Lesch-Nyhan disease: from mechanism to model and back again

Abstract

Lesch-Nyhan disease (LND) is a rare inherited disorder caused by mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT). LND is characterized by overproduction of uric acid, leading to gouty arthritis and nephrolithiasis. Affected patients also have characteristic neurological and behavioral anomalies. Multiple cell models have been developed to study the molecular and metabolic aspects of LND, and several animal models have been developed to elucidate the basis for the neurobehavioral syndrome. The models have different strengths and weaknesses rendering them suitable for studying different aspects of the disease. The extensive modeling efforts in LND have questioned the concept that an ‘ideal’ disease model is one that replicates all of its features because the pathogenesis of different elements of the disease involves different mechanisms. Instead, the modeling efforts have suggested a more fruitful approach that involves developing specific models, each tailored for addressing specific experimental questions.

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

“…However, this hypothesis does not explain why LNS variant phenotypes (>1% enzymatic activity) that have only slightly active HPRT do not exhibit the self-injurious behavior [Bakay et al, 1979;Sege-Peterson et al, 1992]. Furthermore, patients who are prenatally diagnosed with LNS and are administered allopurinol upon birth and never have significantly elevated levels of uric acid in their blood still develop the classic LNS neurobehavioral phenotype [Jinnah, 2009], suggesting a limited role of uric acid in the neurological features of LNS. Today, uric acid overproduction is still treated using allopurinol, and while this effectively manages several aspects of the disease, including gout and liver failure, it is not thought to influence the development of the neurobehavioral symptoms of LNS [Nyhan, 2005].…”

“…The earliest models used to study LNS were based on non-neural cells that could be easily acquired from patients, mostly from blood (erythrocytes and lymphocytes) or skin (fibroblasts) [Jinnah, 2009]. These models were easy to establish and had direct relevance to the patients they were derived from.…”

“…Further studies administering adenine did so in tandem with allopurinol to control 2,8-dioxyadenine concentration and did not observe any improvement in behavior [Watts et al, 1974]. As uric acid levels can usually be managed well using allopurinol alone [Jinnah, 2009], adenine therapy is no longer used in the treatment of LNS.…”

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

“…Despite substantial research efforts, the link between HPRT deficiency and self-injurious behavior in LND is still unknown (Jinnah 2009;Harris 2010;Duley et al 2011).…”

Orange-colored diapers as first sign of Lesch-Nyhan disease in an asymptomatic infant

“…At 20 months, the patient was unable to control his head or speak; he also showed swallowing and severe dystonic-dyskinetic movement disorder of the upper limbs with generalized hypertonia crisis towards opistotonus. LND is a rare X-linked recessive disorder [2] characterized by the progressive development of mental retardation, spasticity, choreo-athetosis, self-mutilation, and hyperuricemia [3,4], due to complete deficiency of the activity of HGPRT (OMIM 308000) [2]. However, partially HGPRTdeficient patients (OMIM 300323) present these symptoms with different degrees of intensity [5].…”