New Mutation Affecting Hypoxanthine Phosphoribosyltransferase Responsible for Severe Tophaceous Gout

Lahaye, Clément; Augé, Franck; Soubrier, Martin; Ceballos-Picot, Irène

doi:10.3899/jrheum.131168

Cited by 10 publications

(5 citation statements)

References 9 publications

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“…High serum urate concentrations were a key risk factor for the presentation of tophaceous disease in the study of young Taiwanese adults with juvenile-onset gout [31]. Genetic variants contributing to hyperuricaemia have also been associated with a higher risk for tophaceous disease [32,33].…”

Section: Clinical Presentation Of Tophaceous Goutmentioning

confidence: 97%

The Gouty Tophus: a Review

2015

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The tophus is the cardinal feature of advanced gout. This review summarises recent research into the biology, impact and treatment of tophaceous gout. Microscopically, tophi are chronic foreign body granuloma-like structures containing collections of monosodium urate (MSU) crystals surrounded by inflammatory cells and connective tissue. Extracellular trap formation mediated by neutrophil interactions with MSU crystals may be a central checkpoint in tophus formation. Gouty tophi impact on many aspects of health-related quality of life. Tophi are also implicated in the development of structural joint damage and increased mortality risk in people with gout. Effective treatment of tophaceous gout requires long-term urate-lowering therapy, ideally to achieve a serum urate concentration of <5 mg/dL (300 μmol/L). Recent advances in gout therapeutics have expanded urate-lowering therapy options for patients with severe tophaceous disease to allow faster regression of tophi, improved health-related quality of life and, potentially, improved structural outcomes.

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Section: Clinical Presentation Of Tophaceous Goutmentioning

confidence: 97%

The Gouty Tophus: a Review

2015

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“…The probability is high that such patients with EOG developed gout largely because of genetic polymorphisms, given the fact that they were not particularly heavy drinkers, had on average better renal function, took fewer diuretics, and had less prevalent metabolic syndrome features. Genetic mutations, such as partial hypoxanthine guanine phosphoribosyltransferase deficiency , or mostly UA transportosome mutations , are not routinely tested for in clinical practice for gout management, and the weight of genetics in the development of gout in younger patients cannot be thoroughly addressed by this study. High frequencies of ABCG2 proteins have been found in a recent retrospective cohort study from China, without a difference between EOG and common gout .…”

Section: Discussionmentioning

confidence: 99%

Patients With Early‐Onset Gout and Development of Earlier Severe Joint Involvement and Metabolic Comorbid Conditions: Results From a Cross‐Sectional Epidemiologic Survey

Pascart

Norberciak

et al. 2019

Arthritis Care & Research

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“…They have a developmental delay from 3 to 6 months after birth and most of them never walk or even sit without support. Xanthine oxidase inhibitors, such as febuxostat or allopurinol, are given to patients after diagnosis to decrease their uric acid levels and prevent the formation of urate crystals in kidney, which can lead to renal failure (Kelley et al 1967 ;Lahaye et al 2014 ). However, there is as yet no treatment to alleviate the neurobehavioral symptoms of LND Jinnah et al 2010 ;Madeo et al 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in Drosophila

Petitgas,

Seugnet,

Dulac

et al. 2024

eLife

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Lesch-Nyhan disease (LND) is a rare genetic disorder induced by deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT), an enzyme of the purine salvage pathway. This leads in early age to hyperuricemia and severe neurobehavioral disturbances, including dystonia, spasticity and compulsive self-injury. To date, no treatment is available for these neurological symptoms and no animal model recapitulates all the defects observed in LND patients. Here we studied LND-related mechanisms in the fruit fly Drosophila melanogaster. We confirmed that no HGPRT activity is expressed in this organism, where the only purine-recycling enzyme is adenine phosphoribosyltransferase (Aprt). This enzyme is also present in humans but its deficiency does not trigger neurological defects. In contrast, we observed that Drosophila Aprt mutants showed both metabolic and neurobehavioral disturbances, including increased uric acid levels, locomotor reactivity impairments, sleep alterations, seizure-like behavior, reduced lifespan, and reduction of adenosine signaling and content. Locomotor defects could be rescued by neuronal Aprt re-expression in mutant context and reproduced by knocking down Aprt selectively in the protocerebral anterior medial (PAM) clusters of dopaminergic neurons, the mushroom bodies and glia subsets. Ingestion of allopurinol normalized uric acid levels in Aprt mutants but not their neurological defects, as is the case in LND patients, whereas feeding adenosine or N 6-methyladenosine during development fully rescued the epileptic behavior. Intriguingly, pan-neuronal expression of an LND-associated mutant form of human HGPRT (I42T), but not the wild-type enzyme, resulted in early locomotor defects and seizure in flies, similar to Aprt deficiency. Overall, this shows that Drosophila can be used as a new model in different ways to better understand LND and seek a cure for this dramatic disease.

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New Mutation Affecting Hypoxanthine Phosphoribosyltransferase Responsible for Severe Tophaceous Gout

Cited by 10 publications

References 9 publications

The Gouty Tophus: a Review

The Gouty Tophus: a Review

Patients With Early‐Onset Gout and Development of Earlier Severe Joint Involvement and Metabolic Comorbid Conditions: Results From a Cross‐Sectional Epidemiologic Survey

Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in Drosophila

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