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

Abstract

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.

Keywords: Clinical outcome.; Hyperphenylalaninemia; Neurotransmitter; Newborn screening; PTPS deficiency; Prolactin; Tetrahydrobiopterin.

Figure 1.

Phenylalanine levels (measured in newborn screening blood spots or by plasma amino acids) in infants with PTPS deficiency as a function of age before initiation of treatment. The green shaded area represents the normal range for phenylalanine in newborns. The dashed line represents the cut-off for newborn screening. The two squares represent normal values of phenylalanine in two infants whose first newborn screening card was collected at one day of life, the empty circles abnormal values measured in other infants or after 1 day of life in the infants represented with a square.

Figure 2.

Z-scores for anthropometric data in patients with PTPS deficiency. Scores for weight (A), height (B), and head circumference (C) were averaged at specific age points and are shown with their confidence intervals. Note the overlap of the confidence intervals with the 0 for all parameters after 1 year of age.

Figure 3.

Correlation between average prolactin levels (excluding those in the neonatal period) and weight, height and BMI (Z-scores) in patients with PTPS deficiency. The line represents a linear regression to the data with the parameters indicated. The green area represents the normal range for prolactin levels.

Figure 4.

DQ/IQ levels in patients with PTPS deficiency at different ages. Patients had initially a low DQ followed by an improvement in the pre-school period and an IQ mostly in the normal range during school, with a small decline in the later age. DQ: Development quotient; IQ: Intelligence quotient.