Abstract

Copper is indispensable for various metabolic processes, notably mitochondrial respiration. In humans, copper homeostasis hinges on transporters such as copper transporter 1 (CTR1), encoded by the SLC31A1 gene. Recently, bi-allelic mutations in SLC31A1 have been associated with a new neurodevelopmental disorder. This study presents clinical, genetic, and biochemical findings from 13 new cases across 10 families worldwide. RNA sequencing evaluated gene expression, and Western blotting assessed copper transporter 1 protein levels. Additionally, mitochondrial respiratory capacity was measured via high-resolution respirometry. Affected individuals exhibited a distinct clinical phenotype characterized by early-onset epileptic encephalopathy, severe neurodevelopmental delay and hypotonia, with high mortality. Neuroimaging revealed significant brain atrophy and white matter abnormalities. Genetic analysis identified bi-allelic SLC31A1 variants, predominantly p.His120Gln in six cases and p.(Arg102Cys/His) in three cases. Functional studies in patient fibroblasts demonstrated impaired mitochondrial respiration. This study significantly broadens the clinical spectrum of this recently described syndrome, presenting as a severe developmental encephalopathy with high mortality risk, and suggests mitochondrial dysfunction as a potential pathomechanism. These findings contribute to the mounting evidence linking copper transporter 1 dysfunction to neurodegeneration, underscoring the urgency for further therapeutic investigations.