These symptoms are present in all HPRT-deficient patients and are not related to the severity of the enzyme defect. All characteristic findings associated with gout may be present (acute arthritis, tophi, nephrolithiasis or urolithiasis, and renal disease). Hyperuricemia-related presentations include orange crystals in the diapers, crystalluria in the first years of life, or juvenile arthritis. If the diagnosis and treatment is delayed, tophi and renal failure may appear. However, nowadays allopurinol treatment prevents the development of gouty manifestations.

Neurological symptoms may differentiate HPRT-deficient variants. The presence and severity of these symptoms are relevant for prognosis. They may reflect the degree of enzyme deficiency and can render the patient partially or completely dependent on others for daily activities and personal care. We have proposed a classification of HPRT deficiency in four grades according to the severity of the neurological symptoms (see below) 18. Other classifications in three grades have also been proposed 19. Neurological symptoms affect the motor sphere, cognitive, and behavioural aspects.

◦ Motor disorder: In their original report on two affected brothers, M. Lesch and W. Nyhan 1 described the motor abnormalities as spasticity and choreoathetosis. However, in a recent revision by H. A. Jinnah et al. 17, the motor syndrome of complete HPRT deficiency is best classified as a severe action dystonia, superimposed on a baseline hypotonia. Dystonia is generalized to all parts of the body and its severity may lead to an inability to stand up and walk, and patients are confined to a wheelchair. Involuntary movements such as choreoathetosis and ballismus are usually present but are not evident at rest. These symptoms are associated with voluntary movements and increase with excitement and anxiety. Dysarthria and dysphagia and opisthotonus are frequently reported. Corticospinal tract signs such as spasticity, hyperreflexia and extensor plantar reflex are generally reported in later years and they may reflect an acquired defect.

In partial HPRT-deficient patients, a complete motor syndrome may be present in the most severe forms. In other patients the grade of dystonia is less severe and appears in the form of a dystonic gait, speech difficulties, exercised-induced dystonia or is unapparent.

◦ Cognitive impairment: The first Lesch-Nyhan description included mental retardation as a characteristic of the syndrome. However complete HPRT-deficient patients, when evaluated with specific tests for motor difficulties, show mild to moderate mental retardation. These patients show attention deficit disorders but the non-verbal intelligence is well preserved in the majority 202122.

Partial HPRT deficient patients can present variable degrees of mental retardation including apparently normal intelligence, but they usually show various grades of attention deficit 20.

◦ Compulsive self-injurious behaviour is the most striking feature of Lesch-Nyhan syndrome and is only present in patients with the complete enzyme defect, although some Lesch-Nyhan patients never show auto-destructive behaviour. The patients begin to bite their lips, tongue or fingers and, without restrictions, important auto-mutilating lesions can develop 2324. The mutilation is not the result of a lack of sensation (the patients feel pain and are relieved when protected from themselves) and recently it has been ascribed to an obsessive-compulsive behaviour. In some instances, the aggressive behaviour is also directed against family and friends, with patients spitting or using abusive language. Self-mutilation may start between 2 and 16 years of age and, in some instances, is associated with or aggravated by psychological stress (adolescence, familial conflicts). Despite their periodic aggressive behaviour, Lesch-Nyhan patients are frequently happy and engaging children when they are restrained. The neuro-behavioural disorder may be markedly modulated by numerous environmental factors, among which education is the most relevant 25. Partial patients do not show self-injurious behaviour but in some cases an obsessive-compulsive disorder has been reported.

In Lesch-Nyhan patients the presence of megaloblastic anaemia is frequent and in some cases severe 26. Microcitic anaemia can also be present, usually associated with hiatus hernia.

Several mechanisms can be identified that contribute to uric acid overproduction in HPRT deficiency 2728. a) HPRT catalyses the salvage synthesis of inosine monophosphate (IMP) and guanosine monophosphate (GMP) from the purine bases hypoxanthine and guanine respectively, utilizing 5'-phosphoribosyl-1-pyrophosphate (PRPP) as a co-substrate (Figure 1). The HPRT defect results in the accumulation of its substrates, hypoxanthine and guanine, which are converted into uric acid by means of xanthine oxidase. b) The increased availability of PRPP for PRPP amidotransferase, the rate-limiting enzyme of de novo synthesis of purine nucleotides (Figure 1), increases purine synthesis. c) On the other hand, there is decreased formation of PRPP amidotransferase feedback inhibitors, IMP and GMP. This dual mechanism results in an increased de novo synthesis of purine nucleotides. The combination of deficient recycling of purine bases with increased synthesis of purine nucleotides explains marked uric acid overproduction in HPRT deficiency. Elevated APRT activity may also contribute to purine overproduction.

