Lesch-Nyhan variant syndrome: variable presentation in 3 affected family members.
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.
Sarafoglou
Kyriakie
K
Department of Pediatrics, University of Minnesota, MMC 8404, 13-124 PWB, 516 Delaware St. SE, Minneapolis, MN 55455, USA. saraf010@umn.edu
Grosse-Redlinger
Krista
K
Boys
Christopher J
CJ
Charnas
Laurence
L
Otten
Noelle
N
Broock
Robyn
R
Nyhan
William L
WL
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*
D007041:Hypoxanthine Phosphoribosyltransferase