Pathological and immunological observations in a case of Lesch-Nyhan-syndrome

Bassermann, R; Gutensohn, Wolf; Jahn, Heidi; Springmann, J. S.

doi:10.1007/bf00447375

Cited by 13 publications

(5 citation statements)

References 11 publications

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“…22,25,28 The brain size was considered small in 4 of these cases. 22,24,26,27 Less commonly noted findings have included demyelinative lesions, 22 cerebral edema, 26 marked hydrocephalus, 29 and periodic acid-Schiff-positive inclusions in the olivary nuclei. 28 These abnormalities may be related to postmortem changes secondary to chronic renal failure in untreated patients or ischemia in patients dying of pneumonia and aspiration.…”

Section: Commentmentioning

confidence: 99%

“…It is noteworthy that neuropathologic examination results were completely normal in 3 patients. 24,25,27 Although the small brains observed in several prior neuroimaging and neuropathologic studies have been interpreted as showing diffuse atrophy, the term atrophy may be misleading since it implies a pathophysiologic process that has not been substantiated. In particular, the small brain may reflect a developmental, rather than a degenerative, process.…”

Section: Commentmentioning

confidence: 99%

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Craniocerebral Magnetic Resonance Imaging Measurement and Findings in Lesch-Nyhan Syndrome

Harris¹,

Lee²,

Jinnah³

et al. 1998

Arch Neurol

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Section: Commentmentioning

confidence: 99%

Section: Commentmentioning

confidence: 99%

Craniocerebral Magnetic Resonance Imaging Measurement and Findings in Lesch-Nyhan Syndrome

Harris¹,

Lee²,

Jinnah³

et al. 1998

Arch Neurol

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“…Studies of mutant HPRT proteins showed a wide range of enzyme activities, differences in thermal stability, and altered kinetic behavior, suggesting that a variety of structural mutations may occur (23). The first reports using immune techniques found material that crossreacted with antibody to normal HPRT (25)(26)(27)(28)(29)(30)(31)(32). Arnold and Kelley (25) found that all 14 patients studied had normal amounts of crossreacting material, and Rubin et aL (26) made a similar observation.…”

Section: Resultsmentioning

confidence: 69%

Protein variations associated with Lesch-Nyhan syndrome.

Merril¹,

Goldman²,

Ebert³

1981

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

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Patients having Lesch-Nyhan syndrome were studied by using enzymatic, immunologic, and two-dimensional electrophoretic techniques. Four hundred proteins were analyzed on each two-dimensional electrophoretogram for positional or quantitative variation. In autoradiograms of lymphocytes stimulated with phytohemagglutinin, there were 11 quantitative differences found in all patients that were significant at the 2P1 <0.01 level. A significant quantitative difference was also found in an analysis of silver-stained gels of unstimulated lymphocytes. Patients had trace amounts of erythrocyte hypoxanthine phosphoribosyl transferase (HPRT)'activity and trace or no immunoprecipitable HPRT. However, HPRT was observed in silver-stained' erythrocyte electrophoretograms and in autoradiograms from phytohemagglutinin-stimulated lymphocytes. Unstimulated lymphocytes contained 65% of the control HPRT concentration. Currently, the technology of two-dimensional electrophoresis detects a fraction of the total cellular proteins and defective proteins may not show electrophoretic alterations. However, specific secondary changes in other polypeptides may be observed and, when catalogued, will serve as an aid in the diagnosis and understanding of the pathophysiology of metabolic diseases.Human behavioral disorders are particularly difficult to investigate at the molecular level. The Lesch-Nyhan syndrome is one 6f the few neuropsychiatric diseases for which the metabolic origin is known (1). For this reason, it was chosen as a model system to find markers and uncover pathophysiologic protein changes by using quantitative two-dimensional electrophoretic techniques.Lesch-Nyhan disease is characterized by self-mutilation, spasticity, and hyperuricemia. The failure ofazathioprine to inhibit excessive uric acid production in these patients (2, 3) led to the discovery that they are deficient in hypoxanthine phosphoribosyltransferase (HPRT; IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8).Erythrocyte adenine phosphoribosyltransferase (APRT) was found to be elevated when it was used as a control enzyme for HPRT assays (4). Inosinic acid dehydrogenase activity was also elevated. These elevated activities appear to be due to increases in specific activity (4-9). Other enzymes found to be increased in activity are orotate phosphoribosyltransferase and orotate decarboxylase in erythrocytes, but not in leukocytes or fibroblasts (10), and phosphoribosylpyrophosphate glutamine amidotransferase in cultured fibroblasts (11), and lymphoblasts (12).A systematic search for protein alterations is now possible by using two-dimensional electrophoresis (13). Only a fraction of the total cellular protein can be detected and alterations in enzyme activity that are not associated with variations in electrophoretic mobility or concentration are not visible. However, hundreds of proteins can be surveyed for alterations in mass, charge, or concentration; We have examined 400 proteins in two-dimensional electrophoretograms of stimulated and unstimulated...

