a powerful reducing agent and likely an important human antioxidant, in high concentration in blood. thus, it has been suggested that free radicals, oxidative stress, and reactive oxygen species may play some role in the neuropathology of lns. however, some evidence suggests against a role for uric acid in the neuropathology of lesch–nyhan syndrome: hyperuricemia associated with classic primary gout, which is caused by low uric acid renal clearance rather than uric acid overproduction, is not associated with neuropathology. hypouricemia occurs in a number of purine disorders, in particular xanthinuria. despite having complete absence of blood uric acid, xanthinuria patients do not have any neuropathology, nor any other disease states – other than the kidney stones caused by accumulation of insoluble xanthine in lieu of uric acid. similarly, uric acid does not penetrate the blood–brain barrier well. however, oxidative stress due to uric acid is now thought to figure in metabolic syndrome, atherosclerosis, and stroke, all syndromes associated with high uric acid levels. similarly, superoxide dismutase ( "sod" ) and sod-mimetics such as tempol ameliorate the effects of hyperuricemia. likewise, 6-hydroxydopamine (the putative animal model for lesch–nyhan's neuropathy) apparently acts as a neurotoxin by generation of reactive oxygen species. it may be that oxidative stress induced by some other oxypurine such as xanthine causes the disease. diagnosis when an affected individual has fully developed the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, diagnosis of lns is easily made. diagnosis is less easy in the early stages, when the three features are not yet obvious. signs of self-injurious behavior (sib), results of pedigree analysis and novel molecular biology with genetic testing (called as diagnostic triad for lns), often confirms the diagnosis. suspicion often comes about when the developmental delay of the individual is associated with hyperuricemia. otherwise, the diagnosis should be alleged when developmental delay is associated with kidney stones (nephrolithiasis) or blood in the urine (hematuria), caused by uric acid stones. for the most part, lesch–nyhan syndrome is first suspected when self-inflicted injury behavior develops. however, self-injurious behaviors occur in other conditions, including nonspecific intellectual disability, autism, rett syndrome, cornelia de lange syndrome, tourette syndrome, familial dysautonomia, choreoacanthocytosis, sensory neuropathy including hereditary sensory neuropathy type 1, and several psychiatric conditions. of these, only individuals with lesch–nyhan syndrome, de lange syndrome, and familial dysautonomia recurrently display loss of tissue as a consequence. biting the fingers and lips is a definitive feature of lesch–nyhan syndrome; in other syndromes associated with self-injury, the behaviors usually consist of head banging and nonspecific self-mutilation, but not biting of the cheeks, lips and fingers. lesch–nyhan syndrome ought to be clearly considered only when self-injurious behavior takes place in conjunction with hyperuricemia and neurological dysfunction. diagnostic approach the urate to creatinine (breakdown product of creatine phosphate in muscle) concentration ratio in urine is elevated. this is a good indicator of acid overproduction. for children under ten years of age with lns, a urate to creatinine ratio above two is typically found. twenty-four-hour urate excretion of more than 20 mg/kg is also typical but is not diagnostic. hyperuricemia (serum uric acid concentration of >8 mg/dl) is often present but not reliable enough for diagnosis. activity of the hgprt enzyme in cells from any type of tissue (e.g., blood, cultured fibroblasts, or lymphoblasts) that is less than 1.5% of normal enzyme activity confirms the diagnosis of lesch–nyhan syndrome. molecular genetic studies of the hprt gene mutations may confirm diagnosis, and are particularly helpful for subsequent 'carrier testing' in at-risk females such as close family relatives on the female side. testing the use of biochemical testing for the detection of carriers is technically demanding and not often used. biochemical analyses that have been performed on hair bulbs from at risk women have had a small number of both false positive and false negative outcomes. if only a suspected carrier female is available for mutation testing, it may be appropriate to grow her lymphocytes in 6-thioguanine (a purine analogue), which allows only hgprt-deficient cells to survive. a mutant frequency of 0.5–5.0 × 10−2 is found in carrier females, while a non-carrier female has a frequency of 1–20 × 10−6. this frequency is usually diagnostic by itself. molecular genetic testing is the most effective method of testing, as hprt1 is the only gene known to be associated with lns. individuals who display the full lesch–nyhan phenotype all have mutations in the hprt1 gene. sequence analysis of mrna is available clinically and can be utilized in order to detect hprt1 mutations in males affected with lesch–nyhan syndrome. techniques such as rt-pcr, multiplex genomic pcr, and sequence analysis (cdna and genomic dna), used for the diagnosis of genetic diseases, are performed on a research basis. if rt-pcr tests