Dopamine Transporters are Markedly Reduced in Lesch-Nyhan Disease in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 11; pp. 5539 - 5543
• Main Authors: Wong, Dean F., Harris, James C., Naidu, Sakkubai, Yokoi, Fuji, Marenco, Stefano, Dannals, Robert F., Ravert, Hayden T., Yaster, Myron, Evans, Alan, Rousset, Olivier, Bryan, R. Nick, Gjedde, Albert, Kuhar, Michael J., Breese, George R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 28.05.1996; National Acad Sciences; National Academy of Sciences
• Subjects: Adolescent; Adult; Amino acids; Brain - diagnostic imaging; Brain - metabolism; Brain - pathology; Carbon Radioisotopes; Carrier Proteins - metabolism; Cerebellum - diagnostic imaging; Cerebellum - metabolism; Cerebellum - pathology; Cocaine - analogs & derivatives; Cocaine - metabolism; Corpus Striatum - diagnostic imaging; Corpus Striatum - metabolism; Corpus Striatum - pathology; Disease; Disorders; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors - metabolism; Estimation methods; Humans; Intellectual disability; Kinetics; Lesch Nyhan syndrome; Lesch-Nyhan Syndrome - diagnostic imaging; Lesch-Nyhan Syndrome - metabolism; Ligands; Magnetic Resonance Imaging; Medical research; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins - metabolism; Nerves; Neurology; Neurons; Organ Specificity; Positron emission tomography; Putamen; Putamen - diagnostic imaging; Putamen - metabolism; Putamen - pathology; Quantification; Reference Values; Rett Syndrome - diagnostic imaging; Rett Syndrome - metabolism; Time Factors; Tomography, Emission-Computed
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.11.5539

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· 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 neuro-developmental disorders.