Clinical Guidance

The clinical spectrum of PTPSD is broad and differs according to age of onset, severity of disease, and whether preventative therapies were initiated and maintained from an early age. In general, this condition can be divided into two forms : severe and mild (or peripheral). Infants are usually identified due to elevated phenylalanine (Phe) levels on newborn screening (NBS) and started on a low-Phe diet while confirmatory testing is still pending. However, unlike phenylalanine hydroxylase (PAH) deficiency, a low-Phe diet may not prevent symptom onset and progression in people with PTPSD, particularly if they have the severe form that impacts the production of neurotransmitters. • Severe form. Affected individuals have decreased levels of cerebrospinal fluid (CSF) monoamine neurotransmitter metabolites, including 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA). Those who are treated with sapropterin dihydrochloride (BH4) and neurotransmitter precursors prior to age two months have a better prognosis and frequently experience progressive improvements in neurologic and developmental symptoms. However, most affected individuals still have some signs and symptoms, even on such therapy. • Mild (or peripheral) form. The mild form does not impact CSF neurotransmitter levels. Affected individuals may have either milder developmental issues or, less commonly, a normal neurologic outcome with BH4 therapy alone or in combination with neurotransmitter precursors . Severe PTPSD Affected individuals can experience symptoms as early as the neonatal period. Clinical signs can include hypotonia, movement disorders, abnormal eye movements, autonomic dysregulation, and impaired development. However, affected infants who are diagnosed through NBS are usually asymptomatic, although there is an increased risk of prematurity and low birth weight (even without prematurity). Once results of confirmatory testing are available, these children are started on BH4 therapy and can revert to a totally normal diet without the need of Phe or protein restriction. Table 3. Select Features of Severe 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

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

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)"