Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Preferred molecular test for ATP7A-related copper transport disorders
Initial screening tests for ATP7A gene-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.
- Menkes disease: 1/100,000
- OHS: unknown
- ATP7A-related DMN: unknown
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
- Clinical sensitivity
- Analytical sensitivity/specificity
- Sequencing: 99%
- Deletion/duplication: 99%/95%
- 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
- 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
Kaler SG, Holmes CS, Goldstein DS, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008;358(6):605-614.PubMed
Desai V, Donsante A, Swoboda KJ, et al. Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease. Clin Genet. 2011;79(2):176-182.PubMed
Tümer Z, Birk Møller L, Horn N. Screening of 383 unrelated patients affected with Menkes disease and finding of 57 gross deletions in ATP7A. Hum Mutat. 2003;22(6):457-464.PubMed
Culotta VC, Gitlin JD. Disorders of copper transport. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed., Vol 2. McGraw-Hill; 2001:3105-3126.
Kaler SG. ATP7A-related copper transport disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2021. [Last update: Aug 2016; Accessed: Aug 2020]