Clinical description: Menkes disease, occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN) are disorders of copper transport caused by pathogenic variants in ATP7A (encoding a copper-transporting ATPase).
Diagnosis/testing: Menkes disease and OHS are characterized by low concentrations of copper in some tissues as a result of impaired intestinal copper absorption, accumulation of copper in other tissues, and reduced activity of copper-dependent enzymes such as dopamine beta hydroxylase (DBH) and lysyl oxidase. While serum copper concentration and serum ceruloplasmin concentration are low in Menkes disease and OHS, they are normal in ATP7A-related DMN. The diagnosis of ATP7A-related copper transport disorders is most commonly established in a proband by detection of either a hemizygous ATP7A pathogenic variant in a male or a heterozygous ATP7A pathogenic variant in a female.
Management: Treatment of manifestations: Classic Menkes disease: gastrostomy tube placement to manage caloric intake; surgery for bladder diverticula. Prevention of primary manifestations: Subcutaneous injections of copper histidine or copper chloride before age ten days normalizes developmental outcome in some children and improves the neurologic outcome in others. Prevention of secondary complications: Antibiotic prophylaxis may prevent bladder infection.
Genetic counseling: The ATP7A-related copper transport disorders are inherited in an X-linked manner. Approximately one third of affected males have no family history of Menkes disease/OHS/DMN. If the mother is a heterozygote, the risk of transmitting the ATP7A pathogenic variant is 50% in each pregnancy: a male who inherits the pathogenic variant will be affected with the disorder present in his brother; females who inherit the pathogenic variant will be heterozygotes and will not be affected. Males with OHS or ATP7A-related DMN will pass the pathogenic variant to all of their daughters and none of their sons. Individuals with classic Menkes disease do not reproduce. When the pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible. Prenatal testing for Menkes disease is technically possible by copper transport studies in cultured chorionic villus cells or amniocytes, although its availability is limited.
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