Lesch‐Nyhan syndrome and its pathogenesis: Normal nicotinamide‐adenine dinucleotide but reduced ATP concentrations that correlate with reduced poly (ADP‐ribose) synthetase activity in HPRT‐deficient lymphoblasts

McCreanor, G. M.; Harkness, R. A.

doi:10.1007/bf02436765

Cited by 15 publications

(23 citation statements)

References 58 publications

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“…Low erythrocyte NAD glycohydrolase activity was found in LNS patients, probably accounting for the high levels of NAD [101]. Normal concentrations of NAD(H) and NADP(H) were found in LNS lymphoblasts, associated with decreased activity of PARP [102]. By contrast decreased NAD, ATP and GTP concentrations and increased NAD production from nicotinic acid were measured in LNS fibroblasts [93].…”

Section: Hypoxanthine-guanine Phosphoribo-syltransferase Deficiency Amentioning

confidence: 99%

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

100

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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

100

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“…Alternative intrinsic biochemical mechanisms must be considered. Because ATP is a downstream product of HPRT, HPRT deficiency may result in energy limitation (McKeran, 1977;McCreanor and Harkness, 1995;Jinnah and Friedmann, 2000). HPRT deficiency also causes secondary metabolic changes that may increase oxidative stress (Visser et al, 2002;Smith and Jinnah, 2007).…”

mentioning

confidence: 99%

Consequences of impaired purine recycling in dopaminergic neurons

et al. 2008

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A unique sensitivity to specific biochemical processes is responsible for selective vulnerability of midbrain dopamine neurons in several diseases. Prior studies have shown these neurons are susceptible to energy failure and mitochondrial dysfunction, oxidative stress, and impaired disposal of misfolded proteins. These neurons also are especially vulnerable to the loss of purine recycling. In the brains of humans or mice with inherited defects of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), the most prominent defect is loss of basal ganglia dopamine. To investigate the nature of the relationship between HPRT deficiency and dopamine, the mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking HPRT. The mutant sublines grew more slowly than the parent line, but without morphological signs of impaired viability. As a group, the mutant sublines had significantly lower dopamine than the parent line. The loss of dopamine in the mutants did not reflect impaired energy status, as judged by ATP levels or vulnerability to inhibitors of energy production. Indeed, the mutant lines as a group appeared energetically more robust than the parent line. The loss of dopamine also was not accompanied by enhanced susceptibility to oxidative stress or proteasome inhibitors. Instead, the loss of dopamine reflected only one aspect of a broad change in the molecular phenotype of the cells affecting mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase. These changes were selective for the dopamine phenotype, since multiple control mRNAs were normal. These studies suggest purine recycling is an intrinsic metabolic process of particular importance to the molecular phenotype of dopaminergic neurons independent of previously established mechanisms involving energy failure, oxidative stress, or proteasome dysfunction.

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“…Instability of the respiratory oscillator in the medulla oblongata has been implicated in respiratory dysrhythmias and sudden deaths observed in other disorders such as Rett syndrome. 15 This mechanism has been considered in detail in previous studies of patients Case Report 925 with LND, 7,16,17 though evidence has so far been lacking. The sleep studies of cases 2 and 3 provided evidence for a defect in central respiratory control similar to previous sleep studies, 7,18 though it was difficult to conclude that it was the sole process responsible for respiratory dysfunction and it did not appear to operate in other cases.…”

Section: Discussionmentioning

confidence: 96%

Sudden death in Lesch‐Nyhan disease

Neychev

Jinnah

2006

Develop Med Child Neuro

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To increase awareness of sudden and unexpected death in Lesch‐Nyhan disease (LND) and to explore its potential causes, we report the anteceding clinical features and laboratory evaluations of five males with LND who ultimately experienced sudden and unexpected death, along with three additional males who suffered serious respiratory events during life. The ages of patients ranged from 2 to 45 years. The cause of sudden death in LND appears to have a respiratory rather than a cardiogenic basis. All cases cannot be linked readily with a single respiratory process. Instead, different respiratory processes appear to operate in different cases. These may include aspiration, laryngospasm, central apnea, cyanotic breath‐holding spells, and high cervical spine damage. Better recognition of these processes will help to guide appropriate workup and management that could include chest imaging, endoscopy of the airways, polysomnography, electroencephalogram, and brain and/or spine imaging.

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Lesch‐Nyhan syndrome and its pathogenesis: Normal nicotinamide‐adenine dinucleotide but reduced ATP concentrations that correlate with reduced poly (ADP‐ribose) synthetase activity in HPRT‐deficient lymphoblasts

Cited by 15 publications

References 58 publications

Neurological Disorders of Purine and Pyrimidine Metabolism

Neurological Disorders of Purine and Pyrimidine Metabolism

Consequences of impaired purine recycling in dopaminergic neurons

Sudden death in Lesch‐Nyhan disease

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