Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients
Uric acid (UA) is the end product of purine nucleotide degradation. Abnormal levels of UA in serum/urine can guide the detection of some metabolic errors such as deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT-d), xanthine oxidase and molybdenum cofactor (MoCo-d). HPRT-d, w...
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Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
2022
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| Acceso en línea: | https://revistas.unc.edu.ar/index.php/med/article/view/39080 |
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I10-R327-article-39080 |
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Universidad Nacional de Córdoba |
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I-10 |
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R-327 |
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Revista de la Facultad de Ciencias Médicas de Córdoba |
| format |
Artículo revista |
| topic |
uric acid purines metabolites enzyme mutations ácido úrico purinas metabolitos enzima mutaciones |
| spellingShingle |
uric acid purines metabolites enzyme mutations ácido úrico purinas metabolitos enzima mutaciones Laróvere, LE Grosso, CL Guelbert, NB Becerra, AB Dodelson de Kremer, R Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients |
| topic_facet |
uric acid purines metabolites enzyme mutations ácido úrico purinas metabolitos enzima mutaciones |
| author |
Laróvere, LE Grosso, CL Guelbert, NB Becerra, AB Dodelson de Kremer, R |
| author_facet |
Laróvere, LE Grosso, CL Guelbert, NB Becerra, AB Dodelson de Kremer, R |
| author_sort |
Laróvere, LE |
| title |
Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients |
| title_short |
Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients |
| title_full |
Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients |
| title_fullStr |
Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients |
| title_full_unstemmed |
Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients |
| title_sort |
uric acid as a biomarker of genetic disorders of purine metabolism. phenotypic and molecular characterization of argentine patients |
| description |
Uric acid (UA) is the end product of purine nucleotide degradation. Abnormal levels of UA in serum/urine can guide the detection of some metabolic errors such as deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT-d), xanthine oxidase and molybdenum cofactor (MoCo-d). HPRT-d, with X-linked inheritance, causes Lesch-Nyhan disease (LND) and its variants (LNV) characterized by hyperuricemia/hyperuricosuria, self-mutilation (LND), gout, nephrolithiasis, kidney failure, and variable neurological involvement. MoCo-d is a rare autosomal recessive neurodegenerative disorder characterized by combined deficiency of molybdenum cofactor-dependent enzymes, such as xanthine oxidase, and presents with hypouricemia/hypouricosuria, microcephaly, intractable seizures, and severe developmental delay. The objective of this work is to characterize Argentine paediatric patients with defects in purine metabolism in which the value of UA together with the phenotype data allowed to guide the biochemical/molecular studies for the exact diagnosis.
Twenty-nine patients with HPRT-d and 2 MoCo-d, first/main clinical manifestations, onset and diagnosis ages were included. UA concentrations in serum/urine, urinary hypoxanthine and xanthine, enzyme activity and genotype were determined. The quantification of metabolites and enzyme activity assays were performed by liquid chromatography and genetic studies by PCR and sequencing.
All patients with HPRT-d presented hyperuricemia (range 7.7-17 mg/dl; normal 3.7-7); increased urinary UA (range 1400-2300 μmol/mmol creatinine; normal >1300), hypoxanthine (range 55-778; normal >45) and xanthine (range 23-200; normal >43). Deficient HPRT activity and identification of pathogenic genetic variants (private to each family) allowed the diagnostic confirmation; there was high phenotypic variability, being able to classify the cases in LND and LNV. The two patients with MoCo-d had a similar clinical presentation and fatal outcome; laboratory findings included hypouricemia (AU >0.5 mg/dl), hypouricosuria (AU >30 μmol/mmol creatinine), increased urinary xanthine/hypoxanthine, and mutations in the MOCS2 gene.
Purine metabolic defects comprise a group of diseases with highly variable clinical manifestations. Altered levels of UA and clinical suspicion are indicative for its detection, biochemical-enzymatic and genetic studies allow the exact nosological definition. Early diagnosis is beneficial for the patient and allows genetic counseling for these diseases considered rare or infrequent.
