CMT 2: ATP7A-related copper transport diseases-emerging concepts and future tren

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Nat Rev Neurol. 2011 Jan;7(1):15-29.

ATP7A-related copper transport diseases-emerging concepts and future trends.

Kaler SG; Medscape.

Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy

Shriver National Institute of Child Health and Human Development, NIH, Building

10 Room 10N313, 10 Center Drive MSC 1853, Bethesda, MD 20892-1853, USA.

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.