Lesch-Nyhan disease (LND) is an inherited disorder of purine metabolism that is characterized by severe motor impairment, intellectual disability (mental retardation), compulsive self-injury, and hyperuricemia. There are also partial or milder phenotypes know as Lesch-Nyhan variants (LNV). The pathogenesis of both LND and LNV begins with a mutation of the Hprt gene, which encodes the enzyme hypoxanthine-guanine phosophoribosyl transferase (HGprt). This enzyme has two distinct functions: It recycles hypoxanthine (Hprt) and guanine (Gprt) into the purine pools. While the enzyme defect likely leads to neurophysiologic and neuroanatomic abnormalities that define the clinical phenotype, it is unknown whether this results from the failure to recycle hypoxanthine, guanine, or both. However, through recently-funded R21 research, we found that some mutations produce large differential effects on Hprt and Gprt recycling. Thus, a crucial next step in elucidating the pathophysiology of LND is to determine which of the two known functions of HGprt relates most directly to specific aspects of the disease phenotype. Post-mortem neurochemical and positron emission tomography studies point to a marked depletion of dopamine from the basal ganglia in LND. Neuroimaging and post-mortem neuropathological studies point to global (intracranial) and local (caudate) reductions in LND brain volumes. In this application, we bridge strengths in neurology, biochemistry, neuropsychology, neuroimaging and pathology with extensive clinical experience to elucidate relationships between the phenotype and biochemical and anatomical biomarkers across the full spectrum of HGprt deficiency. This revised proposal now includes fully integrated molecular, biochemical, behavioral, neurological, neuroimaging, and autopsy studies of a disease that has served as a prototype for a single-gene disorder with devastating neurobehavioral consequences. In addition to a these cross-sectional studies, we also propose to conduct the largest, longest, and first quantitative longitudinal follow-up study to begin determining whether or not LND is a progressive neurodegenerative disorder. This project includes fully integrated molecular, biochemical, behavioral, neurological, neuroimaging, and autopsy studies that will greatly advance our understanding of Lesch-Nyhan disease (LND) and related conditions.

Public Health Relevance

LND is an inherited metabolic disorder that is characterized by mental retardation, compulsive self-injury, and severe neurological deficits. These studies will provide crucial information for future clinical trials.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD053312-02
Application #
7692892
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2008-09-30
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$490,540
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Schretlen, David J; Callon, Wynne; Ward, Rebecca E et al. (2016) Do clinical features of Lesch-Nyhan disease correlate more closely with hypoxanthine or guanine recycling? J Inherit Metab Dis 39:85-91
Schretlen, David J; Varvaris, Mark; Vannorsdall, Tracy D et al. (2015) Brain white matter volume abnormalities in Lesch-Nyhan disease and its variants. Neurology 84:190-6
Fu, Rong; Sutcliffe, Diane; Zhao, Hong et al. (2015) Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways. Mol Genet Metab 114:55-61
Dammer, Eric B; Göttle, Martin; Duong, Duc M et al. (2015) Consequences of impaired purine recycling on the proteome in a cellular model of Lesch-Nyhan disease. Mol Genet Metab 114:570-579
Goodman, Emily M; Torres, Rosa J; Puig, Juan G et al. (2014) Consequences of Delayed Dental Extraction in Lesch-Nyhan Disease. Mov Disord Clin Pract 1:225-229
Luciano, Angelo Y; Jinnah, H A; Pfeiffer, Ronald F et al. (2014) Treatment of myoclonus-dystonia syndrome with tetrabenazine. Parkinsonism Relat Disord 20:1423-6
Fu, Rong; Chen, Chung-Jen; Jinnah, H A (2014) Genotypic and phenotypic spectrum in attenuated variants of Lesch-Nyhan disease. Mol Genet Metab 112:280-5
Göttle, Martin; Prudente, Cecilia N; Fu, Rong et al. (2014) Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease. Ann Neurol 76:95-107
Dauphinot, Luce; Mockel, Lionel; Cahu, Julie et al. (2014) Transcriptomic approach to Lesch-Nyhan disease. Nucleosides Nucleotides Nucleic Acids 33:208-17
Fu, Rong; Ceballos-Picot, Irene; Torres, Rosa J et al. (2014) Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain 137:1282-303

Showing the most recent 10 out of 25 publications