Browsing by Author "Andjelkovic, Marina (57197728167)"

Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder with heterogeneous presentation, where acute encephalopathy is rarely described in literature. Therefore, initial neurologic symptoms could make the diagnosis and treatment challenging. Case presentation: A four-month-old male infant presented with acute encephalopathy, vomiting, bulging fontanel, decreased appetite and failure to thrive. He had extremely lipemic serum and anemia. Intracranial computed tomography (CT) revealed lipid collection which was suspected to be epidermoid cyst, and also lipid deposits with extra-axial and intravascular location. This was initially described as a ruptured intracranial epidermoid cyst with dissemination of lipid content, including intravascular dissemination. Together with clinical signs of raised intracranial pressure it was discussed whether the cyst should be surgically removed. Since the blood sample appearence was milky and the child was rather stable, surgery wasn’t performed and the treatment with exchange transfusion (ET) was started immediately. Only after ET it was possible to obtain laboratory results including lipid status (triglycerides were 106.8 mmol/l). At that point we suspected that the underlining cause is a genetic disease. Three cycles of plasmapheresis followed ET, after which symptoms resolved almost completely, despite remaining lipid deposits on brain CT scan and brain ultrasound, with some signs of regression. After these repeated imaging studies, it was concluded that the ‘cyst’ was actually the largest brain lipid collection. The definitive genetic diagnosis confirmed FCS. A short course of insulin, antioxidants and fibrates was initially given, but discontinued after the diagnosis confirmation due to lack of supporting data in the literature. Effective and the only maintenance treatment was the diet consisting of formula low in fat and high in medium-chain triglycerides. On the discharge the infant’s neurological status, except mild hypotonia, was normal, he was thriving well, had good appetite and no anemia. Conclusions: This is a rare case of FCS presenting with neurological symptoms that mimicked the clinical picture of ruptured intracranial epidermoid cyst, which was initially the differential diagnosis of this case. Initial interpretation of imaging studies didn’t delay treatment. With the right treatment, the symptoms of the disease could be reversible with satisfactory outcome. © The Author(s) 2024.

Genetic predisposition to systemic sclerosis (SSc) has still not been fully revealed. Interleukin-6 (IL-6) is a mediator of T cell proliferation and fibrotic events in SSc. Polymorphisms in the IL-6 are found to be important in susceptibility to development of SSc. We aimed to assess the frequency of -174 C/G of IL-6 gene polymorphism in SSc patients and healthy controls, as well as correlation with disease manifestations. In the case-control study, 102 patients with SSc and 93 controls were included. PCR-RFLP method was performed for genotyping promotor variants -174 C/G of IL-6 gene. The expression level of IL-6 was determined by qRT-PCR on subset of 50 patients and 13 healthy controls with different IL-6 genotypes. We used UCLA GIT 2.0 questionnaire to assess gastrointestinal involvement in SSc patients. The expression level of IL-6 gene was significantly higher in patients with SSc in comparison with healthy controls (p < 0.05). Carriers of C-allele of IL-6 gene compared to those with G allele, showed higher expression of IL-6 gene (95.8 vs. 41.2, p < 0.05), higher GIT total score (0.85 vs. 0.5, p < 0.05) and higher distension scale score (1.4 ± 0.9 vs. 0.78 ± 0.8, p = 0.05). No significant differences in genotype distribution and allele frequency were observed between patients and controls. The expression of IL6 gene varies significantly during the course of SSc. The IL-6 gene variant -174 C/G (presence of C-allele) is associated with higher IL-6 gene expression and greater GIT impairment in patients with SSc. © 2018, International League of Associations for Rheumatology (ILAR).

Background: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurrence. Because ICG invades the hypothalamus and/or pituitary, endocrine dysfunction is one of the common determinants of these tumours. We present two brothers with a history of ICG. Patient 1 is a 25-year-old male who suffered from weakness of the right half of his body at the age of 18 years. Cranial MRI revealed a mass lesion in the left thalamus. He underwent neurosurgery, and the tumour was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumour after radiation therapy. At the age of 22 years a diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Molecular genetic analysis of the tumour tissue detected the mutation within exon 2 in KRAS gene. Patient 2 is a 20-year-old man who presented with diabetes insipidus at the age of 12 years. MRI detected tumour in the third ventricle and pineal region. After endoscopic tumour biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy and was treated with GH during childhood. At the age of 18 years GH replacement was reintroduced. A six-month follow-up during the subsequent two years in both brothers demonstrated the IGF1 normalisation with no MRI signs of tumour recurrence. Conclusion: To the best of our knowledge, so far only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside Japan. They have been treated successfully with GH therapy in adulthood. © 2018 Via Medica. All rights reserved.

