title: Lesch-Nyhan variant syndrome: variable presentation in 3 affected family members.
abstract: BACKGROUND
  Lesch-Nyhan disease is an inborn error of purine metabolism that results from deficiency of the activity of hypoxanthine phosphoribosyltransferase (HPRT). The heterogeneity of clinical phenotypes seen in HPRT deficiency corresponds to an inverse relationship between HPRT enzyme activity and clinical severity. With rare exception, each mutation produces a stereotypical pattern of clinical disease; onset of neurologic symptoms occurs during infancy and is thought to be nonprogressive.
  
  
  OBJECTIVE
  To document a family in which a single HPRT gene mutation has led to 3 different clinical and enzymatic phenotypes.
  
  
  METHODS
  Case report. Settings A university-based outpatient metabolic clinic and a biochemical genetics laboratory. Patients Three males (2 infants and their grandfather) from the same family with Lesch-Nyhan variant, including one of the oldest patients with Lesch-Nyhan variant at diagnosis (65 years).
  
  
  METHODS
  Clinical and biochemical observations.
  
  
  RESULTS
  Sequencing of 5 family members revealed a novel mutation c.550G>T in exon 7 of the HPRT gene. The considerably variable clinical phenotype corresponded with the variable enzymatic activity in the 3 males, with the grandfather being the most severely affected.
  
  
  CONCLUSIONS
  The different phenotypes encountered in the enzymatic analysis of cultured fibroblasts from a single mutation in the same family is unprecedented. The significant decrease in the grandfather's HPRT enzymatic activity compared with that of his grandchildren could be a function of the Hayflick Limit Theory of cell senescence.
authors.affiliation: Department of Pediatrics, University of Minnesota, MMC 8404, 13-124 PWB, 516 Delaware St. SE, Minneapolis, MN 55455, USA. saraf010@umn.edu
authors.forename: Kyriakie
authors.initials: K
authors.lastname: Sarafoglou
authors.forename: Krista
authors.initials: K
authors.lastname: Grosse-Redlinger
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Boys
authors.forename: Laurence
authors.initials: L
authors.lastname: Charnas
authors.forename: Noelle
authors.initials: N
authors.lastname: Otten
authors.forename: Robyn
authors.initials: R
authors.lastname: Broock
authors.forename: William L
authors.initials: WL
authors.lastname: Nyhan
mesh_terms: D000368:Aged; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics* / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D009154:Mutation / Q000235:genetics*
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase