About this item:

521 Views | 678 Downloads

Author Notes:

Address correspondence to Dr Jinnah, 6300 Woodruff Memorial Research Building, Department of Neurology, Emory University, Atlanta, GA 30322. Email: hjinnah@emory.edu

Tissue from controls was obtained from the Johns Hopkins Brain Resource Center, the Emory Alzheimer's Disease Research Center, the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland (contract HHSN275200900011C, #N01-HD-9–0011), and Children's Healthcare of Atlanta Pediatric Hospital.

Potential Conflicts of Interest: H.A.J.: travel expenses, Dystonia Medical Research Foundation, Bachmann-Strauss Dystonia and Parkinson's Foundation, American Academy of Neurology, Movement Disorders Society; consultancy, Psyadon Pharmaceuticals; grants/grants pending, NIH, Lesch–Nyhan Syndrome Children's Research Foundation; speaking fees, Georgia Neurological Society.


Research Funding:

This work was supported by the Lesch–Nyhan Syndrome Children's Research Foundation (HAJ); grants from the NIH National Institute of Neurological Disorders and Stroke (NINDS; R01 NS40470; HAJ), the NIH National Institute of Child Health and Human Development (NICHD; R01 HD053312; HAJ), and the Office of Rare Diseases Research at the National Center for Advancing Translational Studies of the NIH (U54 NS065701; HAJ); the Emory Alzheimer's Disease Research Center (P50 AG025688; JDG, MG); an Emory University NINDS Neuroscience Core Facilities grant (P30 NS055077); and the Netherlands Organization for Scientific Research (NWO/ZonMw, VENI 916.12.167; JEV).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences
  • Neurosciences & Neurology

Loss of Dopamine Phenotype Among Midbrain Neurons in Lesch-Nyhan Disease

Show all authors Show less authors


Journal Title:

Annals of Neurology


Volume 76, Number 1


, Pages 95-107

Type of Work:

Article | Post-print: After Peer Review


Objective Lesch-Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy. Methods Histopathological studies were conducted using autopsy tissue from 5 LND cases and 6 controls. Specific findings were replicated in brain tissue from an HGprt-deficient knockout mouse using immunoblots, and in a cell model of HGprt deficiency by flow-activated cell sorting (FACS). Results Extensive histological studies of the LND brains revealed no signs suggestive of a degenerative process or other consistent abnormalities in any brain region. However, neurons of the substantia nigra from the LND cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. In the HGprt-deficient mouse model, immunohistochemical stains for TH revealed no obvious loss of midbrain dopamine neurons, but quantitative immunoblots revealed reduced TH expression in the striatum. Finally, 10 independent HGprt-deficient mouse MN9D neuroblastoma lines showed no signs of impaired viability, but FACS revealed significantly reduced TH immunoreactivity compared to the control parent line. Interpretation These results reveal an unusual phenomenon in which the neurochemical phenotype of dopaminergic neurons is not linked with a degenerative process. They suggest an important relationship between purine recycling pathways and the neurochemical integrity of the dopaminergic phenotype. Ann Neurol 2014;76:95-107 © 2014 American Neurological Association.

Copyright information:

© 2014 American Neurological Association

Export to EndNote