title: Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo.
abstract: Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a genetic disorder that is characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury. To establish that DA deficiency is present in LND, the ligand WIN-35,428, which binds to DA transporters, was used to estimate the density of DA-containing neurons in the caudate and putamen of six patients with classic LND. Comparisons were made with 10 control subjects and 3 patients with Rett syndrome. Three methods were used to quantify the binding of the DA transporter so that its density could be estimated by a single dynamic positron emission tomography study. These approaches included the caudate- or putamen-to-cerebellum ratio of ligand at 80-90 min postinjection, kinetic analysis of the binding potential [Bmax/(Kd x Vd)] using the assumption of equal partition coefficients in the striatum and the cerebellum, and graphical analysis of the binding potential. Depending on the method of analysis, a 50-63% reduction of the binding to DA transporters in the caudate, and a 64-75% reduction in the putamen of the LND patients was observed compared to the normal control group. When LND patients were compared to Rett syndrome patients, similar reductions were found in the caudate (53-61%) and putamen (67-72%) in LND patients. Transporter binding in Rett syndrome patients was not significantly different from the normal controls. Finally, volumetric magnetic resonance imaging studies detected a 30% reduction in the caudate volume of LND patients. To ensure that a reduction in the caudate volume would not confound the results, a rigorous partial volume correction of the caudate time activity curve was performed. This correction resulted in an even greater decrease in the caudate-cerebellar ratio in LND patients when contrasted to controls. To our knowledge, these findings provide the first in vivo documentation of a dopaminergic reduction in LND and illustrate the role of positron emission tomography imaging in investigating neurodevelopmental disorders.
authors.affiliation: Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Wong
authors.forename: J C
authors.initials: JC
authors.lastname: Harris
authors.forename: S
authors.initials: S
authors.lastname: Naidu
authors.forename: F
authors.initials: F
authors.lastname: Yokoi
authors.forename: S
authors.initials: S
authors.lastname: Marenco
authors.forename: R F
authors.initials: RF
authors.lastname: Dannals
authors.forename: H T
authors.initials: HT
authors.lastname: Ravert
authors.forename: M
authors.initials: M
authors.lastname: Yaster
authors.forename: A
authors.initials: A
authors.lastname: Evans
authors.forename: O
authors.initials: O
authors.lastname: Rousset
authors.forename: R N
authors.initials: RN
authors.lastname: Bryan
authors.forename: A
authors.initials: A
authors.lastname: Gjedde
authors.forename: M J
authors.initials: MJ
authors.lastname: Kuhar
authors.forename: G R
authors.initials: GR
authors.lastname: Breese
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism*; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007926:Lesch-Nyhan Syndrome / Q000000981:diagnostic imaging / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009928:Organ Specificity; D011699:Putamen / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D012016:Reference Values; D015518:Rett Syndrome / Q000000981:diagnostic imaging / Q000378:metabolism*; D013997:Time Factors; D014055:Tomography, Emission-Computed
chemical_list: D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine