OBJECTIVES: Serum levels of uric acid (S-UA) are influenced by the interaction of genetic and environmental factors; detailed studies of hyperuricemia in children are rare. This retrospective study aimed to analyze the causes, risk factors, and therapeutic approaches associated with the development of hyperuricemia in childhood. METHODS: In a single-center study, serum uric acid levels were analyzed in 33,900 samples from 13,890 children and adolescents<19 years (6760 girls and 7130 boys) obtained between 2013 and 2023. Hyperuricemia was defined as S-UA>370μmol/L (6.22mg/dL) in girls and>420μmol/L (7.06mg/dL) in boys; mild hyperuricemia was defined as 370-420μmol/L in boys<13 years. RESULTS: In the analyzed group, hyperuricemia was found in 1753 patients (12.6%), including 586 girls and 864 boys; mild hyperuricemia was found in 303 boys<13 years. The most common associated conditions were obesity with body mass index>95th percentile (27.8% of girls, 26.3% of boys) and chronic kidney disease (18.6% of boys, 11.4% of girls). Hyperuricemia was also relatively common in children with connective tissue disorders (10.6%) or different inherited metabolic disorders (10.7%). Transitory hyperuricemia was found in 19.1% of girls and 10.1% of boys with acute gastroenteritis. Urate-lowering therapy was used in 73 children and adolescents with severe hyperuricemia (S-UA 556±107μmol/L, fraction excretion of UA 3.27±1.98%). Eight treated children had chronic kidney disease, nine were extremely obese, one had combined antiepileptic therapy, and 55 had inherited metabolic diseases, including 26 children with disorders of purine metabolism. The initial daily dose of allopurinol (50-100mg) normalized the S-UA (350±80μmol/L) in a majority of children, except for extremely obese adolescents (weight 98-149kg) where the dose had to be increased to 200-300mg. CONCLUSIONS: Asymptomatic hyperuricemia is a relatively common biochemical finding in pediatric clinical practice. The etiology of hyperuricemia should be carefully analyzed, and the value of individualized hyperuricemia management and the eventual benefits of urate-lowering therapy in children must be carefully considered.
- MeSH
- dítě MeSH
- hyperurikemie * krev epidemiologie diagnóza MeSH
- kojenec MeSH
- kyselina močová * krev MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: Somatic mutations in UBA1 have recently been causally linked to a severe adult-onset inflammatory condition referred to as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Ubiquitin-activating enzyme E1 (UBA-1) is of fundamental importance to the modulation of ubiquitin homeostasis and to the majority of downstream ubiquitylation-dependent cellular processes. Direct sequencing analysis of exon 3 containing the prevalent variants p.Met41Leu, p.Met41Val, and/or p.Met41Thr is usually used to confirm the disease-associated mutations. METHODS: We studied the clinical, biochemical, and molecular genetic characteristics of a 59-year-old man with a 2-year history of arthritis, fever, night sweats, nonspecific skin rash, lymphadenopathy, and myelodysplastic syndrome with multilineage dysplasia. RESULTS: The mutational analysis revealed a previously undescribed sequence variant c.1430G>C in exon 14 (p.Gly477Ala) in the gene UBA1. In vitro enzymatic analyses showed that p.Gly477Ala led to both decreased E1 ubiquitin thioester formation and E2 enzyme charging. CONCLUSION: We report a case of a patient of European ancestry with clinical manifestations of VEXAS syndrome associated with a newly identified dysfunctional UBA-1 enzyme variant. Due to the patient's insufficient response to various immunosuppressive treatments, allogeneic hematopoietic stem cell transplantation was performed, which resulted in significant improvement of clinical and laboratory manifestations of the disease.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- myelodysplastické syndromy * MeSH
- pacienti MeSH
- ubikvitin aktivující enzymy * genetika MeSH
- ubikvitiny MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Košice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon-intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C>T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C>T, and two compound heterozygotes for c.1400C>T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: ABCG2 is a high-capacity urate transporter that plays a crucial role in renal urate overload and extra-renal urate underexcretion. Previous studies have suggested an association between hyperuricemia and gout susceptibility relative to dysfunctional ABCG2 variants, with rs2231142 (Q141K) being the most common. In this study, we analyzed the ABCG2 gene in a hyperuricemia and gout cohort focusing on patients with pediatric-onset, i.e., before 18 years of age. METHOD: The cohort was recruited from the Czech Republic (n = 234) and consisted of 58 primary hyperuricemia and 176 gout patients, with a focus on pediatric-onset patients (n = 31, 17 hyperuricemia/14 gouts); 115 normouricemic controls were used for comparison. We amplified, sequenced, and analyzed 15 ABCG2 exons. The chi-square goodness-of-fit test was used to compare minor allele frequencies (MAF), and the log-rank test was used to compare empirical distribution functions. RESULTS: In the pediatric-onset cohort, two common (p.V12M, p.Q141K) and three very rare (p.K360del, p.T421A, p.T434M) allelic ABCG2 variants were detected. The MAF of p.Q141K was 38.7% compared to adult-onset MAF 21.2% (OR = 2.4, P = 0.005), to the normouricemic controls cohort MAF 8.5% (OR = 6.8, P < 0.0001), and to the European population MAF 9.4% (OR = 5.7, P < 0.0001). The MAF was greatly elevated not only among pediatric-onset gout patients (42.9%) but also among patients with hyperuricemia (35.3%). Most (74%) of the pediatric-onset patients had affected family members (61% were first-degree relatives). CONCLUSION: Our results show that genetic factors affecting ABCG2 function should be routinely considered in a hyperuricemia/gout diagnosis, especially in pediatric-onset patients. Genotyping of ABCG2 is essential for risk estimation of gout/hyperuricemia in patients with very early-onset and/or a family history.
- MeSH
- ABC transportér z rodiny G, člen 2 genetika MeSH
- alopurinol terapeutické užití MeSH
- antiuratika terapeutické užití MeSH
- dítě MeSH
- dna (nemoc) diagnóza farmakoterapie genetika MeSH
- dospělí MeSH
- febuxostat terapeutické užití MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci genetika MeSH
- genotyp MeSH
- hyperurikemie diagnóza farmakoterapie genetika MeSH
- jednonukleotidový polymorfismus * MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
