Objective: To assess morbility and clinical outcome of patients affected by defect of tetrahydrobiopterin (BH4) synthesis due to PTPSd.

Background: PTPSd is a treatable genetic disorder causing early onset dystonia-parkinsonism and developmental delay characterized by high blood phenylalanine (and as such detectable by newborn screening) and depletion of biogenic amines in the brain.

Method: 28 PTPSd patients (aged 19.9±10.9 years) underwent assessment of executive function (Brief Rating Inventory of Executive Function, BRIEF), adaptive profile (Vineland Adaptive Behaviour Scale II Edition, VABS-II) and IQ evaluation. According to CSF homovanillic (HVA) and 5-hydroxyindolacetic acid (HIAA) levels, and pterins concentration the patients were classified as severe (low diagnostic level of CSF HVA and HIAA, and altered Neopterin/Biopterin-Neo/Bio) and mild (normal HVA and HIAA with altered Neo/Bio) form.

Results: 36% PTPSd patients were affected by a mild form. At the last examination: 43% of subjects showed movement disorders; 32% autonomic dysfunctions; 32% sleep disorders; 11% epilepsy. 43% of subjects had variable degrees of intellectual disability. 39% of PTPSd patients met criteria for a psychiatric disorder. 9 out of 12 PTPSd patients who started the treatment by the age of 2 months and 4 out of 16 who started the treatment later showed a normal neurological development (χ²=6.892, p=0.009).
As compared to mild forms PTPSd patients with the severe form showed lower mean IQ (72±28.56 vs 107.43±19.67, p=0.005); more problems in executive functioning (BRIEF Global Executive Composite Scale – GEC, p= 0.001); and poorer adaptive functioning (VABS-II Adaptive Behaviour Composite domain – ABC, p=0.001).
A significant correlation was found between CSF HVA levels at diagnosis and: last IQ (p=0.047, r_s=0.462); BRIEF GEC score (p=0.020, r_s=-0.517); ABC domain (p=0.000, r_s=0.764).
A significant correlation was found between CSF HIAA at diagnosis and: BRIEF GEC score (p=0.011, r_s=-0.556); ABC domain (p=0.000, r_s=0.839).

Conclusion: PTPSd is characterized by a suboptimal clinical outcome, which is influenced by the delay in starting the treatment. Notably, the levels of CSF HVA and HIAA at diagnosis predict the neurological and psychiatric outcome.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-outcome-of-6-pyruvoyl-tetrahydropterin-synthase-deficiency-ptpsd/