Background: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurrence. Because ICG invades the hypothalamus and/or pituitary, endocrine dysfunction is one of the common determinants of these tumours. We present two brothers with a history of ICG. Patient 1 is a 25-year-old male who suffered from weakness of the right half of his body at the age of 18 years. Cranial MRI revealed a mass lesion in the left thalamus. He underwent neurosurgery, and the tumour was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumour after radiation therapy. At the age of 22 years a diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Molecular genetic analysis of the tumour tissue detected the mutation within exon 2 in KRAS gene. Patient 2 is a 20-year-old man who presented with diabetes insipidus at the age of 12 years. MRI detected tumour in the third ventricle and pineal region. After endoscopic tumour biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy and was treated with GH during childhood. At the age of 18 years GH replacement was reintroduced. A six-month follow-up during the subsequent two years in both brothers demonstrated the IGF1 normalisation with no MRI signs of tumour recurrence. Conclusion: To the best of our knowledge, so far only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside Japan. They have been treated successfully with GH therapy in adulthood. © 2018 Via Medica. All rights reserved.

Introduction: Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) genes and sarcoidosis, as well as the association between these SNPs and 25(OH)D levels in sarcoidosis patients. Material and methods: For that purpose we genotyped 86 sarcoidosis patients and 50 healthy controls using the PCR-RFLP method. Results: Subjects carrying the CC genotype of CYP27B1 rs10877012 have 10 times lower odds of suffering from sarcoidosis. Moreover, DBP rs4588 AA genotype was shown to be a susceptibility factor, where carriers of this genotype had eight times higher odds for developing sarcoidosis. In addition, the A allele of the DBP gene (rs4588) was associated with lower levels of 25(OH)D in sarcoidosis patients. Conclusions: These results suggest that patients with vitamin D deficiency should be regularly tested for genetic modifiers that are related to sarcoidosis in order to prevent development of serious forms of sarcoidosis. Copyright © 2018 Termedia & Banach

Introduction: Single nucleotide variants (SNVs) represent important genetic risk factors for susceptibility to posttraumatic sepsis and a potential target for immunotherapy. We aimed to evaluate the association between 8 different SNVs within tumor necrosis factor alpha (TNFA), lymphotoxin alpha (LTA) and Toll-like receptor (TLR2 and TLR4) genes and the risk of posttraumatic sepsis. Methods: Nested case-control study was conducted in the emergency department of the Clinical Centre of Serbia including 228 traumatized patients (44 with sepsis and 184 without sepsis). To compare the results of trauma subjects with the data from the general population, a control group of 101 healthy persons was included in the study. Genotyping of TNFA (rs1800629 and rs361525), LTA (rs909253), TLR2 (rs3804099, rs4696480 and rs3804100), and TLR4 (rs4986790 and rs4986791) was performed for all patients within all three groups using the real-time PCR method. MutationTaster database and in silico software SIFT were used to predict the variant pathogenic effect. Results: Carriage of the G allele of the TNFA rs1800629 gene variant (OR 2.1, 95%CI 1.06-4.16) and T allele-carriage of the TLR4 rs4986791 genetic variant (OR 3.02, 95%CI 1.31-6.57) were associated with significantly higher risk of sepsis in trauma patients when compared to the general population prone to sepsis and traumatized patients without developing a sepsis, respectively. Of these two variants, only variant in TLR4 gene (rs4986791) has been labeled as disease causing by both the MutationTaster database and the in-silico software SIFT, which further supports the role of this variant in various pathologies including sepsis. For the remaining six variants no significant association with the susceptibility to sepsis was detected. Conclusions: Carriage of the G allele of the TNFA rs1800629 gene variant and T allele-carriage of the TLR4 rs4986791 genetic variant confer significant risk of posttraumatic sepsis. TLR4 gene variants (rs4986790 and rs4986791) has been labelled as disease causing. © 2021 Elsevier Ltd

Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease with unknown etiology. Numerous studies have indicated that the disease heterogeneity implies various genetic abnormalities. Considering that SSc is characterized by a strong sex bias and that the position of IRAK1 gene is on the X chromosome, we assume that variations in IRAK1 gene could explain female predominance of SSc. It was previously described that miR-146a has a role in ‘fine-tuning’ regulation of the TLR/NF-kB signaling pathway through down-regulation of IRAK1 gene. The aim of the present study was to analyze both variants and expression level of IRAK1 and miR-146a genes in terms of susceptibility to SSc and clinical presentation of SSc patients. We analyzed variants IRAK1 rs3027898 C > A and miR-146a rs2910164 C > G in 102 SSc patients and 66 healthy subjects. Genotyping was performed by Sanger sequencing. Expression level of IRAK1 mRNA and miR-146a in PBMCs was performed in subset of 50 patients and 13 healthy controls by RT-qPCR. Our results showed that there was no association between IRAK1 rs3027898 and the risk of SSc in women. However, the analysis of genotype distribution of the mir-146a rs2910164 C > G variant indicated that CC genotype shows strong association with lung fibrosis and active form of the disease. When expression level of IRAK1 gene was analyzed, we detected significant downregulation of IRAK1 mRNA in SSc patients compared to controls, as well as in male compared to female patients, in patients with ACAs autoantibodies and in patients with severe skin involvement. Regarding the expression level of miR-146a, we have found significantly reduced expression in SSc patients, in patients with skin involvement and in male SSc patients. The results from this study indicate that expression of IRAK1 gene could explain phenotypic heterogeneity of SSc and may be involved in the pathogenesis of SSc due to its differential expression in certain subgroups. Our results also suggested that miR-146a rs2910164 CC genotype may be predisposing factor for development lung fibrosis and more progressive form of SSc. Results from relative expression analysis of miR-146a demonstrated that changes in the level of this miRNA may have an impact on development and clinical course of SSc. © 2018 European Federation of Immunological Societies

Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease with unknown etiology. Numerous studies have indicated that the disease heterogeneity implies various genetic abnormalities. Considering that SSc is characterized by a strong sex bias and that the position of IRAK1 gene is on the X chromosome, we assume that variations in IRAK1 gene could explain female predominance of SSc. It was previously described that miR-146a has a role in ‘fine-tuning’ regulation of the TLR/NF-kB signaling pathway through down-regulation of IRAK1 gene. The aim of the present study was to analyze both variants and expression level of IRAK1 and miR-146a genes in terms of susceptibility to SSc and clinical presentation of SSc patients. We analyzed variants IRAK1 rs3027898 C > A and miR-146a rs2910164 C > G in 102 SSc patients and 66 healthy subjects. Genotyping was performed by Sanger sequencing. Expression level of IRAK1 mRNA and miR-146a in PBMCs was performed in subset of 50 patients and 13 healthy controls by RT-qPCR. Our results showed that there was no association between IRAK1 rs3027898 and the risk of SSc in women. However, the analysis of genotype distribution of the mir-146a rs2910164 C > G variant indicated that CC genotype shows strong association with lung fibrosis and active form of the disease. When expression level of IRAK1 gene was analyzed, we detected significant downregulation of IRAK1 mRNA in SSc patients compared to controls, as well as in male compared to female patients, in patients with ACAs autoantibodies and in patients with severe skin involvement. Regarding the expression level of miR-146a, we have found significantly reduced expression in SSc patients, in patients with skin involvement and in male SSc patients. The results from this study indicate that expression of IRAK1 gene could explain phenotypic heterogeneity of SSc and may be involved in the pathogenesis of SSc due to its differential expression in certain subgroups. Our results also suggested that miR-146a rs2910164 CC genotype may be predisposing factor for development lung fibrosis and more progressive form of SSc. Results from relative expression analysis of miR-146a demonstrated that changes in the level of this miRNA may have an impact on development and clinical course of SSc. © 2018 European Federation of Immunological Societies

