Abstract
This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder—isolated distal motor neuropathy—has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot–Marie–Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.
Key Points
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The critical involvement of copper-transporting ATPase 1 (ATP7A) in axonal outgrowth, synapse integrity and neuronal activation underlines the fundamental role of copper metabolism in neurological function
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Mutations in ATP7A yield three distinct clinical syndromes—Menkes disease, occipital horn syndrome (OHS) and isolated distal motor neuropathy—each of which has distinct neurological effects
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Menkes disease results in lethal infantile neurodegeneration if left untreated, but normal neurodevelopmental outcomes are sometimes possible if therapy can be administered on the basis of neonatal diagnosis
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In OHS, leaky splice junction or hypomorphic missense mutations in ATP7A allow considerable ATP7A-mediated copper transport, thereby sparing the CNS, but cuproenzyme deficiencies can cause dysautonomia and connective tissue problems
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A newly discovered ATP7A phenotype, adult-onset distal motor neuropathy, shares no clinical or biochemical abnormalities with Menkes disease or OHS, and results from missense mutations that cause mistrafficking of ATP7A
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A rich array of model organisms provides an opportunity for further exploration of human copper metabolism and evaluation of potential disease remedies, including gene therapy
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Acknowledgements
Written consent was obtained for publication of Figure 2a from the patient's mother. The author is supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH). The author apologizes to any colleagues whose work was not cited in this Review as a result of length constraints.
L. Barclay, freelance writer and reviewer, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.
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Supplementary information
Supplementary Figure 1
Cellular copper metabolism. (DOC 994 kb)
Supplementary Figure 2
The occipital 'horns' of occipital horn syndrome. (DOC 255 kb)
Supplementary Figure 3
Mutant ATP7A alleles that cause distal motor neuropathy traffic abnormally. (DOC 212 kb)
Supplementary Table 1
Proteins important for human copper metabolism (DOC 146 kb)
Supplementary Table 2
The multiple and varied functions of ATP7A (DOC 82 kb)
Supplementary Table 3
ATP7A mutations cause three distinct disorders (DOC 107 kb)
Supplementary Table 4
Mutant alleles at the mottled mouse locus (DOC 140 kb)
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Kaler, S. ATP7A-related copper transport diseases—emerging concepts and future trends. Nat Rev Neurol 7, 15–29 (2011). https://doi.org/10.1038/nrneurol.2010.180
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DOI: https://doi.org/10.1038/nrneurol.2010.180
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