Selenium Status in Paediatric Patients with Neurodevelopmental Diseases

Abstract

Neurodevelopmental diseases are often associated with other comorbidities, especially inflammatory processes. The disease may affect the trace element (TE) status, which in turn may affect disease severity and progression. Selenium (Se) is an essential TE required for the biosynthesis of selenoproteins including the transporter selenoprotein P (SELENOP) and extracellular glutathione peroxidase (GPX3). SELENOP deficiency in transgenic mice resulted in a Se status-dependent phenotype characterized by impaired growth and disturbed neuronal development, with epileptic seizures on a Se-deficient diet. Therefore, we hypothesized that Se and SELENOP deficiencies may be prevalent in paediatric patients with a neurodevelopmental disease. In an exploratory cross-sectional study, serum samples from children with neurodevelopmental diseases (n = 147) were analysed for total serum Se, copper (Cu), and zinc (Zn) concentrations as well as for the TE biomarkers SELENOP, ceruloplasmin (CP), and GPX3 activity. Children with epilepsy displayed elevated Cu and Zn concentrations but no dysregulation of serum Se status. Significantly reduced SELENOP concentrations were found in association with intellectual disability (mean ± SD (standard deviation); 3.9 ± 0.9 mg/L vs. 4.4 ± 1.2 mg/L, p = 0.015). A particularly low GPX3 activity (mean ± SD; 172.4 ± 36.5 vs. 192.6 ± 46.8 U/L, p = 0.012) was observed in phacomatoses. Autoantibodies to SELENOP, known to impair Se transport, were not detected in any of the children. In conclusion, there was no general association between Se deficiency and epilepsy in this observational analysis, which does not exclude its relevance to individual cases. Sufficiently high SELENOP concentrations seem to be of relevance to the support of normal mental development. Decreased GPX3 activity in phacomatoses may be relevant to the characteristic skin lesions and merits further analysis. Longitudinal studies are needed to determine whether the observed differences are relevant to disease progression and whether correcting a diagnosed TE deficiency may confer health benefits to affected children.

Keywords: biomarker; inflammation; micronutrient; neurodevelopment; trace element.

Figure 1

Correlations between age and biomarkers of trace elements in the paediatric patients. The analyses were comprising age and biomarkers of Se, Zn, and Cu status. There was no correlation between (A) age and serum Se, or (B) age and serum SELENOP concentration. Significant positive correlation was observed between (C) age and GPX3 activity (r = 0.292, p = 0.0004), and (D) age and serum Zn concentration (r = 0.146, p = 0.049). Strong negative correlation was observed between (E) age and serum Cu (r = −0.465, p < 0.0001) and between (F) age and CP concentration (r = −0.269, p = 0.002), indicating a declining Cu status with age. Correlation coefficients were calculated by Spearman test. Significant correlations are indicated by p-values; **** indicates p < 0.0001, *** indicates p < 0.001, ** indicates p < 0.01, and * indicates p < 0.05. SELENOP, selenoprotein P; GPX3, plasma glutathione peroxidase; CP, ceruloplasmin; Se, selenium; Zn, zinc; Cu, copper.

Figure 2

Comparison of serum TE (trace element) concentrations between female and male paediatric patients. All six TE biomarkers were compared between the groups of diseased girls (n = 55) and boys (n = 92). There were no significant sex-specific differences in (A) serum Se, (B) SELENOP concentrations, or (C) GPX3 activity. Similarly, (D) serum Zn, (E) Cu, or (F) CP concentrations did not differ between the sexes. Data are presented as box plots (10th–90th centiles); Student’s t-test or Mann–Whitney U test was used. All tests were two-sided and p-values < 0.05 were considered statistically significant.

Figure 3

Interrelations between serum biomarkers of Cu, Se, and Zn status in paediatric patients. The analyses comprised three serum biomarkers of Se and two of Cu status, along with total serum Zn concentration. (A) The direct comparisons of Se and SELENOP (r = 0.655, p < 0.0001), or (D) Cu and CP (r = 0.389, p < 0.0001) yielded strong linear correlations over the full range of data. Similarly, (B) GPX3 activities and serum Se (r = 0.2507, p = 0.0026) as well as (C) GPX3 activities and SELENOP concentrations (r = 0.2495, p = 0.0027) showed positive correlations. A significant, albeit weak, interaction was observed between (E) Cu and Se. No interrelation was observed between (F) Cu and Zn, (G) Zn and Se, or (H) CP and SELENOP concentrations. Correlation coefficients were calculated by Pearson correlation test for normally distributed values, and by Spearman test for non-normally distributed values. Significance is indicated by p-values; **** p < 0.0001, ** p < 0.01, and * p < 0.05.

Figure 4

Comparison of serum biomarkers of TE status between paediatric patients in relation to epilepsy. All six TE biomarkers were compared between the groups of children with (n = 49) and without (n = 98) epilepsy. There were no significant differences in (A) serum Se, or (B) SELENOP concentrations, or (C) GPX3 activity between the two groups. (D) Serum Zn (p = 0.004) as well as (E) serum Cu levels (p = 0.023) were relatively elevated in the children with epilepsy, whereas (F) CP concentrations did not differ between the two groups. Data are presented as box plots (10th–90th centiles); general linear models with univariate test adjusted for age were used for analysis. p-values < 0.05 were considered statistically significant. ** indicates p < 0.01, and * indicates p < 0.05.

Figure 5

Serum TE status of paediatric patients in relation to phacomatoses. The cohort of paediatric patients was separated according to a diagnosis of phacomatoses. Patients with phacomatoses (n = 30) displayed a slightly lower but not significantly different (A) serum Se, and (B) serum SELENOP concentration, along with significantly lower (C) serum GPX3 activities (p = 0.012), as compared with the patients without phacomatoses (n = 117). No differences between the groups with or without phacomatoses were observed in relation to (D) serum Zn, (E) Cu, or (F) CP concentrations. Data are presented as box plots (10th–90th centiles); general linear model with univariate test adjusted for age was used. p-values < 0.05 were considered statistically significant; * indicates p < 0.05.

Figure 6

Serum TE status of paediatric patients with and without intellectual disability. The children with intellectual disability displayed no difference in (A) serum Se but (B) significantly lower serum SELENOP concentrations (p = 0.016) as compared with the children without intellectual disability. No differences in serum (C) GPX3 activities, (D) serum Zn, (E) serum Cu, or (F) serum CP concentrations were noted. Data are presented as box plots (10th–90th centiles); general linear model with univariate test adjusted for age and gender was used to compare the groups. All tests were two-sided and p-values < 0.05 were considered statistically significant; * indicates p < 0.05.