Macrocytic anemia in Lesch–Nyhan disease and its variants

Çakmaklı, Hasan Fatih; Torres, Rosa J.; Menendez, Araceli; Yalçın‐Çakmaklı, Gül; Porter, Christopher C.; Puig, Juan; Jinnah, Hyder A.

doi:10.1038/s41436-018-0053-1

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…But even in the case that folic acid supplements could not solve the neurological problems, they might be useful to improve some cellular alterations. For instance, patients with LND frequently present macrocytic anemia in adulthood (51,52), and folic acid deficiency induces macrocytic anemia in humans (53). It is possible that the high rate of de novo purine biosynthesis in patients with LND limits the availability of folic acid in the erythroblasts, which in turn would induce ZMP accumulation and ATP depletion to cause macrocytic anemia.…”

Section: (F)mentioning

confidence: 99%

Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease

López

Outtrim

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Lesch-Nyhan disease (LND), caused by a deficient salvage purine pathway, is characterized by severe neurological manifestations and uric acid overproduction. However, uric acid is not responsible for brain dysfunction, and it has been suggested that purine nucleotide depletion, or accumulation of other toxic purine intermediates, could be more relevant. Here we show that purine alterations in LND fibroblasts depend on the level of folic acid in the culture media. Thus, physiological levels of folic acid induce accumulation of 5-aminoimidazole-4-carboxamide riboside 5′-monophosphate (ZMP), an intermediary of de novo purine biosynthetic pathway, and depletion of ATP. Additionally, Z-nucleotide derivatives (AICAr, AICA) are detected at high levels in the urine of patients with LND and its variants (hypoxanthine-guanine phosphoribosyltransferase [HGprt]-related neurological dysfunction and HGprt-related hyperuricemia), and the ratio of AICAr/AICA is significantly increased in patients with neurological problems (LND and HGprt-related neurological dysfunction). Moreover, AICAr is present in the cerebrospinal fluid of patients with LND, but not in control individuals. We hypothesize that purine alterations detected in LND fibroblasts may also occur in the brain of patients with LND.

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Section: (F)mentioning

confidence: 99%

Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease

López

Outtrim

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Tissue differences are most obvious in bone marrow cells and particularly mature erythrocytes, which lack a functional de novo synthetic pathway because of the absence of the first enzyme in the pathway 45 , 46 , 73 . Indeed, the dependence of erythrocytes on HGprt-mediated salvage of hypoxanthine supplied into the circulation by the liver 74 may explain why macrocytic anemia is so common in LND 9 , 45 . Similarly, de novo purine synthesis seems to contribute to cell division and neurogenesis in the developing brain 56 , 75 – 77 , but the mature brain depends more on purine salvage 55 , 56 , 78 .…”

Section: Discussionmentioning

confidence: 99%

“…This enzyme is ubiquitously expressed in all tissues of the body at all stages of development 4 . HGprt deficiency produces pleiotropic clinical effects including overproduction of uric acid leading to kidney stones and gout 5 , brain abnormalities 6 – 8 , and macrocytic anemia 9 .…”

Section: Introductionmentioning

confidence: 99%

Induced pluripotent stem cells from subjects with Lesch-Nyhan disease

Sutcliffe

Dinasarapu

Visser

et al. 2021

Sci Rep

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Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.

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“…In particular, aplastic anaemia which is a serious condition and is clinically problematic. Patients with Lesch–Nyhan syndrome who have HPRT deficiency show anaemic symptoms (Cakmakli et al, ; Hakoda et al, ; Hidalgo‐Laos, Kedar, Williams, & Neiberger, ). Hakoda et al () reported that HPRT is important for early blood cell formation.…”

Section: Discussionmentioning

confidence: 99%

Perfecting a high hypoxanthine phosphoribosyltransferase activity–uricase KO mice to test the effects of purine‐ and non‐purine‐type xanthine dehydrogenase (XDH) inhibitors

Hosoya

Uchida

Shibata

et al. 2020

British J Pharmacology

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Background and Purpose: Purine metabolism in mice and human differ in terms of uricase (Uox) activity as well as hypoxanthine phosphoribosyltransferase (HPRT) activity. The aim of this study was the establishment of high HPRT activity-Uox knockout (KO) mice as a novel hyperuricaemic model. Then to investigate the effects of purine-type xanthine dehydrogenase (XDH) inhibitor, allopurinol, and non-purinetype XDH inhibitor, topiroxostat, on purine metabolism. Experimental Approach: A novel hyperuricaemic mouse model was established by mating B6-ChrXC MSM mice with uricase KO mice. The pharmacological effects of allopurinol and topiroxostat were explored by evaluating urate, hypoxanthine, xanthine and creatinine in the plasma and urine of these model mice. Furthermore, we analysed the effect of both drugs on erythrocyte hypoxanthine phosphoribosyltransferase activity. Key Results: Plasma urate level and urinary urate/creatinine ratio significantly decreased after administration of allopurinol 30 mgÁkg −1 or topiroxostat 1 mgÁkg −1 for 7 days. The urate-lowering effect was equivalent for allopurinol and topiroxostat.However, the urinary hypoxanthine/creatinine ratio and xanthine/creatinine ratio after treatment with topiroxostat were significantly lower than for allopurinol. In addition, the urinary oxypurine/creatinine ratio was significantly lowered after treatment with topiroxostat, but allopurinol elicited no such effect. Furthermore, allopurinol inhibited mouse erythrocyte hypoxanthine phosphoribosyltransferase, while topiroxostat did not. Conclusions and Implications:High hypoxanthine phosphoribosyltransferase activity-uricase KO mice were established as a novel hyperuricaemic animal model.In addition, topiroxostat, a non-purine-type xanthine dehydrogenase inhibitor, elicited a potent plasma urate-lowering effect. However, unlike allopurinol, topiroxostat did not perturb the salvage pathway, resulting in lowered total oxypurine excretion.Abbreviations: BUN, blood urea nitrogen; CRP, C-reactive protein; FE, fractional excretion; HPRT, hypoxanthine phosphoribosyltransferase; IMP, inosine 5 0 -monophosphate; KO, knockout; PRPP, 5-phosphoribosyl-1-pyrophosphate; ULE, urate-lowering effect; Uox, urate oxidase (uricase); WT, wild-type; XDH, xanthine dehydrogenase.Takuji Hosoya and Makoto Hosoyamada contributed equally to this work.

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Macrocytic anemia in Lesch–Nyhan disease and its variants

Cited by 19 publications

References 30 publications

Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease

Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease

Induced pluripotent stem cells from subjects with Lesch-Nyhan disease

Perfecting a high hypoxanthine phosphoribosyltransferase activity–uricase KO mice to test the effects of purine‐ and non‐purine‐type xanthine dehydrogenase (XDH) inhibitors

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