Lesch-Nyhan syndrome

Lesch-Nyhan syndrome is a severe hereditary disorder of purine metabolism caused by pathogenic variants in the HPRT1 gene. The resulting enzyme deficiency leads to an overproduction of uric acid and affects the nervous system, manifesting as neurological and behavioral abnormalities. Most affected individuals are males who present in early childhood with developmental delays and cognitive challenges. This condition is rare, affecting approximately 1 to 9 per million people.

Individuals with Lesch-Nyhan syndrome typically present with global developmental delay, intellectual disability, and hypotonia, all of which are consistently observed. Additional features include hyperuricemia, poor head control, and self-injurious behavior, which occurs in most cases. Some affected individuals may also develop complications such as nephrocalcinosis, seizures, or hip dislocation. Not all individuals experience all features, and severity varies considerably.

Lesch-Nyhan syndrome results from pathogenic variants in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyltransferase that plays a key role in purine metabolism. The deficiency of this enzyme disrupts normal purine recycling and leads to excess uric acid production. Inherited in an X-linked recessive pattern, the condition primarily affects males, while female carriers may experience mild symptoms due to skewed X-inactivation and should discuss monitoring with their healthcare provider. Genetic counseling is recommended to help families understand inheritance and family planning options. Associated genes include HPRT1.