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  • Updated 10.21.2020
  • Released 01.17.2002
  • Expires For CME 10.21.2023

Menkes disease and other ATP7A-related disorders

Introduction

Overview

The copper-transporting ATPase ATP7A has diverse and important biological functions. Pathologic mutations in ATP7A produce 3 distinct neurologic syndromes: Menkes disease, occipital horn syndrome, and isolated distal motor neuropathy. Neonatal diagnosis of Menkes disease and early treatment with copper injections enhances survival and can normalize clinical outcomes when mutant ATP7A molecules possess small amounts of residual activity, predictable by a yeast complementation assay. Gene therapy with an adeno-associated viral vector restored ATP7A function and rescued a mouse model of Menkes disease in combination with copper, suggesting a potential therapeutic alternative for individuals with complete loss-of-function ATP7A defects. A newly discovered ATP7A disorder, adult-onset distal motor neuropathy resembling Charcot-Marie-Tooth disease type 2, shares none of the clinical or biochemical abnormalities characteristic of Menkes disease or its milder allelic variant, occipital horn syndrome.

Key points

• The copper-transporting ATPase ATP7A has diverse and important biological functions.

• Pathologic mutations in ATP7A produce 3 distinct neurologic syndromes: Menkes disease, occipital horn syndrome, and isolated distal motor neuropathy.

• In Menkes disease, severe ATP7A copper transport defects lead to infantile central nervous system neurodegeneration. Plasma catecholamine analysis is valuable for newborn screening, and yeast complementation analysis has predictive value for response to early copper treatment.

• In occipital horn syndrome, leaky splice junction or hypomorphic missense mutations allow considerable ATP7A-mediated copper transport and largely spare the central nervous system. Symptoms of dysautonomia, related to dopamine-beta-hydroxylase deficiency, and connective tissue problems predominate. Onset is in early childhood.

• Adult-onset distal motor neuropathy resembling Charcot-Marie-Tooth disease type 2, is caused by unique missense ATP7A mutations and shares none of the clinical or biochemical abnormalities of Menkes disease and occipital horn syndrome. Defective intracellular trafficking underlies this phenotype and implicates an important role of ATP7A in normal motor neuron function.

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