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“…Since the kynurenine pathway is downstream of the cGAS-STING viral/pathogen sensing pathway, this observation could contribute to explaining why disease severity worsens in LN patients upon infection [ 49 , 50 , 51 , 52 ]. Finally, it is interesting to speculate that increased reticulocytosis or mitochondrial-containing mature erythrocytes—as it is observed for example in sickle cell patients [ 53 ] or lupus erythematosus [ 54 ]—results in an increased basal activation of humoral immune responses downstream of interferon signaling .…”

Section: Discussionmentioning

confidence: 99%

Red Blood Cells from Individuals with Lesch–Nyhan Syndrome: Multi-Omics Insights into a Novel S162N Mutation Causing Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency

Reisz,

Dzieciatkowska,

Stephenson

et al. 2023

Antioxidants

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Lesch–Nyhan syndrome (LN) is an is an X-linked recessive inborn error of metabolism that arises from a deficiency of purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The disease manifests severely, causing intellectual deficits and other neural abnormalities, hypercoagulability, uncontrolled self-injury, and gout. While allopurinol is used to alleviate gout, other symptoms are less understood, impeding treatment. Herein, we present a high-throughput multi-omics analysis of red blood cells (RBCs) from three pediatric siblings carrying a novel S162N HPRT1 mutation. RBCs from both parents—the mother, a heterozygous carrier, and the father, a clinically healthy control—were also analyzed. Global metabolite analysis of LN RBCs shows accumulation of glycolytic intermediates upstream of pyruvate kinase, unsaturated fatty acids, and long chain acylcarnitines. Similarly, highly unsaturated phosphatidylcholines are also elevated in LN RBCs, while free choline is decreased. Intracellular iron, zinc, selenium, and potassium are also decreased in LN RBCs. Global proteomics documented changes in RBC membrane proteins, hemoglobin, redox homeostasis proteins, and the enrichment of coagulation proteins. These changes were accompanied by elevation in protein glutamine deamidation and methylation in the LN children and carrier mother. Treatment with allopurinol incompletely reversed the observed phenotypes in the two older siblings currently on this treatment. This unique data set provides novel opportunities for investigations aimed at potential therapies for LN-associated sequelae.

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Pathological and immunological observations in a case of Lesch-Nyhan-syndrome

Cited by 13 publications

References 11 publications

Craniocerebral Magnetic Resonance Imaging Measurement and Findings in Lesch-Nyhan Syndrome

Craniocerebral Magnetic Resonance Imaging Measurement and Findings in Lesch-Nyhan Syndrome

Protein variations associated with Lesch-Nyhan syndrome.

Red Blood Cells from Individuals with Lesch–Nyhan Syndrome: Multi-Omics Insights into a Novel S162N Mutation Causing Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency

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