Zinc deficiency and zinc/copper ratio imbalance in autism spectrum disorder: a reanalysis of six multinational studies.

Disturbances in zinc (Zn) and copper (Cu) homeostasis have emerged as reproducible biochemical features of autism spectrum disorder (ASD). This study presents an integrative reanalysis of six investigations (2014-2025) encompassing serum, whole-blood, and plasma measurements in ASD cases and controls, and one supplementation trial. Three case-control studies reporting mean ± SD values in circulating matrices were meta-analyzed. Circulating Zn levels were significantly lower in ASD (fixed-effect Hedges' g = -0.95; 95% CI -1.22 to -0.68; Q = 1.72, p = 0.42; I2 = 0%; Egger intercept = 4.86, one-sided p = 0.044). The Zn/Cu ratio showed greater dispersion (random-effects g = -1.28; 95% CI -2.59 to 0.03; Q = 39.5, p < 0.001; I2 = 95%), driven primarily by one cohort (leave-one-out g = -0.63; 95% CI -0.99 to -0.26). In Brazilian subjects, plasma Zn and Cu fell within reference ranges, consistent with short-term plasma buffering of marginal deficits. In an Egyptian 12-week oral elemental Zn intervention in children with ASD, serum Cu fell by ~8%, circulating metallothionein (MT) protein increased, and CARS and TGMD-2 motor scores improved. MT-1A gene expression changed with Zn. Taken together, the evidence indicates that Zn insufficiency and altered Cu homeostasis are recurring features of ASD and that oral elemental Zn lowers serum Cu and increases MT.