ATP7A-related copper transport disorders: A systematic review and definition of the clinical subtypes

J Inherit Metab Dis. 2023 Mar;46(2):163-173. doi: 10.1002/jimd.12590. Epub 2023 Feb 3.


In patients with ATP7A-related disorders, counseling is challenging due to clinical overlap between the entities, the absence of predictive biomarkers and a clear genotype-phenotype correlation. We performed a systematic literature review by querying the MEDLINE and Embase databases identifying 143 relevant papers. We recorded data on the phenotype and genotype in 162 individuals with a molecularly confirmed ATP7A-related disorder in order to identify differentiating clinical criteria, evaluate genotype-phenotype correlations and propose management guidelines. Early seizures are specific for classical Menkes disease (CMD), that is characterized by early-onset neurodegenerative disease with high mortality rates. Ataxia is an independent indicator for atypical Menkes disease, that shows better survival rates than CMD. Bony exostoses, radial head dislocations, herniations and dental abnormalities are specific for occipital horn syndrome (OHS) that may further present with developmental delay and connective tissue manifestations. Intracranial tortuosity and bladder diverticula, both with high risk of complications, are common among all subtypes. Low ceruloplasmin is a more sensitive and discriminating biomarker for ATP7A-related disorders than serum copper. Truncating mutations are frequently associated with CMD, in contrast with splice site and intronic mutations which are more prevalent in OHS.

Keywords: ATP7A; ATPase; Menkes disease; X-linked; copper metabolism; genotype-phenotype; neurodegenerative disorder; occipital horn syndrome.

Publication types

  • Systematic Review
  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Copper / metabolism
  • Copper-Transporting ATPases / genetics
  • Cutis Laxa* / genetics
  • Humans
  • Menkes Kinky Hair Syndrome*
  • Mutation
  • Neurodegenerative Diseases*
  • Peptide Fragments / genetics


  • Copper
  • Copper-Transporting ATPases
  • ATP7A protein, human
  • ATP7A protein, human (2-79)
  • Peptide Fragments

Supplementary concepts

  • Occipital horn syndrome