The pathophysiology of the neurological and behavioural dysfunctions remains unclear 2930. Post mortem studies of brains from Lesch-Nyhan patients have not disclosed any characteristic morphological abnormality 316. Pioneer neurochemistry analysis of post mortem tissues revealed the first biochemical evidence of dysfunction of brain neurotransmitters in Lesch-Nyhan syndrome. In this study, biochemical aspects of the function of dopamine-neuron terminals in the striatum were decreased, whereas serotonin and 5-hydroxyindolacetic were increased 32. Other biochemical studies of the Lesch Nyhan patient's cerebrospinal fluid showed a decreased level of the dopamine metabolite homivanillic acid, together with increased hypoxanthine and xanthine concentrations 313334. More recently, in vivo human studies with positron-emission tomography, in which ligands that bind to dopamine-related proteins in the brain have been used, have confirmed alterations of dopaminergic system in Lesch-Nyhan patients 3536.

Two animal models, pharmacological and knockout, have been employed in the study of Lesch-Nyhan pathogenesis. The pharmacological rat model, developed by Breese et al., supports the relationship between self-injurious behaviour and dopamine deficit. Newborn animals treated with 6-hydroxydopamine, which destroys catecholamine-containing neurons, showed self-injurious behaviour in response to dopa agonist administration 37. Unfortunately, HPRT-deficient knockout mice did not show neurological alterations, but they also presented an age-related decreased content of dopamine in their brains 383940. Various HPRT-deficient cell cultures have been developed to study the effects of the enzyme deficit and purine alterations 4142 and dopamine deficit has been confirmed 4344. However, we must be careful when interpreting cell culture results since different HPRT-deficient cultures have showed different results 45. Alterations in other neurotransmitters systems, such as serotonin 30 or adenosine neurotransmitters systems have also been implicated in patients with Lesch-Nyhan symptoms 46474849.

Among the biochemical alterations described in the central nervous system of Lesch-Nyhan patients, hypoxanthine excess is the most prominent. Toxic effects of this metabolite have been implicated in the pathogenesis of neurological dysfunction by means of alteration of adenosine transport 4749, Na⁺K⁺ ATPase activity 50, etc. Deficit of other purine compounds due to the enzyme defect is controversial, and altered nucleotide concentrations have been postulated as a possible cause of changes in G-protein-mediated signal transduction 51.

In summary, various studies have led to the suggestion that the neurological symptoms of Lesch-Nyhan syndrome could be related to a dysfunction of the dopaminergic neurotransmitter system in the basal ganglia, but the relationship between the dopamine deficit and the purine metabolic disorder is still unknown.

Megaloblastic anaemia in Lesch-Nyhan patients is associated with megaloblastic findings in bone marrow and has been considered the result of increased folic acid consumption, due to enhanced de novo purine synthesis 52. Nevertheless, this anaemia is not corrected by folate therapy.

HPRT deficiency should be suspected in patients with hyperuricemia and uric acid overproduction with or without neurological impairment. During the first year of life, serum and urine uric acid determinations should be included in the differential diagnosis of psychomotor delay. Unfortunately, in previous years Lesch-Nyhan syndrome diagnosis has been delayed until self-mutilation was evident. Nephrolithiasis and obstructive nephropathy are common early manifestations in patients with partial HPRT deficiency.

Neuro imaging tests such as computing tomography (CT) and magnetic resonance imaging (MRI) may show atrophic non-specific changes 653. Electroencephalograms are not diagnostic.

A high serum urate concentration is usually the biochemical finding that prompts special testing for the specific diagnosis, although some patients, particularly young infants, may have borderline serum uric acid levels due to increased renal clearance of uric acid 54. Normal values for serum urate levels depend on age and sex. Similarly, the urinary uric acid/creatinine ratio can be employed as a screening test for inherited disorders of purine metabolism 54 but the values should be evaluated based on the age of the patient. Normal values for the urinary uric acid/creatinine ratio are below 1.0 after age 3-years. Mean plasma concentrations of urate, hypoxanthine, and xanthine, and their urinary excretion rates, are markedly elevated in HPRT-deficient patients. However, there is a non-statistically significant difference in these biochemical variables between partial and Lesch-Nyhan patients, except for xanthine urinary excretion that appears to be increased in Lesch-Nyhan patients as compared to partial HPRT deficient patients 55.

