Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients.

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 ±â€¯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.

Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth.

BACKGROUND: Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition. METHODS: Retrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables. RESULTS: Patients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8 ± 2.4 weeks) and low birth weight (-1.14 ± 0.97 SD below that predicted for gestational age). With time, weight and height approached normal. VALUES: All patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p < 0.01) and weight (p < 0.05). Most patients with PTPS deficiency had delayed development early in life, improving around school age with IQs mostly in the normal range, with a small decline in older individuals. From a neurological standpoint, most patients had normal brain MRI and minor EEG anomalies, although some had persistent neurological symptoms. DISCUSSION: Patients with PTPS deficiency have not only an increased incidence of prematurity, but also decreased birth weight when corrected for gestational age. Hyperphenylalaninemia can be absent in the first day of life. Therapy with sapropterin dihydrochloride normalizes phenylalanine levels and neurotransmitter precursors can improve CSF neurotransmitter metabolites levels. Insufficient dopaminergic stimulation (as seen from elevated prolactin) might result in decreased height in patients with PTPS deficiency. Despite early delays in development, many patients can achieve independence in adult life, with usually normal neuroimaging and EEG.