Clinical Guidance

No clinically relevant genotype-phenotype correlations have been identified.

Source: GeneReviews — "PTS-Related Tetrahydrobiopterin Deficiency (PTPSD)"

Diagnostic Criteria

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 ...

Source: GeneReviews — "PTS-Related Tetrahydrobiopterin Deficiency (PTPSD)"

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 . 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

Management Guidelines

Consensus guidelines for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies have been published (full text).

Evaluations Following Initial Diagnosis

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

Table 5.

PTPSD: Recommended Evaluations Following Initial Diagnosis

Evaluation | Comment

Consultation w/metabolic physician/ biochemical geneticist specialist metabolic dietitian1 | • Transfer to specialist center w/experience in management 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 emergency treatment, prognosis, risks for acute encephalopathic crises).

Developmental assessment | Consider referral to developmental pediatrician.

Consultation w/neurologist | To help obtain CSF studies manage dosage of neurotransmitters, in those w/low neurotransmitter levels

Consultation w/psychologist /or social worker | To ensure understanding of diagnosis assess parental/ affected person's coping skills

Consultation w/PT, OT, speech therapist | To provide eval for physical speech development provide supportive therapies if necessary

Source: GeneReviews — "PTS-Related Tetrahydrobiopterin Deficiency (PTPSD)"

Clinical Guidance

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

Source: GeneReviews — "PTS-Related Tetrahydrobiopterin Deficiency (PTPSD)"

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

Source: GeneReviews — "PTS-Related Tetrahydrobiopterin Deficiency (PTPSD)"

Surveillance Guidelines

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

Source: GeneReviews — "PTS-Related Tetrahydrobiopterin Deficiency (PTPSD)"