Lesch-Nyhan syndrome and its pathogenesis: normal nicotinamide-adenine dinucleotide but reduced ATP concentrations that correlate with reduced poly(ADP-ribose) synthetase activity in HPRT-deficient lymphoblasts.
In hypoxanthine (guanine) phosphoribosyltransferase- (HPRT; EC 2.4.2.8) deficient lymphoblasts, ATP but not nicotinamide-adenine dinucleotide coenzyme concentrations are reduced by limited nutrition. Such reduced ATP concentrations are correlated with reduced poly(ADP-ribose) synthetase (polyADPRT; EC 2.4.2.30) activity; this reduces the breakdown of nicotinamide-adenine dinucleotide coenzymes and thus explains their normal intracellular concentrations. Since reductions in poly(ADP-ribose) synthetase activity reduce DNA repair, alterations in DNA could accumulate even in non-multiplying cells such as neurons, especially in the continuously active 'respiratory centre'. Our Lesch-Nyhan patients suffered respiratory deaths between 15 and 20 years of age.
McCreanor
G M
GM
Division of Inherited Metabolic Diseases, MRC Clinical Research Centre and Northwick Park Hospital, Harrow, Middlesex, London, UK.
Harkness
R A
RA
D000255:Adenosine Triphosphate / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency*; D007926:Lesch-Nyhan Syndrome / Q000209:etiology* / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
D009243:NAD; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D007041:Hypoxanthine Phosphoribosyltransferase