Lesch-Nyhan syndrome

Lesch-Nyhan syndrome (LNS), also known as hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency or Kelley-Seegmiller syndrome in its partial form, is a rare inherited disorder of purine metabolism caused by pathogenic variants in the HPRT1 gene located on the X chromosome. This gene encodes the enzyme hypoxanthine-guanine phosphoribosyltransferase, which plays a critical role in the recycling pathway of purines. Complete deficiency of this enzyme leads to the accumulation of uric acid and disruption of dopaminergic neuron function in the basal ganglia of the brain. The syndrome primarily affects the nervous system, kidneys, and joints. Affected individuals, almost exclusively males, typically appear normal at birth but begin to show developmental delays during the first year of life. Key clinical features include severe motor disability with dystonia and spasticity, intellectual disability, and the hallmark behavioral feature of compulsive self-injurious behavior, most characteristically self-biting of the lips, fingers, and hands. Hyperuricemia (elevated uric acid levels) leads to nephrolithiasis (kidney stones), gout, and, if untreated, renal failure. Orange-colored uric acid crystals in the diaper ("orange sand") may be one of the earliest signs noticed in infancy. There is currently no cure for Lesch-Nyhan syndrome. Treatment is multidisciplinary and primarily supportive. Allopurinol is used to reduce uric acid levels and prevent renal and joint complications but does not improve the neurological or behavioral symptoms. Management of self-injurious behavior requires a combination of physical restraints, behavioral strategies, dental guards or extraction of teeth, and sometimes pharmacological interventions such as benzodiazepines or gabapentin, though no medication has proven consistently effective for this feature. Physical therapy, occupational therapy, and assistive devices are important for managing motor dysfunction. Research into dopaminergic pathways and potential gene therapy approaches is ongoing.

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