SPR pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Because individuals with biallelic SPR pathogenic variants may be asymptomatic, predicting the phenotype based on results of prenatal testing may not be reliable.

Acknowledgments

Thank you to patients and families whose participation has enabled us to learn about sepiapterin reductase deficiency and bring benefit to individuals identified with this condition in the future.

Revision History

• 1 July 2015 (me) Review posted live
• 26 January 2015 (jf) Original submission

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Suggested Reading

• Friedman J, Opladen T. L-dopa-responsive dystonia syndromes. In: Hoffmann G, Blau N, eds. Congenital Neurotransmitter Disorders: A Clinical Approach. New York, NY; Nova Biomedical. 2014:17-38.