6-Pyruvoyltetrahydropterin Synthase (PTPS) Deficiency via the PTS Gene

Hyperphenylalaninemias due to tetrahydrobiopterin (BH4) deficiency are a result of a disruption in phenylalanine homeostasis and dopamine and serotonin biosynthesis. These disorders are caused by pathogenic variants in genes encoding enzymes involved in the biosynthesis or regeneration of BH4. The phenylalanine, tyrosine, and tryptophan hydroxylases all require BH4 as a cofactor, and lack of this cofactor results in secondary hyperphenylalaninemia and depletion of the neurotransmitters dopamine and serotonin. Early detection and treatment can reduce or prevent neurologic symptoms (Blau et al. 2014).

The most common of the tetrahydrobiopterin deficiencies is 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency, which accounts for approximately 60% of all BH4 deficiencies (Blau et al. 2014). The phenotype of PTPS deficient patients is classified as severe or mild. The severe form is observed in approximately 80% of patients, and such patients develop neurologic symptoms including psychomotor retardation, delayed development, tonal abnormalities, seizures, and dystonia. Patients may also present with abnormal thermogenesis, microcephaly, swallowing difficulties and hypersalivation (Blau et al. 2014). Biochemically, patients classified with severe PTPS deficiency are found to have abnormal levels of CSF neurotransmitters (Leuzzi et al. 2010; Blau et al. 2014).

PTPS deficient patients diagnosed with the mild form are generally found to be neurologically normal and have normal neurotransmitter levels, although transient tonal abnormalities, sleeping difficulties and other neurological problems are occasionally observed (Leuzzi et al. 2010; Blau et al. 2014). PTPS deficient patients are usually detected via newborn screening due to hyperphenylalaninemia. To distinguish PTPS deficiency from PAH deficiency and other causes of hyperphenylalaninemia, additional studies must be performed, such as a urinary pterin profile, measurement of DHPR enzyme activity, a BH4 loading test, analysis of pterins, folates and neurotransmitters in CSF, and direct PTPS enzyme activity measurement (Ye et al. 2013; Blau et al. 2014). Early diagnosis and treatment is imperative. The neurological outcome, particularly in patients with severe PTPS deficiency, has been shown to be greatly improved if treatment is started before the second month of life (Leuzzi et al. 2010). A phenylalanine-restricted diet is not sufficient to control symptoms in these patients, and many must also be treated with BH4 and neurotransmitter precursor supplementation, although this does not help all patients (Oppliger et al. 1997; Blau et al. 2014).

6-Pyruvoyltetrahydropterin synthase deficiency is inherited in an autosomal recessive manner. The PTS gene (chromosome 11q22.3, 6 exons) encodes the PTPS enzyme which is involved in the de novo biosynthesis of tetrahydrobiopterin. More specifically, PTPS converts dihydroneopterin triphosphate to 6-pyruvoyl tetrahydropterin (Blau et al. 2014). To date, over 80 pathogenic variants have been reported in the PTS gene. The majority of causative variants are missense, although nonsense, splicing, small deletions and insertions, and one gross deletion have all been reported (Human Gene Mutation Database). Pathogenic variants are spread evenly along the coding sequence. Other inborn errors of BH4 metabolism can present with a similar clinical course and involve dihydropteridine reductase (QDPR gene), GTP cyclohydrolase I (GCH1 gene), and pterin-4α-carbinalamine dehydratase (PCBD1 gene) (Blau et al. 2014, Trujillano et al. 2014).

In a total of 19 patients from different families with a clinical diagnosis of 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency, pathogenic variants were detected by sequencing on 35 out of 38 alleles, suggesting an overall detection rate of ~92% (Leuzzi et al. 2010). Analytical sensitivity should also be high because nearly all reported pathogenic variants thus far are detectable by sequencing.

This test provides full coverage of all coding exons of the PTS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).