LESCH-NYHAN DISEASE: A RARE DISORDER WITH MANY UNRESOLVED ASPECTS V. Micheli 1,2 , M. Bertelli 3 , G. Jacomelli 1 , A. Santucci 1 , G. Bernardini 1 1 Dpt. Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, 53100 Siena, Italy 2 LND Famiglie Italiane ONLUS, Via Giovanetti 15-20, 16149 Genova, Italy 3 MAGI non-profit organization, Via delle Maioliche 57/D, 38068 Rovereto (TN) - Italy Abstract Lesch-Nyhan Disease (LND) is a rare X-linked recessive metabolic and neurological syndrome due to the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). Besides its well known “housekeeping” function this purine salvage enzyme has revealed an unexpected role in neurodevelopment, unveiled by the peculiar neurological symptoms flanking hyperuricemia in LND: dystonia, choreoathetosis, compulsive self-injurious behaviour. Several lines of research have tried to find the molecular basis for the neurological phenotype after the disease was first described in 1964. Dopaminergic deficit was then found to underlie the neurologic symptoms but the aetiology for such alteration seemed inexplicable. A number of detailed studies in the last 50 years addressed the genetic, metabolic, cognitive, behavioral and anatomical features of this disease. Initial investigations seeked for accumulation of toxic metabolites or depletion of essential molecules to disclose potential connections between purine recycling and neuronal dysfunction. In the last two decades sophisticated biotechnological methods were used for a deeper insight in the genetic and molecular aspects, unveiling a network of combined gene dysregulations in neuronal development and differentiation producing neurotransmission defects. These studies, conducted with several different approaches, allowed consistent steps forward, demonstrating transcriptional aberrations affecting different metabolic pathways in HPRT deficiency, yet leaving many questions still unsolved. Keywords Lesch-Nyhan disease  neurological syndrome  hyperuricemia  therapies Medical University 1 Introduction A “bizarre” metabolic and neurological syndrome, characterized by marked hyperuricemia and hyperuricuria, was identified as an X-linked recessive disease and named “Lesch-Nyhan Disease” (LND) after the two physicians who first described it [1,2]. Later, the biochemical cause was identified as a single enzyme deficiency: hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8) [3]. HPRT catalyzes the salvage of the purine bases hypoxanthine and guanine converting them into their respective monophosphate nucleosides (IMP and GMP) by a PRPP-dependent phosphoribosyl transfer reaction (Fig. 1). It is a cytoplasmic enzyme ubiquitously expressed in human tissues, displaying different specific activity in different tissues and during development, with highest activities in testis and brain [4-6]. The human enzyme is encoded by a single structural gene (HPRT1) located at Xq26-27. The gene has been sequenced and more than 400 different mutations in the coding region have been described causing different degrees of deficiency [7]. HPRT aminoacid sequence has been determined and various alterations of the physical and kinetic properties of the enzyme have been reported in Corresponding author: V. Micheli E-mail: vannamiche@gmail.com patients bearing different mutations [8,9], leading to complete or partial deficiency. In few cases deficiency of HPRT activity in intact cultured fibroblasts was reported not to be related to any mutation in the HPRT coding sequence but to markedly decreased HPRT expression of mRNA [10-12]. In these cases deficiency was attributed to a defect in gene regulation of unknown cause. Megaloblastic anaemia unresponsive to folate therapy is also common in LND patients [13]. The basic diagnostic criterion for LND and its variants is HPRT activity assay in lysates or intact erythrocytes or fibroblasts; diagnostic suspect can be raised by grossly increased uric acid amount in plasma and urine, accompanied by increased hypoxanthine and xanthine [13]. Genetic aspects of LND The prevalence of LND is approximately estimated to be 1/380,000 live births. It appears to occur in all populations © 2018 Vanna Micheli. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivs license (http://creativecommons. org/licenses/by-nc-nd/3.0/). Review Article • DOI: http://dx.doi.org/10.2478/medu-2018-0002 Medical University • 1(1) • 2018