HGPRT enzyme deficiency

Xanthine nephropathy has been reported in tumor lysis syndrome (TLS) in patients with hypoxanthine-guanine phosphoribosyl transferase (HGPRT) enzyme deficiency [180b], however, this patients cultured fibroblasts yielded normal levels of HGPRT enzyme. Allopurinol pretreatment allows the build up of both xanthine and hypoxanthine which, in the absence of HGPRT, cannot be recycled and thus xanthine supersaturation in the urine resulting in xanthine stones with subsequent obstructive renal failure. 

The answer is a. (Murray, pp 812—828. Scriver, pp 2537-2570. Sack, pp 97—158. Wilson, pp 287-320.) The child has Lesch-Nyhan syndrome (308000), an X-linked recessive disorder that is caused by HGPRT enzyme deficiency. HGPRT is responsible for the salvage ol purines from nucleotide degradation, and its deficiency elevates levels ol PRPP, purine synthesis, and uric acid. PRPP is also elevated in glycogen storage diseases due to increased amounts of carbohydrate precursors. 

HGPRT is responsible for the conversion of guanine to guanylic acid and hypoxanthine to inosinic acid. These two conversions require PRPP as the cosubstrate and are important reutilization reactions involved in the synthesis of nucleic acids. A deficiency in the HGPRT enzyme leads to increased metabolism of guanine and hypoxanthine to uric acid, and more PRPP to interact with glutamine in the first step of the purine pathway." Complete absence of HGPRT results in the childhood Lesch-Nyhan syndrome, characterized by choreoathetosis, spasticity, mental retardation, and markedly excessive production of uric acid. A partial deficiency of the enzyme may be responsible for marked hyperuricemia in otherwise normal, healthy individuals. 

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. 

Two enzyme abnormalities resulting in an overproduction of uric acid have been well described (Fig. 91-1). The first is an increase in the activity of phosphoribosyl pyrophosphate (PRPP) synthetase, which leads to an increased concentration of PRPP. PRPP is a key determinant of purine synthesis and thus uric acid production. The second is a deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT). 

Ai with other antimetabolites, acquired resistance is a major obstacle. The most common mechanism of 6-MP resistance is deficiency or complete lack of the activating enzyme, HGPRT. Another mechanism of resistance is increased particulate alkaline phosphatase activity. Other potential mechanisms for resistance to 6-MP include (1) decreased drug transport (2) alteration in allosteric inhibition of ribosylamine 5-phosphate synthase (3) altered recognition of DNA breaks and mismatches induced by 6-MP and (4) increased activity of multidrug resistance protein 5, which exports nucleoside analogs. 

Recently a new cause of supposed uric acid stones in children was identified independently by two groups (2, 3), a defect of the companion salvage enzyme adenine phos-phoribosyltransferase (APRT). This results in an inability to salvage the purine base adenine, which is then picked up by xanthine oxidase and converted to the extremely insoluble analogue of uric acid, 2,8-dihydroxyadenine (2,8-DHA) (Fig. 1). In contrast to HGPRT deficiency, other than the urolithiasis, these children are normal and heterozygotes have no clinical abnormality. 

Once the fusion has taken place, it is necessary to eliminate any unfused myeloma cells and to select only hybrid cells secreting antibody. This is primarily achieved by the use of hypoxanthine aminopterin thymidine (HAT) media and cells that are deficient in the enzyme responsible for incorporation of hypoxanthine into DNA. Figure 3 illustrates this process. The unfused splenocytes are not immortal and naturally die off in culture. The elimination of the unfused myeloma cells is carried out by the initial use of mutant myeloma cells selected for a deficiency in the enzymes hypoxanthine guanine phosphoribosyl transferase (HGPRT) and thymidine kinase (TK), rendering them unable to use the salvage pathway for nucleic acid synthesis. The myelomas will die off... 

Lesch-Nyhan disease is an X-linked recessive disorder characterized by hyperuricemia, physical and mental retardation, choreo-athetosis, and compulsive self-mutilation. The disease is associated with absence of activity of an enzyme involved in purine metabolism, namely hypoxanthlne guanine phosphoribosyl transferase (HGPRT), and is believed to affect male only. We present here, however, an unusual case of a girl with the Lesch-Nyhan syndrome, whose mother is not heterozygous for a deficiency of the enzyme. 

These studies show that diagnosis of the aberrant enzyme may be impossible from red cells alone but that altered nucleotide levels together with the raised uric acid values in plasma and urine in both mother and child, provide useful diagnostic tools. This again distinguishes e defect from HGPRT deficiency where mothers are rarely affected. 

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... 

Cultured human skin fibroblasts are commonly utilized in the detection of hemizygosity and heterozygosity for hypoxanthine-guanine phosphoribosyltrans-ferase (HGPRT) deficiency. Two obstacles are encountered in the determination of HGPRT and adenine phosphoribosyl-transferase (APRT) in extracts of cultured skin fibroblasts the sensitivity of these enzymes in dilute cell suspension to freezing and thawing (l), and the presence of nucleotidase activity (2). 

Possession of a genetic marker, such as the lack of an enzyme, to allow cell selection. For example, myelomas deficient in HGPRT (hypoxanthine guanine phosphoribosyl transferase) are commonly used. This allows selection of hybridomas in HAT medium (see selectable gene markers ). 

An inborn error of metabolism occuring in young male children the symptoms of which include aggressive behaviour accompanied by self-mutilation. It is due to a deficiency of hypo-xanthine-guanine phosphoribosyl transferase (HGPRT), an enzyme involved in the recycling of hypoxanthine and other purines. A deficiency of this enzyme results in severe hyper-uricaemia. 

HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE (HGPRT) DEFICIENCY IMMUNOLOGIC STUDIES ON THE MUTANT ENZYME... 

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