Background/Objectives: Numerous studies have demonstrated the safety and efficacy of intraarticular stem cell injections for treating osteoarthritic knee joints, reporting symptom reduction and pain relief within a few months of treatment. Here, we report the results of a 7-year follow-up after a single intraarticular injection of 0.5–1 × 107 autologous adipose tissue-derived mesenchymal stem cells in patients with OA (Kellgren-Lawrence grade 2 to 4). Methods: Nine patients were treated, and two patients had bilateral disease. Patients were evaluated clinically and radiologically using X-ray and MRI. A comprehensive statistical analysis was undertaken to evaluate the obtained results. Results: All clinical scores and range of motion significantly improved within the first six months after injection. At the 18-month time point, a significant improvement in cartilage structure was observed on MRI while X-ray showed no changes in subchondral bone of distal femur and proximal tibia. At the 60-month time point, the clinical scores were still improved compared to baseline, except for the range of motion, which decreased almost back to the baseline level. At 84 months, the clinical scores decreased significantly toward the baseline level, but the MRI structural characteristics of cartilage still remained significantly better than those measured at baseline. Conclusions: Adipose tissue-derived stem cell therapy has substantial long-term clinical effects on patients with knee osteoarthritis. © 2024 by the authors.

Introduction: Maturity onset diabetes of the young (MODY) is a rare form of monogenic diabetes. Being clinically and genetically heterogeneous, it is often misdiagnosed as type 1 or type 2 diabetes, leading to inappropriate therapy. MODY is caused by a single gene mutation. Thirteen genes, defining 13 subtypes, have been identified to cause MODY. A correct diagnosis is important for the right therapy, prognosis, and genetic counselling. Material and methods: Twenty-nine unrelated paediatric patients clinically suspected of having MODY diabetes were analysed using TruSight One panel for next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) assay. Results: In this study we identified variants in MODY genes in 22 out of 29 patients (75.9%). Using two genetic tests, NGS and MLPA, we detected both single nucleotide variants and large deletions in patients. Most of the patients harboured a variant in the GCK gene (11/22), followed by HNF1B (5/22). The rest of the variants were found in the NEUROD1 and HNF1A genes. We identified one novel variant in the GCK gene: c.596T>C, p.Val199Ala. The applied genetic tests excluded the suspected diagnosis of MODY in two patients and revealed variants in other genes possibly associated with the patient’s clinical phenotype. Conclusions: In our group of MODY patients most variants were found in the GCK gene, followed by variants in HNF1B, NEUROD1, and HNF1A genes. The combined NGS and MLPA-based genetic tests presented a comprehensive approach for analysing patients with suspected MODY diabetes and provided a successful differential diagnosis of MODY subtypes. © 2019 Via Medica. All rights reserved.

Introduction: Maturity onset diabetes of the young (MODY) is a rare form of monogenic diabetes. Being clinically and genetically heterogeneous, it is often misdiagnosed as type 1 or type 2 diabetes, leading to inappropriate therapy. MODY is caused by a single gene mutation. Thirteen genes, defining 13 subtypes, have been identified to cause MODY. A correct diagnosis is important for the right therapy, prognosis, and genetic counselling. Material and methods: Twenty-nine unrelated paediatric patients clinically suspected of having MODY diabetes were analysed using TruSight One panel for next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) assay. Results: In this study we identified variants in MODY genes in 22 out of 29 patients (75.9%). Using two genetic tests, NGS and MLPA, we detected both single nucleotide variants and large deletions in patients. Most of the patients harboured a variant in the GCK gene (11/22), followed by HNF1B (5/22). The rest of the variants were found in the NEUROD1 and HNF1A genes. We identified one novel variant in the GCK gene: c.596T>C, p.Val199Ala. The applied genetic tests excluded the suspected diagnosis of MODY in two patients and revealed variants in other genes possibly associated with the patient’s clinical phenotype. Conclusions: In our group of MODY patients most variants were found in the GCK gene, followed by variants in HNF1B, NEUROD1, and HNF1A genes. The combined NGS and MLPA-based genetic tests presented a comprehensive approach for analysing patients with suspected MODY diabetes and provided a successful differential diagnosis of MODY subtypes. © 2019 Via Medica. All rights reserved.