An unexpected female patient within a classical Lesch-Nyhan family

Abstract

The Lesch-Nyhan (LN) disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme Hypoxanthineguanine PhosphoRibosyl Transferase (HPRT). Affected individuals have a striking phenotype characterized by hyperuricemia and uricosuria, spasticity, involuntary movements, developmental disability and self-injurious behavior. The HPRT gene is located on the long arm of the X chromosome (Xq26) and the pattern of inheritance is X-linked recessive. The classical phenotype occurs exclusively in males, while heterozygous, carrier females are generally normal.We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers with normal phenotypes. We identified the HPRT mutation in the family. It is a C→T transition at position 508 of the cDNA that changes the CGA codon for Arg(169) to the TGA stop codon. The female patient was karyotypically normal and heterozygous for the mutation. She inherited the HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of the disease in this female patient.Three cases of female patients with classical LN clinical features have been previously reported. Each of them showed a different de novo molecular alteration that led to a specific HPRT enzyme defect, along with a mechanism of nonrandom inactivation of the X chromosome carrying the normal copy of the HPRT gene. Our family differs in that the HPRT mutation was inherited in at least three individuals, one of whom is our female case. Like the other affected females, she also shows nonrandom inactivation of the normal X chromosome.