Copper-histidine therapy: a targeted metabolic intervention for Menkes disease

Menkes disease (MD) is a rare, X-linked recessive disorder of copper metabolism, characterized by progressive neurodegeneration, connective tissue abnormalities, and the distinctive phenotype of pili torti. The disease is caused by pathogenic variants in the ATP7A gene, which encodes a copper-transporting P-type ATPase essential for cellular copper efflux and delivery of copper to secreted cuproenzymes. Severe forms of MD typically present in early infancy and are associated with rapid neurological decline and death within the first 3 years of life. Currently, therapeutic options are limited, and outcomes are highly dependent on the timing of intervention. Copper-histidine represents a biologically rational intervention designed to bypass defective intestinal copper transport and restore systemic copper availability. Experimental and clinical observations suggest that early administration may partially correct copper deficiency, improve biochemical parameters, and, in selected cases, alter neurological outcomes and survival. This letter summarizes the pathophysiological basis of MD, the rationale for copper-histidine therapy, and the existing evidence supporting its potential role as a disease-modifying intervention when initiated early in life.