ATP7A-Related Copper Transport Disorders

Several metabolic disorders related to copper uptake and serum copper concentrations are caused by pathogenic ATP7A gene variants. Different variants in the gene result in different levels of severity, depending on the amount of residual ATPase enzyme activity.

Menkes disease is the most severe of the conditions and is characterized by an apparently healthy early infancy period of two to three months, followed by the onset of loss of developmental milestones, hypotonia, seizures, and failure to thrive. Other cardinal features of Menkes disease include progressive neurological changes and associated characteristic changes of the hair, rendering it short, sparse, coarse, and usually lightly pigmented. Death typically occurs by early childhood in affected individuals. If an early diagnosis of Menkes disease is established, subcutaneous injections of copper histidine or copper chloride before 10 days of age can improve outcome for some patients, though some do not respond to treatment. 

Occipital horn syndrome (OHS) is distinguished by wedge-shaped calcifications at the point of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone, creating an appearance of “occipital horns,” which may be palpable or visible on radiographic findings. Other features of OHS include skin and joint laxity, inguinal hernias, and vascular tortuosity. Intellect is usually normal or slightly reduced, and affected individuals generally live until at least mid-adulthood.

The mildest disorder is ATP7A-related distal motor neuropathy (DMN), which is an adult-onset disorder with symptoms of slowly progressive distal muscle weakness and atrophy, foot drop, and mild proximal weakness in the legs; generally there are minimal or no sensory symptoms in these individuals.

In both Menkes disease and OHS, serum copper and ceruloplasmin concentrations are low. Copper and ceruloplasmin studies in individuals with ATP7A-related DMN are usually normal.

Disease Overview

Incidence

• Menkes disease: 1/100,000
• OHS: unknown
• ATP7A-related DMN: unknown

Genetics

Gene

ATP7A

Inheritance

X-linked

Penetrance

Dependent on sex of individual and gene variant

• Hemizygous males: 100%; severity depends on ATP7A variant
• Heterozygous females: typically asymptomatic, but some may have clinical features due to skewed X-chromosome inactivation 

Test Interpretation

 Sensitivity/Specificity

• Clinical sensitivity
  • Unknown for ATP7A-related distal motor neuropathy
  • For Menkes disease and occipital horn syndrome
    • Sequencing with deletion/duplication: ~95%
    • Sequencing: ~80%
    • Deletion/duplication: 15-20%  
• Analytical sensitivity/specificity
  • Sequencing: 99%
  • Deletion/duplication: 99%/95%

Results

• Positive
  • One pathogenic variant in a male is diagnostic for Menkes disease, OHS, or ATP7A-related DMN
  • One pathogenic variant in a female confirms carrier status
    • Female carriers may have variable presentations
• Negative: no pathogenic variant detected
  • Reduces the risk but does not exclude a diagnosis of Menkes disease, OHS, or ATP7A-related DMN
• Inconclusive: variants of unknown clinical significance may be detected
• Large ATP7A gene deletions in hemizygous males can result in the failure of sequencing reactions
  • In such cases, deletion/duplication analysis is recommended

Limitations

• Diagnostic errors can occur due to rare sequence variations.
• Not determined or evaluated:
  • Regulatory region or deep intronic variants
  • Breakpoints of large deletions/duplications
  • Variants in genes other than ATP7A