Enzyme deficiency diseases hypoxanthine-guanine

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. 

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. 

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 Lesch-Nyhan (LN) syndrome of mental retardation, hyperuricemia and self-mutilation is an X-linked disease of man resulting from a deficiency of the enzyme hypoxanthine-guanine phosphoribosy 1-transferase (HPRT) (1). It is known that a number of LN patients exhibit no enzyme activity and no crossreacting antigen (1,2) mutation in these patients may be due to substantial deletions or insertions detectable by Southern analysis We have undertaken an initial survey of LN patients looking for major gene alterations detectable by Southern analysis our findings constitute the body of this report ... 

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) ... 

In 1975, Giblett and co-workers (18) described a deficiency of the enzyme purine nucleoside phosphorylase in patients with severe combined immunodeficiency disease characterized clinically by a severe abnormality of T-lymphocyte function. ile these patients often exhibit hypouricemia as a result of the deficiency of purine nucleoside phosphorylase, they exhibit at the same time accelerated levels of purine biosynthesis de novo with increased excretion of adenosine, deoxyinosine,guanosine, and deoxyguanosine (19). In addition, the intracellular levels of PRPP are elevated in patients with purine nucleoside phosphorylase deficiency. It is assumed, therefore, that the accelerated rate of purine biosynthesis may be due, at least in part, to the elevated levels of PRPP. It has been suggested that a decreased availability of the substrates hypoxanthine and guanine leads to a decreased functional activity of the enzyme HPRT thus leading to decreased consumption of PRPP and hence the elevated levels observed. 

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