Introduction: 6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPSd) is a rare autosomal recessive disorder of
synthesis of biogenic amines, which is characterized by variable neurological impairment and hyperphenylalaninemia.
We aimed to assess the long-term clinical outcome of this disorder and the factors affecting it.
Methods: At total of 28 PTPSd patients (aged 19.9 ± 10.9 years) underwent clinical (neurological and psychiatric)
and neuropsychological assessment (BRIEF, VABS-II, and IQ). Based on CSF homovanillic (HVA) and 5-
hydroxyindolacetic acid (5-HIAA) and pterin concentrations at diagnosis, patients were classified as having
either a severe [SF; low level of CSF, HVA, and 5-HIAA with altered neopterin/biopterin (Neo/Bio)] or mild form
(MF; normal HVA and 5-HIAA with altered Neo/Bio) of PTPSd.
Results: Approximately 36% of patients had MF PTPSd. At the last examination, 43% of patients had movement
disorders (2 MF, 10 SF), 43% of patients had variable degrees of intellectual disability (SF only), 39% met the
criteria for a psychiatric disorder (3 MF, 9 SF). Applying a linear regression model, we found that HVA and
phenylalanine levels at birth had a significant influence on IQ, BRIEF, and VABS-II variability. Lastly, 5-HIAA
further contributed to VABS-II variability. The disease showed a self-limiting clinical course and its treatment,
although delayed, is effective in improving the neurological status.
Conclusions: Neurodevelopmental impairment due to PTPSd shows a self-limiting course. A continuous improvement
in the neurological condition has been observed in patients receiving treatment, even when delayed.
The severity of brain biogenic amine depletion at diagnosis predicts neurological and psychiatric outcomes