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| publisher |
Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología |
| publishDate |
2022 |
| url |
https://revistas.unc.edu.ar/index.php/med/article/view/39080 |
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I10-R327-article-390802024-04-15T16:14:45Z Uric acid as a biomarker of genetic disorders of purine metabolism. Phenotypic and molecular characterization of Argentine patients El ácido úrico como biomarcador de defectos genéticos del metabolismo de las purinas. Caracterización fenotípica y molecular de pacientes argentinos Laróvere, LE Grosso, CL Guelbert, NB Becerra, AB Dodelson de Kremer, R uric acid purines metabolites enzyme mutations ácido úrico purinas metabolitos enzima mutaciones Uric acid (UA) is the end product of purine nucleotide degradation. Abnormal levels of UA in serum/urine can guide the detection of some metabolic errors such as deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT-d), xanthine oxidase and molybdenum cofactor (MoCo-d). HPRT-d, with X-linked inheritance, causes Lesch-Nyhan disease (LND) and its variants (LNV) characterized by hyperuricemia/hyperuricosuria, self-mutilation (LND), gout, nephrolithiasis, kidney failure, and variable neurological involvement. MoCo-d is a rare autosomal recessive neurodegenerative disorder characterized by combined deficiency of molybdenum cofactor-dependent enzymes, such as xanthine oxidase, and presents with hypouricemia/hypouricosuria, microcephaly, intractable seizures, and severe developmental delay. The objective of this work is to characterize Argentine paediatric patients with defects in purine metabolism in which the value of UA together with the phenotype data allowed to guide the biochemical/molecular studies for the exact diagnosis. Twenty-nine patients with HPRT-d and 2 MoCo-d, first/main clinical manifestations, onset and diagnosis ages were included. UA concentrations in serum/urine, urinary hypoxanthine and xanthine, enzyme activity and genotype were determined. The quantification of metabolites and enzyme activity assays were performed by liquid chromatography and genetic studies by PCR and sequencing. All patients with HPRT-d presented hyperuricemia (range 7.7-17 mg/dl; normal 3.7-7); increased urinary UA (range 1400-2300 μmol/mmol creatinine; normal >1300), hypoxanthine (range 55-778; normal >45) and xanthine (range 23-200; normal >43). Deficient HPRT activity and identification of pathogenic genetic variants (private to each family) allowed the diagnostic confirmation; there was high phenotypic variability, being able to classify the cases in LND and LNV. The two patients with MoCo-d had a similar clinical presentation and fatal outcome; laboratory findings included hypouricemia (AU >0.5 mg/dl), hypouricosuria (AU >30 μmol/mmol creatinine), increased urinary xanthine/hypoxanthine, and mutations in the MOCS2 gene. Purine metabolic defects comprise a group of diseases with highly variable clinical manifestations. Altered levels of UA and clinical suspicion are indicative for its detection, biochemical-enzymatic and genetic studies allow the exact nosological definition. Early diagnosis is beneficial for the patient and allows genetic counseling for these diseases considered rare or infrequent. El ácido úrico (AU) es el producto final de la degradación de nucleótidos de purina. Niveles anormales de AU en suero/orina pueden orientar la detección de algunos errores metabólicos como las deficiencias de hipoxantina-guanina fosforribosiltransferasa (d-HPRT), xantina oxidasa y cofactor molibdeno (d-CoMo). La d-HPRT, con herencia ligada al cromosoma X, causa la enfermedad de Lesch-Nyhan (ELN) y sus variantes (VLN) caracterizadas por hiperuricemia/hiperuricosuria, automutilación (ELN), gota, nefrolitiasis, insuficiencia renal y compromiso neurológico variable. La d-CoMo es un raro trastorno neurodegenerativo autosómico recesivo caracterizado por deficiencia combinada de enzimas dependientes del cofactor molibdeno como la xantina oxidasa; se caracteriza por hiporuricemia/hipouricosuria, microcefalia, convulsiones intratables, grave retraso del desarrollo. El objetivo del trabajo es caracterizar pacientes pediátricos argentinos con defectos en el metabolismo de purinas en los cuales el valor de AU aunado al fenotipo permitió orientar los estudios bioquímicos/moleculares para el diagnóstico exacto. Se incluyeron 29 pacientes con d-HPRT y 2 d-CoMo, sus primeras/principales manifestaciones clínicas, edad debut y diagnóstico. Se determinaron las concentraciones de AU en suero/orina, hipoxantina y xantina urinarias, actividad enzimática y genotipo. La cuantificación de metabolitos y actividad enzimática se realizó por cromatografía líquida y los estudios genéticos por PCR y secuenciación. Todos los pacientes con d-HPRT presentaron hiperuricemia (rango 7,7-17 mg/dl; normal 3,7-7); incremento urinario de AU (rango 1400-2300 μmol/mmol creatinina; normal >1300), hipoxantina (rango 55-778; normal >45) y xantina (rango 23-200; normal >43). La actividad HPRT deficiente e identificación de variantes genéticas patogénicas (privativas de cada familia) permitió la confirmación diagnóstica; existió alta variabilidad fenotípica pudiendo clasificar los casos en ELN y VLN. Los dos pacientes con d-CoMo, tuvieron similar presentación clínica y desenlace fatal, presentaron hipouricemia (AU >0,5 mg/dl), hipouricosuria (AU >30 μmol/mmol creatinina), incremento urinario de xantina/hipoxantina y mutaciones en gen MOCS2. Los defectos metabólicos de las purinas comprenden un grupo de enfermedades con manifestaciones clínicas muy variables. Los niveles alterados de AU y la sospecha clínica son orientativos para su detección, estudios bioquímicos-enzimáticos y genéticos permiten la exacta definición nosológica. El diagnóstico precoz es beneficioso para el paciente y permite realizar asesoramiento genético de estas enfermedades consideradas raras o poco frecuentes. Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología 2022-10-26 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion texto https://revistas.unc.edu.ar/index.php/med/article/view/39080 Revista de la Facultad de Ciencias Médicas de Córdoba.; Vol. 79 No. Suplemento JIC XXIII (2022): Suplemento JIC XXIII Revista de la Facultad de Ciencias Médicas de Córdoba; Vol. 79 Núm. Suplemento JIC XXIII (2022): Suplemento JIC XXIII Revista da Faculdade de Ciências Médicas de Córdoba; v. 79 n. Suplemento JIC XXIII (2022): Suplemento JIC XXIII 1853-0605 0014-6722 Derechos de autor 2022 Universidad Nacional de Córdoba http://creativecommons.org/licenses/by-nc/4.0 |