Lesch Hypoxanthine guanine phosphoribosyl

In many cells, the capacity for de novo synthesis to supply purines and pyrimidines is insufficient, and the salvage pathway is essential for adequate nucleotide synthesis. In patients with Lesch-Nyhan disease, an enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent. People with this genetic deficiency have CNS deterioration, mental retardation, and spastic cerebral palsy associated with compulsive self-mutilation, Cells in the basal ganglia of the brain (fine motor control) normally have very high HPRT activity. These patients also all have hyperuricemia because purines cannot be salvaged. 

Rare hereditary deficiency Avoid in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), such as Lesch-Nyhan and Kelley-Seegmiller syndromes. 

EXAMPLE 14.13 In some diseases, excessive amounts of purines are produced in the body, leading to accumulation of urate. Patients with Lesch-Nyhan syndrome lack the enzyme hypoxanthine-guanine phosphoribosyl-transferase (HG-PRTase). Children born with this disorder are mentally retarded and prone to self-mutilation. They produce excessive amounts of purines due to accumulation of P-Rib-PP which stimulates the first enzyme of the purine synthesis pathway, amido PRTase (Fig. 14-18). Patients with Lesch-Nyhan syndrome may also suffer from gout, which is due to an accumulation of urate in the body with deposition of crystals of sodium urate in the joints and kidneys, or due to accumulation of P-Rib-PP for reasons other than a deficiency of HG-PRTase. 

The mutant gene in Lesch-Nyhan syndrome (Seegmiller et al.y 1967 Rosenbloom et al.y 1967) is an X-linked recessive and the enzyme involved is hypoxanthine guanine phosphoribosyl transferase (HG-PRT), which has been associated with resistance to analogs of these purines in hetero-nuclear cell lines. Selective systems for both forward and reverse mutations affecting the activity of HG-PRT are available and will be discussed subsequently. 

The quantitative importance of the salvage pathway in purine metabolism is difficult to estimate [156]. Comparison between uric acid production in normal children and in children affected with a deficiency in hypoxanthine guanine phosphoribosyl transferase has, however, permitted researchers to approximate how much the salvage pathway contributes to purine metabolism. Thus, whereas in normal children uric acid excretion in the urine (per 24 hours and per kilogram of body weight) is of the order of 10 mg, in children affected with the Lesch-Nyhan syndrome, uric acid excretion is around 47 mg. The difference between enzyme-deficient and normal children is believed to reflect the amount of uric acid normally used in the salvage pathway. 

The biochemical mechanism regulating the balance between de novo and salvage pathways remains to be discovered. But observation of patients afflicted with gout or the Lesch-Nyhan syndrome suggests that hypoxanthine guanine phosphoribosyl transferase may play an important role in maintaining the balance between de novo and salvage pathways. 

An elevated plasma dopamine-j8-hydroxylase is associated in some cases of Lesch-Nyhan syndrome with the hypoxanthine guanine phosphoribosyl transferase activity. The hydroxylase is found, among other sites, in the synaptic vesicles where it converts dopamine to norepinephrine. Elevation of the hydroxylase occurs when the patients are exposed to stress that generates acute sympathetic stimulation. Blood pressure does not increase as it does in normal individuals. Those individuals with low transferase, but normal hydroxylase activity do not mutilate themselves. 

C. H. M. M. de Bruyn. An atypical case of hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome) I. Clinical Studies. Clin.Genet., 40 348 (1973). 

An almost complete deficiency of the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT) is known to be the cause of the Lesch-Nyhan syndrome (1,2) The gene for HPRT is located on the X-chromosome, so that heterozygous females show two populations of cells, one HPRT and one HPRT ", as predicted by the hypothesis of Lyon (3,4). Such mosaicism has been demonstrated in populations of cultured fibroblasts and in hair root follicles of heterozygotes (4,5). 

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) ... 

Lesch-Nyhan syndrome (juvenile hyperuricaemia). A rare inborn error of metabolism due to a deficiency of hypox-anthine-guanine phosphoribosyl transferase, an enzyme involved in the recycling of hypoxanthine and other purines. 

The Lesch-Nyhan syndrome is a rare, X-linked genetic disease due to a functional absence of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (Seegmiller, Rosenbloom and Kelley, 1967). This enzyme catalyzes the transfer of the 5-phos-phoribosyl moiety of 5-phosphoribosyl-l-pyrophosphate (PP-ribose-P) to the purine bases guanine and hypoxanthine to form the nucleotides inosinic acid and guanylic acid. 

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