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Gene: ATP7A

Green List (high evidence)

Well-established gene-disease association. Menkes disease and Occipital horn syndrome are caused by an inborn error of copper metabolism.

ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein.

Treatment for Menkes disease: subcutaneous injections of copper histidine or copper chloride

ClinGen has assessed as moderate evidence for actionability.

Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.

Menkes disease results from complete loss of transcript, while minimal residual transcript causes the milder OHS. Females have been described with the Occipital horn syndrome phenotype (OMIM).

Created: 7 Aug 2024, 4:51 a.m. | Last Modified: 7 Aug 2024, 4:51 a.m.

Panel Version: 1.82

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Menkes disease(MIM#309400); Occipital horn syndrome(MIM#304150)

Publications

• 20170900
• 33137485
• 31969342
• 31558336
• 7842019
• 8981948