result in cdna showing the absence of an entire exon or exons, then multiplex genomic pcr testing is performed. multiplex genomic pcr testing amplifies the nine exons of the hprt1 gene as eight pcr products. if the exon in question is deleted, the corresponding band will be missing from the multiplex pcr. however, if the exon is present, the exon is sequenced to identify the mutation, therefore causing exclusion of the exon from cdna. if no cdna is created by rt-pcr, then multiplex pcr is performed on the notion that most or all of the gene is obliterated. treatment treatment for lns is symptomatic. gout can be treated with allopurinol to control excessive amounts of uric acid. kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. there is no standard treatment for the neurological symptoms of lns. some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol. it is essential that the overproduction of uric acid be controlled in order to reduce the risk of nephropathy, nephrolithiasis, and gouty arthritis. the drug allopurinol is utilized to stop the conversion of oxypurines into uric acid, and prevent the development of subsequent arthritic tophi (produced after having chronic gout), kidney stones, and nephropathy, the resulting kidney disease. allopurinol is taken orally, at a typical dose of 3–20 mg/kg per day. the dose is then adjusted to bring the uric acid level down into the normal range (<3 mg/dl). most affected individuals can be treated with allopurinol all through life. no medication is effective in controlling the extrapyramidal motor features of the disease. spasticity, however, can be reduced by the administration of baclofen or benzodiazepines. there has previously been no effective method of treatment for the neurobehavioral aspects of the disease. even children treated from birth with allopurinol develop behavioral and neurologic problems, despite never having had high serum concentrations of uric acid. self-injurious and other behaviors are best managed by a combination of medical, physical, and behavioral interventions. the self-mutilation is often reduced by using restraints. sixty percent of individuals have their teeth extracted in order to avoid self-injury, which families have found to be an effective management technique. because stress increases self-injury, behavioral management through aversive techniques (which would normally reduce self-injury) actually increases self-injury in individuals with lns. nearly all affected individuals need restraints to prevent self-injury, and are restrained more than 75% of the time. this is often at their own request, and occasionally involves restraints that would appear to be ineffective, as they do not physically prevent biting. families report that affected individuals are more at ease when restrained. the matheny medical and educational center in peapack, nj, has six lesch–nyhan syndrome patients, believed to be the largest concentration of lns cases in one location, and is recognized as the leading source of information on care issues. treatment for lns patients, according to gary e. eddey, md, medical director, should include: 1) judicious use of protective devices; 2) utilization of a behavioral technique commonly referred to as 'selective ignoring' with redirection of activities; and 3) occasional use of medications. an article in the august 13, 2007 issue of the new yorker magazine, written by richard preston, discusses "deep-brain stimulation" as a possible treatment. it has been performed on a few patients with lesch–nyhan syndrome by dr. takaomi taira in tokyo and by a group in france led by dr. philippe coubes. some patients experienced a decrease in spastic self-injurious symptoms. the technique was developed for treating people with parkinson's disease, according to preston, over 20 years ago. the treatment involves invasive surgery to place wires that carry a continuous electric current into a specific region of the brain. an encouraging advance in the treatment of the neurobehavioural aspects of lns was the publication in the october, 2006 issue of journal of inherited metabolic disease of an experimental therapy giving oral s-adenosyl-methionine (same). this drug is a nucleotide precursor that provides a readily absorbed purine, which is known to be transported across the blood–brain barrier. administration of same to adult lns patients was shown to provide improvement in neurobehavioural and other neurological attributes. the drug is available without prescription and has been widely used for depression, but its use for treating lns should be undertaken only under strict medical supervision, as side effects are known. prognosis the prognosis for individuals with severe lns is poor. death is usually due to kidney failure or complications from hypotonia, in the first or second decade of life. less severe forms have better prognosis. history michael lesch was a medical student at johns hopkins and william nyhan, a pediatrician and biochemical geneticist, was his mentor when the two identified lns and its associated hyperuricemia in two affected brothers, ages 4 and 8. lesch and nyhan published their findings in 1964. within three years, the metabolic cause was identified by j. edwin seegmiller and his colleagues at the nih.