Hair iron-manganese balance in a large pediatric autism spectrum disorder cohort: Coordinated variation and an exploratory low-Fe/high-Mn subgroup.

BACKGROUND: Iron (Fe) and manganese (Mn) are essential metals that share several transport and regulatory pathways. Reduced Fe status may increase Mn uptake and retention, potentially increasing susceptibility to Mn-associated neurotoxicity. Children with autism spectrum disorder (ASD) frequently have selective diets and micronutrient inadequacies, but the relationship between hair Fe and Mn has received limited attention. OBJECTIVES: This study aimed to describe age- and sex-specific distributions of hair Fe and Mn in a large pediatric ASD cohort, evaluate the association between the two elements, and explore the occurrence of a subgroup with relatively low hair Fe and relatively high hair Mn. METHODS: This retrospective cross-sectional study analyzed pre-existing hair trace-element records from a commercial laboratory for 2151 children and adolescents with an ASD diagnosis recorded in the laboratory datasets, including 1808 boys and 343 girls aged 0-18 years. Individual diagnostic records were unavailable, and the recorded diagnoses could not be independently verified. The laboratory-referred cohort was not population-representative, and no neurotypical control group was available. Hair Fe and Mn were measured by inductively coupled plasma mass spectrometry and reported in mg/100 g hair. Distributions were summarized by sex and two-year age bands. Associations between natural-log-transformed Fe and Mn were examined using correlation and linear regression adjusted for age and sex. An exploratory low-Fe/high-Mn subgroup was defined using cohort-relative thresholds of hair Fe ≤ 0.7 mg/100 g and hair Mn ≥ 0.042 mg/100 g. RESULTS: Median hair Fe was 0.8 mg/100 g, and median hair Mn was 0.024 mg/100 g. Concentrations showed little consistent variation across age groups or between boys and girls. Log-transformed Fe and Mn were strongly positively correlated (r = 0.66). In linear regression, log Fe was positively associated with log Mn (β = 1.22; 95% CI, 1.16-1.28; p < 0.001), and the association was unchanged after adjustment for age and sex. The model explained 44% of the variability in log Mn. The exploratory low-Fe/high-Mn subgroup comprised 62 participants (2.9%) and had a markedly lower median Fe:Mn ratio than the remaining cohort. More stringent sensitivity definitions identified progressively smaller subgroups. CONCLUSIONS: Hair Fe and Mn concentrations were strongly and positively associated in this pediatric ASD cohort, rather than showing the inverse relationship that might be expected from Fe deficiency-related Mn accumulation. A small, threshold-dependent subgroup had relatively low hair Fe, relatively high hair Mn, and a reduced Fe:Mn ratio. These hair-based patterns should not be interpreted as evidence of systemic Fe deficiency, excessive Mn exposure, or a distinct clinical phenotype. Future studies should combine standardized hair analysis with established Fe-status biomarkers, direct measures of Mn exposure, dietary and supplementation data, appropriate control groups, and validated neurodevelopmental assessments.