Clinical Guidance

No clinically relevant genotype-phenotype correlations have been identified. Homozygosity for the intronic pathogenic c.596-2AG variant was the most common genotype found in a cohort of affected individuals from Malta, suggesting a possible founder effect .

Source: GeneReviews — "Sepiapterin Reductase Deficiency"

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

Source: GeneReviews — "Sepiapterin Reductase Deficiency"

Differential Diagnosis

The genetic differential diagnosis of sepiapterin reductase deficiency (SRD) includes monoamine neurotransmitter disorders, hereditary dystonia, juvenile-onset Parkinson disease, and disorders of biopterin metabolism . Table 3. Genes of Interest in the Differential Diagnosis of Sepiapterin Reductase Deficiency

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.

Table 4:

Sepiapterin Reductase Deficiency: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Constitutional

| Measure weight, length/height, head circumference. | To assess for growth deficiency /or microcephaly

Neurologic

| Neurologic eval | • Assess for signs/symptoms of dystonia, tone abnormalities, weakness, movement disorders.

• Consider EEG if seizures are a concern.

Measurement of CSF dopamine serotonin metabolites | As a baseline to monitor efficacy of (See also .)

Ataxia/

Dystonia

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

• Gross motor fine motor skills

• Features of oculogyric crisis

• Mobility, ADL, need for adaptive devices

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education

Neurobehavioral/

Psychiatric

| Neuropsychiatric eval | For persons age 12 mos: screening for con...

Source: GeneReviews — "Sepiapterin Reductase Deficiency"

Clinical Guidance

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 ;

• Methotrexate, which inhibits dihydropteridine reductase, an enzyme involved in BH4 regeneration ;

• Nitrous oxide, which may impair folate metabolism ;

• Neuroleptics and other dopamine antagonists (e.g., metoclopramide).

Source: GeneReviews — "Sepiapterin Reductase Deficiency"

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.

Source: GeneReviews — "Sepiapterin Reductase Deficiency"

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.

• Monitor those w/seizures as clinically indicated.

• Assess for new manifestations such as seizures, changes in tone, movement disorders.

| At each visit

Feeding/growth

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

Development

| Monitor developmental progress educational needs.

Neurobehavioral/

Psychiatric

| Behavioral assessment for sleep disturbances, inattention, depression, anxiety, /or irritability

Musculoskeletal

| Physical medicine OT/PT assessment of mobility self-help skills

Family/Community

| Assess 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).

CSF = cerebrospinal fluid; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "Sepiapterin Reductase Deficiency"