HEREDITARY NEUROPATHIES & ALS: P.109 Expanding the phenotype of ATP7A-related copper transport diseases: Understanding the pathophysiology of neuropathy and copper metabolism

Abstract

Genetic disorders related to ATP7A copper transporter includes classical Menkes disease (MD) and its milder form occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN). The DMN phenotype was recently described and is thought to be a distinct and clinical isolate phenotype of ATP7A related disorders, with different pathophysiology of MD and OHS. We describe clinical, biochemical, radiological characteristics and functional studies in fibroblast of two patients with a novel ATP7Agene mutation. Two related patients, nephew (patient 1) and uncle (patient 2) with the diagnosis of OHS. Patient 2 presents clinical manifestations of OHS and DMN and worsening of the neuropathy after copper treatment and functional motor recovery after a few weeks of treatment withdrawal. Genetic studies: The patients are hemizygous for c.4236delA (p.K1412NFsX15) in the exon 23 of the ATP7Agene (NM_000052.4). Pathogenic mutations of neuropathies-related genes were ruled out in a genetic panel. Mutations in the ATP7Agene presenting with the association of motor distal neuropathy and clinical features of MD or OHS have not been reported previously. It has been hypothesized that the ATP7A mutations leading to DNM may have a different impact on the function of the protein than those mutations causing MD or OHS phenotype. Further studies in the evaluation of the biological mechanisms of this novel mutation could contribute to a better understanding of the complex pathophysiology of ATP7A related disorders. Supplementation with copper-histidinate seems plausible when plasma copper is low, however, exogenous copper could be also dangerous and lead to cellular intoxication. Treatment with copper-histidinate in patients with OHS and DMN should be cautiously considered and monitored, since different repercussion of mutations in ATPA7 function may determine the copper treatment effect.