ABSTRACT
OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with Neutral lipid storage disease with myopathy (NLSDM). METHODS: A child who was admitted to the First Affiliated Hospital of Zhengzhou University in February 2021 for a history of elevated creatine kinase (CK) for over 2 months was selected as the study subject. Clinical and laboratory examinations were carried out, and the child was subjected to whole exome sequencing. Candidate variants were validated by Sanger sequencing of her family members. RESULTS: The patient, a 9-year-old female, had exhibited weakness in the lower limbs, elevated CK level, and refractory cardiomyotrophy. Genetic testing revealed that she has harbored c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene, which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PM1+PM2_Supporting+PP3+PP4). CONCLUSION: The c.32C>G (p.S11W) and c.516C>G (p.N172K) compound heterozygous variants of the PNPLA2 gene probably underlay the myasthenia gravis and elevated creatine kinase in this child.
Subject(s)
Lipase , Lipid Metabolism, Inborn Errors , Muscular Diseases , Humans , Female , Child , Muscular Diseases/genetics , Lipid Metabolism, Inborn Errors/genetics , Lipase/genetics , Mutation , Genetic Testing , Exome Sequencing , Creatine Kinase/blood , Pedigree , Phenotype , AcyltransferasesABSTRACT
Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (VL-HLH) is indistinguishable from those of HLH of other etiologies due to the overlap symptoms, posing a serious threat to life. In this study, we aimed to provide insights for early diagnosis and improve outcomes in pediatric patients with VL-HLH. We retrospectively analyzed the clinical and laboratory data of 10 pediatric patients with VL-HLH and 58 pediatric patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The median time from symptom onset to cytopenia in patients with VL-HLH and EBV-HLH was 11 days (interquartile range, 7-15 days) and five days (interquartile range, 3.75-9.25 days) (P = 0.005). Both groups showed liver injury and increased lactate dehydrogenase levels; however the levels of aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and lactate dehydrogenase in patients with VL-HLH were significantly lower than those in patients with EBV-HLH (P < 0.05). The fibrinogen and triglyceride levels were almost normal in VL-HLH patients but were significantly altered in EBV-HLH cases ( P < 0.05). The positive rate of first bone marrow microscopy examination, anti-rK39 IgG detection, and blood metagenomic next-generation sequencing was 50%, 100%, and 100%, respectively. After VL diagnosis, eight patients were treated with sodium stibogluconate and two were treated with liposomal amphotericin B. All the patients with VL-HLH recovered. Our study demonstrates that regular triglyceride and fibrinogen levels in pediatric patients with VL-HLH may help in differential diagnosis from EBV-HLH. VL-HLH is milder than EBV-HLH, with less severe liver injury and inflammatory responses, and timely treatment with antileishmanial agents is essential to improve the outcomes of pediatric patients with VL-HLH.
Subject(s)
Epstein-Barr Virus Infections , Leishmaniasis, Visceral , Lymphohistiocytosis, Hemophagocytic , Child , Humans , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/diagnosis , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Herpesvirus 4, Human , Leishmaniasis, Visceral/complications , Leishmaniasis, Visceral/diagnosis , Leishmaniasis, Visceral/drug therapy , Retrospective Studies , Fibrinogen , Triglycerides/therapeutic use , Lactate DehydrogenasesABSTRACT
OBJECTIVE: Acute myeloid leukemia (AML) remains a common hematopoietic malignancy, and drug resistance greatly blunts the efficacy of chemotherapy in AML treatment. Adriamycin (ADM, also called doxorubicin), is one of the most widely used chemotherapeutics for treating cancers. Herein, we studied the molecular mechanisms underlying microRNA-188-5p (miR-188-5p)-mediated ADM resistance in AML. METHODS: Differentially expressed miRNAs were screened in normal and malignant hematopoietic cells by bioinformatics tools. MiR-188-5p expression in primary bone marrow CD34+ cells and AML cells was evaluated. AML/ADM cells were established using THP-1 and Kasumi-1 cells. The effect of miR-188-5p on the drug resistance in AML/ADM cells was examined by delivery of miR-188-5p-inhibitor. The binding relationship between TET1 and miR-188-5p was analyzed by ChIP, and the downstream target of miR-188-5p was predicted by bioinformatics analysis and validated by dual-luciferase assay. Finally, rescue experiments were carried out in vitro and in vivo. RESULTS: miR-188-5p was highly expressed in AML cells, and miR-188-5p-inhibitor sensitized the AML/ADM cells to ADM. Inhibition of TET1 reduced miR-188-5p promoter hydroxymethylation and downregulated miR-188-5p. miR-188-5p bound to the 3'UTR of PTEN to inhibit PTEN expression, and the PI3K/AKT signaling was activated upon inhibition of PTEN. Suppression of PTEN conferred resistance again to AML/ADM cells in the presence of miR-188-5p inhibitor. CONCLUSION: TET1 elevates miR-188-5p expression by promoting miR-188-5p promoter hydroxymethylation, and miR-188-5p inhibits PTEN expression to induce PI3K/AKT signaling pathway activation, leading to ADM resistance in AML.