Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. Despite having been characterized over 50 years ago, it remains unclear precisely how deficits in HGprt enzyme activity can lead to LND. Several studies have proposed different hypotheses regarding the etiology of this disease, and several treatments have been tried in patients. However, up to now, there is no satisfactory explanation of the disease and for many LND patients, efficacious treatment for persistent self-injurious behavior remains unreachable. Here, I discuss current knowledge about this mater and future directions in the field. A role for epistasis between mutated hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) and amyloid precursor protein (APP) genes is suggested. This finding may provide new directions not only for investigating the role of APP in neuropathology associated with HGprt-deficiency in LND but also for the research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases and may pave the way for new strategies applicable to rational antisense drugs design.
Author(s): Khue Vu Nguyen