メンケス病

Studies investigating the relationship between trace element status and disease variability in humans are steadily increasing. Experimental and clinical data suggest that normal brain function critically depends on the homeostasis of several trace elements, and that disturbances in this balance may contribute to epileptogenesis. Trace elements in epilepsy have therefore emerged as a growing field of research, with numerous studies exploring the mechanisms by which different metal ions influence epileptic seizures in both animal models and patients. This review summarizes current evidence on the trace elements most frequently associated with epilepsy, including selenium, iron, copper, zinc and manganese, and highlights inherited metabolic disorders Menkes diseases and Congenital Hypomagnesemia, as well as selected mitochondrial syndromes, in which profound trace element imbalances converge with epileptic phenotypes. In addition, we discuss how antiepileptic drugs and the ketogenic diet can modify trace element levels in serum and other biological matrices. We performed a bibliographical synthesis to examine the correlation between epilepsy and abnormal concentrations of trace elements; namely zinc, copper, iron, selenium, manganese, magnesium and phosphorus, in blood and brain. Overall, available evidence suggests that trace element dysregulation may influence epileptogenesis, seizure susceptibility, and response to antiepileptic therapies.

ATP7A is a P-type ATPase copper transporter and a central component of the intracellular network to maintain copper (Cu) homeostasis, trafficking between the trans-Golgi network (TGN) and the cell periphery in response to intracellular Cu levels. Pathogenic ATP7A variants cause Menkes disease (MNK), occipital horn syndrome (OHS) and X-linked distal hereditary motor neuropathy (HMNX), with the clinical severity inversely related to residual ATP7A function. In MNK and OHS, variants result in loss of ATP7A function due to absent (MNK) or markedly reduced (OHS) protein levels, leading to abolished ATP7A trafficking and/or impaired Cu transport capacity. HMNX-associated variants are thought to retain partial Cu transport activity, although functional data remain limited. To date, three missense variants (p.T994I, p.P1386S, p.A991D) are established causes of HMNX, but the number of ATP7A variants reported in patients with a distal motor neuropathy phenotype is increasing, creating a need for functional assessment of variants of uncertain significance (VUS). We have developed a functional framework for evaluating HMNX-associated ATP7A variants. Using three patient fibroblast lines carrying the confirmed variants, we demonstrate reduced ATP7A TGN localization under low-Cu conditions and impaired capacity of these cell lines to maintain intracellular Cu levels. By applying these assays to five VUS (p.R703H, p.Y760C, p.A768G, p.Q990P, p.M1311V) identified in individuals from unsolved peripheral neuropathy families, we identify p.Q990P as a novel ATP7A variant in a patient with progressive peripheral motor neuropathy. This approach enables comparison of Cu trafficking and handling across ATP7A alleles, providing a functional framework to support diagnostic variant classification.

Copper (Cu) is an essential cofactor for cytochrome c oxidase (CcO), a mitochondrial respiratory chain enzyme that is metalated in the intermembrane space (IMS) primarily using Cu derived from the mitochondrial matrix pool. While Cu import into the matrix depends on the inner membrane carrier SLC25A3, the route by which matrix Cu is exported to the IMS for insertion into CcO has remained a major, unresolved step in intramitochondrial Cu trafficking. Here, we leveraged our recent discovery that the Cu ionophore elesclomol (ES) releases Cu directly into the mitochondrial matrix to show that SLC25A3 is required for exporting Cu to the IMS for CcO metalation. Loss of SLC25A3 decreases mitochondrial Cu content and CcO activity as expected. Strikingly, bypassing the loss of SLC25A3 with ES-mediated Cu delivery to the matrix fails to restore CcO function; rather, it drives toxic Cu retention and triggers cuproptosis, revealing that SLC25A3-facilitated Cu export is the limiting determinant of CcO metalation. Heterologous expression in Lactococcus lactis confirms that SLC25A3 can mediate Cu export. These results suggest that SLC25A3 is the long-sought mitochondrial Cu exporter with a dual role in enabling CcO metalation and gating susceptibility to cuproptosis.

Menkes disease (MD) is a rare X-linked recessive disorder caused by mutations in the ATP7A gene, leading to impaired copper transport and deficiency of essential copper-dependent enzymes. The disease is characterized by progressive neurodegeneration, refractory seizures, hypotonia, and connective tissue abnormalities, typically presenting within the first months of life. Without effective treatment, the prognosis remains poor, with most affected children dying before 3 years of age. Traditional therapeutic strategies have included oral copper salts; however, these approaches have shown limited clinical efficacy due to inadequate correction of systemic and cerebral copper deficiency. Parenteral copper histidinate therapy represented a significant advancement by improving copper bioavailability and enhancing systemic absorption. Early initiation of therapy, particularly within the first month of life, has been associated with improved survival and better neurodevelopmental outcomes in some patients. Recently, the U.S. Food and Drug Administration approved Zycubo (copper histidinate) as the first disease-specific treatment for children with MD, marking an important milestone in the management of this rare condition. Despite its clinical benefits, treatment may be associated with adverse effects including infections, respiratory complications, anemia, and injection-site reactions, necessitating careful monitoring during therapy. Continued research is required to evaluate long-term safety, optimize therapeutic strategies, and further improve outcomes for affected children.