title: An unexpected affected female patient in a classical Lesch-Nyhan family.
abstract: Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically 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 and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). 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 disease in this female patient.
authors.affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: L
authors.initials: L
authors.lastname: De Gregorio
authors.forename: W L
authors.initials: WL
authors.lastname: Nyhan
authors.forename: E
authors.initials: E
authors.lastname: Serafin
authors.forename: N A
authors.initials: NA
authors.lastname: Chamoles
mesh_terms: D000328:Adult; D001118:Argentina; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004303:Dosage Compensation, Genetic; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency / Q000235:genetics*; D007926:Lesch-Nyhan Syndrome / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors / Q000235:genetics; D014960:X Chromosome / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D014157:Transcription Factors; C077885:XIST non-coding RNA; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase