Lesch-Nyhan Syndrome

Rare inborn error of purine metabolism that becomes apparent between the ages of 3 and 6 months. Characterized by the presence of orange crystal-like deposits (“orange sand”) in the diapers of infants with the disorder. This is frequently the first symptom of Lesch-Nyhan syndrome. Other clinical features include hematuria, urinary tract infections, arthritis, choreoathetosis manifested by raising and lowering of the shoulders, and facial grimacing. Hypotonia, hypertonia, hyperreflexia, and spasticity have been reported. Megaloblastic anemia, self-mutilating behavior, irritability, screaming, uncontrolled aggressiveness, and compulsive actions complete the clinical presentation.

Hyperuricemia Syndrome; Hypoxanthine-Phosphoribosyl-Transferase Deficiency Disease; Complete HGPRT Deficiency Disease; Kelley-Seegmiller Syndrome; Hyperuricemia-Oligophrenia Syndrome.

Genetically transmitted error of metabolism of purine bases.

Estimated at 1:380,000 live births in the United States; almost exclusively males, although a few females are reported (heterozygotes, mild form of the disease).

X-linked (Xq26-Xq27) recessive disorder caused by a mutation in the gene coding for the enzyme hypoxanthine phosphoribosyltransferase (HPRT). Different mutations have been described.

The mutation leads to total or partial loss of function of HPRT, which normally catalyzes the conversion of hypoxanthine and guanine to inosinic and guanylic acid, a reaction that allows reuse of preformed purine bases resulting from cell turnover and catabolism. The absence of this reaction results in overproduction of uric acid and leads to hyperuricemia and uricosuria and thus urate nephropathy, urinary tract calculi, and gout. The neurologic features of the syndrome (choreoathetosis, self-mutilation, spasticity) are caused by abnormalities in brain neurotransmitters, mainly decreased dopaminergic activity in the basal ganglia. Treatment with inhibitors of xanthine oxydase (allopurinol 10 mg/kg/day, maximum 800 mg/day) can control hyperuricemia but does not prevent the effect on neurologic system. Poor prognosis (few patients live beyond age 40 years).

Patients are normal at birth; onset after a few months. Diagnosis can be clinically evocated by the observation of orange crystals in the diapers or crystalluria with obstruction of the urinary tract. Psychomotor retardation appears quickly (delay in acquisition of sitting and head support), followed by spasticity and athetoid movements. Self-mutilation is characteristic and can start as soon as teeth are present. Enzyme and molecular studies confirm diagnosis.

Boys only are affected; the first symptom is often the presence of orange-colored crystal-like deposits (“orange sand”) of urates in the diapers of affected infants.

Total Deficit in HPRT: Manifests during the first year of life with motor development delays. Thereafter, choreoathetotic movements with dysphagia and dysarthria; later, axial hypotonia and limb spasticity. Compulsive self-mutilation (biting of lips, fingers, and hands) and aggressive behavior usually appear between ages 2 and 4 years, Nephrolithiasis and gouty arthritis occur if no allopurinol treatment is given. Mental retardation is present, but the severity is difficult to determine because IQ testing is problematic.

Partial Deficit in HPRT: The child presents with juvenile gout with nephrolithiasis; there is no self-mutilation and the neurologic signs are mild (some choreic or athetotic involuntary movements). Partial Lesch-Nyhan syndrome should be excluded in children with uric nephrolithiasis.

Evaluate neurologic status (obtain full history, clinical, electroencephalogram, CT/MRI), particularly concerning dysphagia and extrapyramidal signs. Evaluate hyperuricemia consequences (clinical, laboratory investigations including blood and urinary uric acid, echography, CT, radiography). Coagulation disorder is possible in severe cases.

Careful intraoperative positioning is necessary. Strict asepsis is needed considering infectious risk. The risk of pulmonary aspiration is high because of oropharyngeal abnormal motility. Perioperative observation of the patient is needed considering the degree of aggressivity, explosive compulsive action, and severe behavioral problems. Cooperation is not possible, and sedation should be considered.

Although propofol may increase urinary acid excretion in normal subjects, it has been used without problems in patients with Lesch-Nyhan syndrome. Nevertheless, prolonged propofol infusion probably should be avoided. There is some evidence of abnormal adrenergic function and diminished sympathetic response to stress; consequently, exogenous catecholamines should be administered with care (titration to effect).

Inherited chorea syndromes may rarely be confused with Lesch-Nyhan syndrome, the diagnosis of which is easy (orange crystal in the diaper).