Clinical Guidance

The phenotypic spectrum of sepiapterin reductase deficiency (SRD) is broad and the severity varies; some individuals manifest significant motor and cognitive deficits and others have only minimal findings. Those with minimal findings may manifest symptoms at an older age or be identified because of the diagnosis of SRD in a sib. Broad features may include the following: • Developmental delays with axial hypotonia • Unexplained "cerebral palsy," especially if dystonia is present • A levodopa-responsive motor disorder that may include dystonia Levodopa responsiveness is evaluated in the following manner: • Levodopa (in combination with 10%-25% carbidopa) may be introduced at 1 mg/kg/day and advanced slowly by 0.5-1 mg/kg/day per week, monitoring for symptomatic improvement and side effects as the dose is raised. • Benefit is most often achieved at a low dose and is dramatic and rapid (hours to days). For affected individuals weighing up to 40 kg, the dosage should be adjusted according to body weight, while for affected individuals weighing more than 40 kg, it should be adjusted according to clinical symptoms . • Because the response may be delayed or require a high dose (≥10 mg/kg/day), the dose should be increased and maintained for two to four weeks – barring side effects – to fully assess efficacy of levodopa [J Friedman, personal observation]. • Further information about levodopa treatment can be found in the consensus guidelines for the diagnosis and treatment of BH4 deficiencies . Given the broad range of neurologic manifestations (from asymptomatic to severe global developmental delay) and dramatic response to levodopa, clinicians should maintain a high index of suspicion for SRD or other monoamine neurotransmitter disorders in individuals with unexplained neurologic dysfunction. To date, at least 60 individuals have been identified with SRD [, , , , , , , , , , , , , , , , , , , , , , , , ]. The following description of the phenotypic features associated with this condition is based on these reports. Table 2. Sepiapterin Reductase Deficiency: Frequency of Select Features

Diagnostic Criteria

Tetrahydrobiopterin (BH4) deficiencies are a group of inherited metabolic disorders including sepiapterin reductase deficiency (SRD). Unlike other BH4 deficiency disorders, SRD does not lead to elevated phenylalanine levels and is not typically detected on newborn screening. The International Working Group on Neurotransmitter Related Disorders proposed a diagnostic algorithm for the BH4 deficiencies including SRD .

Suggestive Findings

SRD should be suspected in probands with any of the following clinical findings and family history.

Clinical findings

Management Guidelines

No clinical practice guidelines for sepiapterin reductase deficiency (SRD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

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

Surveillance Guidelines

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

Table 7.

Sepiapterin Reductase Deficiency: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic

| Eval of CSF neurotransmitter metabolites1,2 | As needed during drug dose titration if the clinical response is not satisfactory, or during clinical follow up to clarify otherwise unexplainable discrepancies. This is particularly important for children younger than age 2 yrs, since neurologic symptoms can be difficult to evaluate in this age group.