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Menkes disease (MD) and occipital horn syndrome (OHS) are X-linked recessive disorders that affect young infants. They are caused by a defect in copper transportation across the intestinal mucosa, resulting in a copper deficiency and dysfunction of copper-dependent enzymes. The incidence is estimated at 1 in 50,000 to 1 in 250,000 live births; one third of cases result from new mutations. MD usually affects males; however, a few affected females with unfavorable X-lyonization or X chromosome anomalies have been reported.

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The genetic defect of MD and OHS is related to ATP7A gene mutations.1 This gene mapped to Xq13.3 and encodes for a P1B-type ATPase, a ubiquitously expressed protein that transports copper across cellular membranes and is critical for copper homeostasis. This protein serves to incorporate copper into copper-dependent enzymes and to remove the excess of copper from the cytosol maintaining the intracellular copper levels. Defects in this P-type ATPase lead to a reduced transport of copper from the intestine into the circulation and central nervous system and to a reduced transport of copper into the Golgi apparatus for incorporation into various copper-dependent enzymes.2 The result is a systemic copper deficiency and a reduced activity of various copper-dependent enzymes, which finally account for the characteristic features of the disease. Deficiencies of enzymes such as cytochrome c-oxidase, superoxide dismutase, and lysyl oxidase may explain the severe neurologic deterioration. Other enzymes implicated are: tyrosinase for the hypopigmentation, lysyl oxidase for defects in connective tissue, ascorbate oxidase for the osteoporosis, dopamine β-hydroxylase for faulty catecholamine production, and sulfhydryl oxidase for the steely hair.

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The ATP7A gene is very similar to the gene responsible for Wilson disease, the ATP7B gene, which encodes for another copper-transporting protein. The differential expression of these 2 genes explains the difference in the clinical phenotype. The ATP7A gene is expressed in the intestinal mucosa and other tissues but not liver, whereas the ATP7B gene is expressed in liver and brain.

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In classic Menkes disease,2 the neurologic features may begin in utero or shortly after birth (6 to 10 weeks of age) and consist of developmental regression, seizures, retinal degeneration, and later spasticity. Systemic features consist of failure to thrive; hypothermia; osteoporosis; bladder diverticula; sparse, thin hair that is twisted at the shaft (pili torti) and often lightly pigmented (white, silver, or gray); lax skin; tortuous and elongated arterial vessels; distinctive facial features; pectus excavatum; and hernias. Death by 3 years of age is typical.

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Occipital horn syndrome (OHS), an allelic variant of Menkes disease (MD), has only minimal neurologic features consisting of mild developmental delay and autonomic instability.3 The systemic features consist of inguinal hernias, bladder diverticula, lax skin and joints, vascular tortuosity and a characteristic calcified occipital horn in the skull.

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Differential diagnosis includes infantile-onset neurodegenerative disorders such as biotinidase deficiency, organic acidurias, aminoacidurias, and mitochondrial myopathies. Diagnostic confirmation consists of finding a low serum ...

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