{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T19:37:03Z","timestamp":1776109023730,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2012,12,7]],"date-time":"2012-12-07T00:00:00Z","timestamp":1354838400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2013,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper\u2010transporting adenosine triphosphatase gene, <jats:italic>ATP7A<\/jats:italic>. Among its multiple cellular tasks, ATP7A transfers copper to dopamine beta hydroxylase (DBH) within the lumen of the Golgi network or secretory granules, catalyzing the conversion of dopamine to norepinephrine. In a well\u2010established mouse model of Menkes disease, <jats:italic>mottled\u2010brindled<\/jats:italic> (<jats:italic>mo\u2010br<\/jats:italic>), we tested whether systemic administration of L\u2010threo\u2010dihydroxyphenylserine (L\u2010DOPS), a drug used successfully to treat autosomal recessive norepinephrine deficiency, would improve brain neurochemical abnormalities and neuropathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>At 8, 10, and 12 days of age, wild\u2010type and <jats:italic>mo\u2010br<\/jats:italic> mice received intraperitoneal injections of 200\u03bcg\/g body weight of L\u2010DOPS, or mock solution. Five hours after the final injection, the mice were euthanized, and brains were removed. We measured catecholamine metabolites affected by DBH via high\u2010performance liquid chromatography with electrochemical detection, and assessed brain histopathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to mock\u2010treated controls, <jats:italic>mo\u2010br<\/jats:italic> mice that received intraperitoneal L\u2010DOPS showed significant increases in brain norepinephrine (<jats:italic>p<\/jats:italic> &lt; 0.001) and its deaminated metabolite, dihydroxyphenylglycol (<jats:italic>p<\/jats:italic> &lt; 0.05). The ratio of a non\u2013beta\u2010hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta\u2010hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain\u2010directed <jats:italic>ATP7A<\/jats:italic> gene therapy (<jats:italic>p<\/jats:italic> &lt; 0.01). However, L\u2010DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We conclude that (1) L\u2010DOPS crosses the blood\u2013brain barrier in <jats:italic>mo\u2010br<\/jats:italic> mice and corrects brain neurochemical abnormalities, (2) norepinephrine deficiency is not the cause of neurodegeneration in <jats:italic>mo\u2010br<\/jats:italic> mice, and (3) L\u2010DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease. 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