Biochemical and molecular study of mentally retarded patient with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase

Micheli, Vanna; Gathof, Birgit; Rocchigiani, Marina; Jacomelli, Gabriella; Sestini, Silvia; Peruzzi, Luana; Notarantonio, L.; Cerboni, Barbara; Hayek, Joussef; Pompucci, G

doi:10.1016/s0925-4439(02)00053-4

Cited by 11 publications

(7 citation statements)

References 34 publications

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“…Increased utilization of exogenous nicotinic acid by intact erythrocytes of most LNS patients [44,98], with increased or normal activities of the enzymes committed to its synthesis were reported Fig. (1) [99,100]. Low erythrocyte NAD glycohydrolase activity was found in LNS patients, probably accounting for the high levels of NAD [101].…”

Section: Hypoxanthine-guanine Phosphoribo-syltransferase Deficiency Amentioning

confidence: 99%

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

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101

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Purines and pyrimidines, regarded for a long time only as building blocks for nucleic acid synthesis and intermediates in the transfer of metabolic energy, gained increasing attention since genetically determined aberrations in their metabolism were associated clinically with various degrees of mental retardation and/or unexpected and often devastating neurological dysfunction. In most instances the molecular mechanisms underlying neurological symptoms remain undefined. This suggests that nucleotides and nucleosides play fundamental but still unknown roles in the development and function of several organs, in particular central nervous system. Alterations of purine and pyrimidine metabolism affecting brain function are spread along both synthesis (PRPS, ADSL, ATIC, HPRT, UMPS, dGK, TK), and breakdown pathways (5NT, ADA, PNP, GCH, DPD, DHPA, TP, UP), sometimes also involving pyridine metabolism. Explanations for the pathogenesis of disorders may include both cellular and mitochondrial damage: e.g. deficiency of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase are associated to the most severe pathologies, the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to impairment of mitochondrial functions. This review gathers the presently known inborn errors of purine and pyrimidine metabolism that manifest neurological syndromes, reporting and commenting on the available hypothesis on the possible link between specific enzymatic alterations and brain damage. Such connection is often not obvious, and though investigated for many years, the molecular basis of most dysfunctions of central nervous system associated to purine and pyrimidine metabolism disorders are still unexplained.

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Section: Hypoxanthine-guanine Phosphoribo-syltransferase Deficiency Amentioning

confidence: 99%

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

Self Cite

101

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“…Suspensions were freezed–thawed twice at −80 °C and centrifuged (10 min, 21,000×g). Enzyme activities were assayed in clear supernatants by previously published HPLC‐linked methods . Protein content was measured for activity normalization.…”

Section: Methodsmentioning

confidence: 99%

Inhibiting PNP for the therapy of hyperuricemia in Lesch–Nyhan disease: Preliminary in vitro studies with analogues of immucillin‐G

Jacomelli

Baldini

Mugnaini

et al. 2019

J of Inher Metab Disea

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Lesch-Nyhan disease (LND) is a rare X-linked genetic disorder, with complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency, uric acid (UA), hypoxanthine and xanthine accumulation, and a devastating neurologic syndrome. UA excess, causing renal failure, is commonly decreased by xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, yielding a xanthine and hypoxanthine increase. Xanthine accumulation may result in renal stones, while hypoxanthine excess seems involved in the neurological disorder. Inhibition of purine nucleoside phosphorylase (PNP) represents a different strategy for lowering urate. PNP catalyzes the cleavage of purine ribo-and d-ribo-nucleosides into ribose/deoxyribose phosphate and free bases, starting catabolism to uric acid. Clinical trials demonstrated that PNP inhibitors, initially developed as anticancer drugs, lowered UA in some gouty patients, in association or not with allopurinol. The present study tested the reliability of an analogue of immucillin-G (C1a), a PNP inhibitor, as a therapy for urate, hypoxanthine, and xanthine excess in LND patients by blocking hypoxanthine production upstream. The therapeutic aim is to limit the administration of XOR inhibitors to LND patients by supplying the PNP inhibitor in low doses, avoiding d-nucleoside toxicity. We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND hyperuricemia. K E Y W O R D S

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“…Grossly increased NAD concentration was reported [47,43] with normal or lower NADH/NAD + ratio in LND erythrocytes [48]. Increased utilization of exogenous NAD precursor nicotinic acid by intact erythrocytes [49,50], with increased or normal erythrocyte activities of the enzymes committed to its synthesis were reported in LND patients [51,52], and low NAD glycohydrolase activity [53] (Fig. 1).…”

Section: Investigations On the Pathogenesis Of Neurological And Behavmentioning

confidence: 97%

Lesch-Nyhan disease: A rare disorder with many unresolved aspects

Micheli

Bertelli²,

Jacomelli

et al. 2018

Medical University

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Lesch-Nyhan Disease (LND) is a rare X-linked recessive metabolic and neurological syndrome due to the defi ciency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). Besides its well known "housekeeping" function this purine salvage enzyme has revealed an unexpected role in neurodevelopment, unveiled by the peculiar neurological symptoms fl anking hyperuricemia in LND: dystonia, choreoathetosis, compulsive self-injurious behaviour. Several lines of research have tried to fi nd the molecular basis for the neurological phenotype after the disease was fi rst described in 1964. Dopaminergic defi cit was then found to underlie the neurologic symptoms but the aetiology for such alteration seemed inexplicable. A number of detailed studies in the last 50 years addressed the genetic, metabolic, cognitive, behavioral and anatomical features of this disease. Initial investigations seeked for accumulation of toxic metabolites or depletion of essential molecules to disclose potential connections between purine recycling and neuronal dysfunction. In the last two decades sophisticated biotechnological methods were used for a deeper insight in the genetic and molecular aspects, unveiling a network of combined gene dysregulations in neuronal development and differentiation producing neurotransmission defects. These studies, conducted with several different approaches, allowed consistent steps forward, demonstrating transcriptional aberrations affecting different metabolic pathways in HPRT defi ciency, yet leaving many questions still unsolved.patients bearing different mutations [8,9], leading to complete or partial defi ciency. In few cases defi ciency of HPRT activity in intact cultured fi broblasts was reported not to be related to any mutation in the HPRT coding sequence but to markedly decreased HPRT expression of mRNA [10][11][12]. In these cases defi ciency was attributed to a defect in gene regulation of unknown cause. Megaloblastic anaemia unresponsive to folate therapy is also common in LND patients [13]. The basic diagnostic criterion for LND and its variants is HPRT activity assay in lysates or intact erythrocytes or fi broblasts; diagnostic suspect can be raised by grossly increased uric acid amount in plasma and urine, accompanied by increased hypoxanthine and xanthine [13].

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Biochemical and molecular study of mentally retarded patient with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase

Cited by 11 publications

References 34 publications

Neurological Disorders of Purine and Pyrimidine Metabolism

Neurological Disorders of Purine and Pyrimidine Metabolism

Inhibiting PNP for the therapy of hyperuricemia in Lesch–Nyhan disease: Preliminary in vitro studies with analogues of immucillin‐G

Lesch-Nyhan disease: A rare disorder with many unresolved aspects

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