Abstract
Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients.
Highlights
Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body
ATP7A disturbances result in complicated copper disorders starting by poor uptake at intestinal brush border, aggravated by poor release from enterocytes, further affecting all barriers in the body, underlining that the basic defect is not a simple copper insufficiency
Copper pumping into secretory pathway and enzyme metalation are clinically significant, and ERGIC enzyme trafficking is emerging as a copper regulated step (LOX)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. ATP7A-related X-linked genetic disturbances exhibit dysfunction of multiple copperdependent processes resulting in a broad spectrum of disease phenotypes. Three clinical groups are described: Menkes disease (MNK), occipital horn syndrome (OHS), and Xlinked distal spinal muscular atrophy 3 (SMAX3) but overlapping intermediate forms (Table 1) confuse grouping [1,2]. OHS presents with connective tissue symptoms, develops pathognomonic occipital bony exostosis (horns), and has reduced life expectancy. Grouping into three phenotypes is arbitrary, and the spectrum is better described as a clinical continuum from severe disease with many affected enzyme systems to very mild affection with few enzyme systems involved. Coarse hair; X-linked family history; connective tissue problems; muscle affection; dysautonomia, Exostoses on occipital bones; skeletal dysplasia; cutis laxa; hyperextensible joints; vascular complications. MNK pathophysiology [4] and will be discussed
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