The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.
Menkes disease (MD) is a lethal infantile neurodegenerative disorder with X-linked inheritance, characterized by progressive neurodegenerative symptoms caused by pathogenic variants in the ATP7A.
Mutations in the ATP7A gene may lead to infantile-onset cerebral degeneration (Menkes disease); occipital horn syndrome (OHS), a related but much milder illness; or an adult-onset isolated distal motor neuropathy.
Indeed, mutations in the central copper exporter ATP7A contribute to a spectrum of diseases, including Menkes disease, with symptoms ranging from neurodegeneration to lax connective tissue.
We determined in silico that all the mutations leading to the classical Menkes disease leave no residual activity of ATP7A including the apparently less severe in-frame deletions.
Mosaic mutant mice displaying functional dysfunction of Atp7a copper transporter (the Menkes ATPase) are an established animal model of Menkes disease and constitute a convenient tool for investigating connections between copper and iron metabolisms.
Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers.
Loss-of-function ATP7A mutations causing systemic Cu deficiency are associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome.
Severe ATP7A loss-of-function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes.
Here, we analyzed changes in the systemic iron metabolism using an animal model of Menkes disease: copper-deficient mosaic mutant mice with dysfunction of the ATP7A copper transporter.