Copper toxicity associated with an ATP7A-related complex phenotype

Abstract Background The ATP7A gene encodes a copper transporter whose mutations cause Menkes disease, occipital horn syndrome (OHS) and, less frequently, ATP7A-related distal hereditary motor neuropathy (dHMN). Here we describe a family with OHS caused by a novel mutation in the ATP7A gene, including a patient with a comorbid dHMN that worsened markedly after being treated with copper histidinate. Methods We studied in detail the clinical features of the patients and performed a genomic analysis by using TruSight One Expanded Sequencing Panel. Subsequently, we determined the ATP7A and ATP7B expression levels, mitochondria membrane potential and redox balance in patient 1 cultured fibroblasts. Results We found the novel ATP7A late truncated mutation p.Lys1412AsnfsX15 in the two affected members of this family. The co-occurrence of OHS and dHMN in patient 1 reveals the variable phenotypic expressivity of the variant. A severe clinical and neurophysiological worsening was observed in the dHMN of patient 1 when he was treated with copper replacement therapy, with a subsequent fast recovery after the copper histidinate was withdrawn. Functional studies revealed that the patient had low levels of both ATP7A and ATP7B, the other copper transporter, and high levels of superoxide ion in the mitochondria. Conclusions Our findings broaden the clinical spectrum of ATP7A-related disorders and demonstrates that two clinical phenotypes can occur in the same patient. The copper-induced toxicity and low levels of both ATP7A and ATP7B in our patient suggest that copper accumulation in motor neurons is the pathogenic mechanism in ATP7A-related dHMN.