Adenine Lesch-Nyhan syndrome

The mechanism by which a decrease in activity of the hypoxanthine adenine phosphoribosyl transferase is responsible for the neurological symptoms observed in the Lesch-Nyhan syndrome is not known. At least two possibilities have been proposed. Some portions... 

The pathogenesis of the neuro-behavioral abnormalities associated with the Lesch-Nyhan syndrome remains obscure despite recent reports of neurotransmitter abnormalities in these patients. Many attempts to correct the characteristic manifestations of spasticity, mental retardation, choreoathetosis, and compulsive self-mutilation have been reported but none have reported sustained clinical efficacy. Many pathogenic mechanisms have been proposed over the past two decades to explain the relationship between the known aberration in purine metabolism and the observed neurologic dysfunction. One of these proposed mechanisms is that the absence of the purine salvage pathway in the central nervous system (CNS) results in (1) the accumulation of oxy-purines in the spinal fluid which then may act as toxic endogenous mediators and (2) the depletion of guanine and adenine nucleotides that are important to normal CNS function. Supplementation of purine intermediates with dietary adenine, guanosine, inosine, and GMP have not altered the clinical course of the disease. 

P J Benke and J Anderson, Use of folic acid, adenine and bicarbonate in newborn twins with the Lesch-Nyhan syndrome, Pediatr Res 3 356 (1969) ... 

A J Pawlak, J S Zaremba, J Barankiewicz, E Zdzienicka, and B Czartoryska, Effect of blood transfusion on activities of hypoxanthine-guanine phosphoribosyltransferase and adenine phosphoribosyltransferase in circulating red blood cells of a patient with Lesch-Nyhan syndrome, Acta Med Pol 19 331 (1978) ... 

Increased intracellular levels of PP-ribose-P have been implicated in the cause of certain hyperuricemic states associated with uric acid overproduction. Fibroblasts from two patients with the Lesch-Nyhan syndrome were found previously to have an elevated intracellular concentration of PP-ribose-P with a normal rate of PP-ribose-P production (Rosenbloom, et al., 1968). Green and Seegmiller (1969) subsequently reported a mean PP-ribose-P value of 47.1 in erythrocytes from seven patients with HGPRT deficiency. We have confirmed these elevated PP-ribose-P levels in three additional patients with the Lesch-Nyhan syndrome with values of 20.5, 39.4 and 49.5 juM (Table 1). The mothers of these patients are obligate heterozygotes and have normal PP-ribose-P levels. Two diseases associated with a deficiency of other PRT enzymes are not associated with altered erythrocyte PP-ribose-P levels (Table 1). PP-ribose-P levels were in the normal range in one patient with a partial deficiency of adenine phosphoribosyltransferase (APRT) and in one patient with orotic aciduria, which is due to a deficiency... 

ACUTE RENAL FAILURE DURING ADENINE THERAPY IN LESCH-NYHAN SYNDROME... 

The influece of adenine on the clinical features and purine metabolism in the Lesch-Nyhan syndrome. Acta Paediat. Scand. 59, 259, 1970. 

It seems useful to us to report here the changes observed in a child affected by the Lesch-Nyhan syndrome when given adenine treatment for 15 months. 

Some rare inherited deficiencies of the purine-salvage enzymes hypoxanthine-phosphoribosyl-transferase (HPRT) and adenine-PRT (APRT) lead to primary purine overproduction (Table 20.5). X-linked Lesch-Nyhan syndrome occurs in complete deficiency of HPRT. It is characterized by mental retardation, self-mutilation, choreoathetosis, gout. 

Adenine and one of its analogs, 2,6-diaminopurine, react with PP-ribose-P in the presence of adenine phosphoribosyltransferase (APRT) to form their respective ribonucleotide derivatives. Both of these compounds were reported by Schulman, et al. (1971) to cause a substantial drop in erythrocyte PP-ribose-P levels when administered to a patient with the Lesch-Nyhan syndrome. In 1 gouty patient given adenine 1 gram, a maximum decrease in erythrocyte PP-ribose-P levels to 25% of control values occurred within three hours (Fig. 3). Adenine has also been shown to be an inhibitor of purine synthesis de novo in normal and gouty subjects (Seegmiller, et al., 1968). 

Fig. 5. Effect of preincubation with adenine and amino-imidazole-carboxamide on heat stability of HGPRT activity in erythrocytes from a patient with the Lesch-Nyhan syndrome. Control, - 0.1 mM adenine or AIC,CM3 0.01 mM adenine or AIC,CIHII.

RESISTANCE OF ERYTHROCYTE ADENINE PHOSPHORIBOSYL-TRANSFERASE IN THE LESCH-NYHAN SYNDROME TO DESTABILIZATION TO HEAT BY HYPOXANTHINE... 

The Lesch-Nyhan Syndrome (LNS) is a rare x-linked neurological disease of children characterized by choreoathetosis, spasticity, mental retardation and compulsive self mutilation accompanied by excessive purine production and hyperuricemia (l). The virtually complete deficiency of activity of a purine salvage enzyme, hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) (EC 2.4.2.8.) (2), due to structural gene mutation (3 4) has been shown to be the basic abnormality in this disease. In erythrocytes of LNS patients, HGPRT deficiency has been found to be associated with increased activity and relative thermal stability of adenine phosphoribosyltransferase (APRT) (EC 2.4.2.7 ) (5 6) an autosomally determined enzyme (7) ... 

E.J.P. Lommen, G.D. Vogels, S.P.M. van der Zee, J.M.F. Trijbels and E.D.A.M. Schretlen (1971) Concentration of purine nucleotides in erythrocytes of patients with the Lesch-Nyhan syndrome before and during oral administration of adenine, Acta Paediat. Scand. 60, 642. 

Recent advances in the understanding of human purine metabolism have been stimulated by the discovery of specific inborn errors of this pathway in man. In particular, the demonstration of the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in the Lesch-Nyhan syndrome and in some patients with gout has contributed essential information on the regulation of purine biosynthesis novo and on the critical role of this reutilization pathway in central nervous system function in man. The search for other disorders led to the description of a partial deficiency of adenine phosphoribosyltransferase (APRT) in four members in three generations of one family. Each of the subjects partially deficient in APRT exhibited a normal serum urate concentration and the propositus had a normal excretion of uric acid (Kelley, et al., 1968). We have investigated a second family partially deficient in APRT (Fox and Kelley, in press). 

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