Hypoxanthine-guanine phosphoribosyltransferase deficiency syndrome

Lesch-Nyhan syndrome This is a severe form of hypoxanthine-guanine phosphoribosyltransferase deficiency, an enzyme involved in the metabolism of the purine bases (pp. 134-135)... 

Kelley, W.N. 1968. Hypoxanthine-guanine phosphoribosyltransferase deficiency in the Lesch-Nyhan syndrome and gout. Fed. Proc. 

Lesch-Nyhan syndrome A deficiency of hypoxanthine-guanine phosphoribosyltransferase results in accumulation of purine bases (Chapter 10). This causes a marked increase in the plasma level of uric acid, and hence can give rise to gout, but it also causes a severe neurological disorder, known as Lesch-Nyhan syndrome, the symptoms of which include... 

A condition known as Lesch-Nyhan syndrome is one of the primary causes of gout. An X-linked recessive trait occurring in males, this condition involves a tremendous overproduction of uric acid due to a deficiency of one of the enzymes involved in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Other abnormalites lead to mental retardation and aggressive behavior. An obvious symptom of the condition is self-mutilation. 

Purines are degraded to urate in human beings. Gout, a disease that affects joints and leads to arthritis, is associated with the excessive accumulation of urate. The Lesch-Nyhan syndrome, a genetic disease characterized by self-mutilation, mental deficiency, and gout, is caused by the absence of hypoxanthine-guanine phosphoribosyltransferase. This enzyme is essential for the synthesis of purine nucleotides by the salvage pathway. 

The clinical picture of the Lesch-Nyhan syndrome shows besides massive hyperuricemia mental retardation and spasticity (later choreoathetosis and self mutilation in the behavior) ( ) The disturbance of purine metabolism is based on the deficiency of hypoxanthine-guanine phosphoribosyltransferase activity (HG-PRT) (2) ... 

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). 

In the Lesch-Nyhan syndrome, hypoxanthine-guanine phosphoribosyltransferase is virtually absent [125], an unstable variant enzyme being present, and, in consequence, guanylic and inosinic acids are not formed from guanine and hypoxanthine. The feed-back inhibition is therefore deficient and the rate of purine biosynthesis is elevated [126]. Uric acid is produced at five to six times the normal rate and at three times the rate, corrected for body weight, found in adults vyith gout. The concentration of uric acid in the blood lies between 8 and 15 mg per 100 ml (normal 5.6 1.1 gouty subjects 9.2 1.1). 

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) ... 

The Lesch-Nyhan syndrome is caused by a deficiency of the phosphoribosyltransferase that is involved in the salvage pathway for hypoxanthine and guanine (HGPRTase). The accumulation of P-Rib-PP stimulates purine biosynthesis. 

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