ATP7A-Related Copper Transport Disorders

Preferred molecular test for ATP7A-related copper transport disorders

Related Tests

Initial screening tests for ATP7A gene-related copper transport disorders

Useful when a pathogenic familial variant identifiable by sequencing is known

Pathogenic variants in the ATP7A gene result in several metabolic disorders (eg, Menkes disease) related to copper uptake and serum copper concentrations. Low copper concentration leads to progressive intellectual delay, bone and skeletal abnormalities, changes to skin and hair structure, hypotonia, and seizures. Symptoms of Menkes disease are progressive. Individuals are typically healthy from birth to 3-5 months, when the infant begins to lose developmental skills. Because of the wide spectrum of phenotypic severity and the progressive nature of symptoms, life expectancy is difficult to predict. Individuals diagnosed as children typically do not survive past early childhood, although some individuals respond to treatment with an improved quality of life and longer life expectancy. A diagnosis of Menkes disease is confirmed by genetic testing.









  • Menkes disease: 100%
  • Occipital horn syndrome: 100% by adulthood


  • ATP7A gene codes for ATP7A protein, an ATP-dependent copper transporter expressed in almost all tissues except liver
  • Severity of symptoms tends to relate to amount of residual enzyme activity 
    • Menkes disease and occipital horn syndrome
      • Loss of function of ATP7A protein results in copper accumulation in intestinal mucosa and severe copper deficiency in multiple organs
      • Clinical spectrum ranges from classic Menkes disease (severe end of spectrum) to occipital horn syndrome to distal motor neuropathy (milder end of spectrum)
  • ATP7A-related distal motor neuropathy
    • May be related to abnormal trafficking of ATP7A copper transporter


  • Menkes disease variants tend to be profound loss-of-function variants
  • Occipital horn syndrome variants allow for some residual copper transport
  • ATP7A-related distal motor neuropathy variants are missense variants within or near luminal surface of protein
  • Heterozygous females may be mildly symptomatic due to X-inactivation patterns, but are generally normal

Disease Overview

  Menkes Disease Occipital Horn Syndrome (X-Linked Cutis Laxa) ATP7A-Related Distal Motor Neuropathy
Age of onset


Infancy to early adulthood

Usually second or third decade of life, but may present in childhood or as late as sixth decade


Subtle or nonspecific symptoms in first few months

Loss of milestones

Intellectual disability





Feeding difficulties

Sparse, coarse, twisted, and lightly pigmented hair with texture like that of steel wool 

  • Analysis of hair with light microscope shows pili torti, trichoclasis, and trichoptilosis

Other clinical findings:

  • Wormian bones
  • Bladder diverticula
  • Tortuous blood vessels
  • Pectus excavatum
  • Skin laxity
  • Jowly appearance
  • Osteoporosis

Developmental disability

Very early treatment with copper histidine or chloride may

  • Enhance survival
  • Reduce seizure activity
  • Improve neurodevelopmental outcomes

Shares many features with Menkes disease

Less severe neurological phenotype

Lax skin and joints

Bladder diverticula

Inguinal hernias

Vascular tortuosity

Mild intellectual disability

Dysautonomia and orthostatic hypotension (decreased dopamine beta-hydroxylase activity)

Occipital horns

  • Distinct, wedge-shaped calcifications in tendons that attach trapezius and sternocleidomastoid muscles to occipital bone
  • May be palpable or observed radiographically
  • Pathognomonic for condition  

Unlike Menkes disease and occipital horn syndrome

Atrophy and weakness of distal muscles in hands and feet

Foot drop with steppage gait

Mild proximal leg weakness

Hand and foot deformities

  • Curled fingers
  • Pes cavus

Symptoms typically slowly progressive: may resemble those of Charcot-Marie-Tooth disease

Related laboratory test results

Copper (serum): low

Ceruloplasmin (serum): low

Dopamine/norepinephrine (serum, CSF): elevated

Homovanillic acid/vanillylmandelic acid (urine): elevated

Copper (serum): normal to low

Ceruloplasmin (serum): normal to low

Dopamine/norepinephrine  (serum, CSF): normal to elevated

Homovanillic acid/vanillylmandelic acid (urine): normal to elevated

No biochemical abnormalities present

Nerve conduction tests: reduced compound motor amplitudes with generally normal conduction velocities

Test Interpretation


  • 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%
  • Analytical sensitivity/specificity
    • Sequencing: 99%
    • Deletion/duplication: 99%/95%


  • Positive
    • One pathogenic variant in a male predicts Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy
    • One pathogenic variant in a female confirms carrier status
      • Female carriers have variable presentations
  • Negative: no pathogenic variant detected
    • Reduces the risk but does not exclude a diagnosis of Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy
  • 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


  • 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
Additional Resources