HPRT deficiency must be confirmed by enzymatic determinations 56. Patients present low or undetectable HPRT activity in haemolysates, with increased adenine phosphoribosyltransferase (APRT) activity. Lesch-Nyhan patients (grade 4) present undetectable HPRT activity, but in partial HPRT-deficient patients HPRT activity in haemolysate ranges from 0 to 10% 1819. Grade 1 patients usually show detectable haemolysate HPRT activity, while grade 2 or 3 patients generally do not. To better characterize the HPRT deficiency, enzyme activity can be measured in intact cells (erythrocytes or fibroblasts). A correlation was found between residual HPRT activity in intact erythrocytes and fibroblasts 1957 and neurological involvement, although values may overlap for patients with very different phenotypes.

Human HPRT is encoded by a single structural gene spanning approximately 45 Kb on the long arm of the X chromosome at Xq26, and consists of nine exons with a coding sequence of 654 bp 5859. Most HPRT-deficient patients present HPRT mRNA expression 60, and molecular diagnosis can be accomplished by cDNA sequencing 61. In other cases, genomic DNA sequencing may be necessary 62. Documented mutations in HPRT deficiency show a high degree of heterogeneity in type and location within the gene: deletions, insertions, duplications, and point mutations have been described as the cause of HPRT deficiency. To date, more than 300 disease-associated mutations have been found 636465. Single point mutations are the main cause of partial deficiency of the enzyme, whereas Lesch-Nyhan syndrome is caused mainly by mutations that modify the size of the predicted protein 64. HPRT deficiency is inherited as an X-linked recessive trait. However, about 30% of patients' mothers are not somatic carriers, and these patients probably carry de novo mutations due to a germinal cell mutation. Molecular diagnosis in HPRT-deficient patients allows faster and more accurate carrier and prenatal diagnosis.

Uric acid overproduction can be controlled with the xanthine oxidase inhibitor allopurinol that blocks the conversion of xanthine and hypoxanthine into uric acid 78. Allopurinol treatment reduces serum urate and urine uric acid levels and thus prevents uric acid crystalluria, nephrolithiasis, gouty arthritis and tophi 4557980. Allopurinol should be started as soon as the enzyme deficiency has been diagnosed, although it has no effect on behavioural and neurological symptoms. In adults, combined treatment with colchicine prophylaxis may be required to prevent acute inflammation. In our experience 55, treatment with allopurinol normalized serum urate level in all patients and resulted in a mean reduction of serum urate of about 50% and a 74% reduction in urinary uric acid/creatinine ratio. In contrast, allopurinol treatment increased mean hypoxanthine and xanthine urinary excretion rates about 5- and 10-fold, respectively, compared to baseline levels. Allopurinol-related biochemical changes are similar in patients with either complete or partial HPRT deficiency. Renal function usually remained stable or improved with treatment. Allopurinol doses ranged from 50 to 600 mg/day. The initial dosage of allopurinol is 5–10 mg/Kg/day and it should be adjusted to maintain high-normal serum uric acid levels and a urinary uric acid/creatinine ratio lower than 1.0. Allopurinol is efficacious and generally safe for the treatment of uric acid overproduction in patients with HPRT deficiency 55. However, xanthine lithiasis may develop as a consequence of allopurinol therapy 81. The optimal allopurinol dose for HPRT-deficient patients has not been established. In our experience, when serum urate is maintained close to its solubility threshold, urate deposition does not occur. Xanthine lithiasis may be prevented by sequential determination of urinary oxypurines, which should be at a certain balance with uric acid excretion.

The lack of precise understanding of the cause of the neurological dysfunction has precluded the development of useful therapies. Spasticity and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen 6. No medication has been found to effectively control the extrapyramidal manifestations of the disease. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control of objects, appropriated walking aids, and a programme of posture management to prevent deformities is recommended.

Self-injurious behaviour must be managed with a combination of physical restraints, behavioural and pharmaceutical treatments 82. Benzodiazepines and carbamazapine are sometimes useful for ameliorating behavioural manifestations and anxiety. Stress increases self-injurious behaviour. Thus, stressful situations should be avoided and aversive techniques should not be employed. Instead, behavioural extinction methods have proven to be partially efficacious in a controlled setting. However, the cornerstone of day-to-day management of Lesch-Nyhan syndrome is still adapted physical restraint to protect patients from themselves. For instance, elbow restraints allow hand use without the possibility of finger mutilation, and dental guards prevent cheek biting (Figure 2). Patients themselves request restrictions and became anxious if they are unrestrained, and sometimes restraints that would appear to be ineffective, such as a pair of gloves to prevent finger biting, are useful.

Some reports have suggested that gabapentin may improve self-injurious behaviour and no side effects have been associated with its use 83. Other treatments under investigation for the management of self-injurious behaviour are local injections of botulin toxin 84, deep brain stimulation in globus pallidus 8586 or dopamine replacement therapy, but they need to prove to be efficacious and safe in the long-term management of these patients.