Browsing by Author "Djordjevic, Maja (7102319301)"

Background: Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. Aims: Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. Methods: Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. Results: About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome. Conclusions: Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment. © 2016, SSIEM.

Background: Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. Aims: Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. Methods: Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. Results: About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome. Conclusions: Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment. © 2016, SSIEM.

Almost any anatomical compartment may be involved in Gaucher disease (GD). Abdominal lymphadenopathy occurred during enzyme replacement therapy in more than a dozen children with GD so far. A fourteen-year-old boy from Serbia developed clinical signs of acute appendicitis six years after the onset of GD type 3 related abdominal lymphadenopathy. Ultrasound examination showed diffuse thickening of the intestinal wall in the ileocoecal region with periappendicular infiltration. An appendectomy was performed four months after conservative treatment with antibiotics. Histopathology revealed macrophages with cytological characteristics of Gaucher cells densely crammed in mesoappendiceal adipose tissue. Also the multifocal replacement of subserosal tissue by Gaucher cells and their infiltration to a variable depth of muscularis propria of the appendix were verified. Frank infiltration of the vermiform appendix with Gaucher cells represents a novel observation in a wide spectrum of manifestations reported in GD. A possible causative relationship of this infiltration with appendicitis is considered. © 2016 Elsevier Inc.

Almost any anatomical compartment may be involved in Gaucher disease (GD). Abdominal lymphadenopathy occurred during enzyme replacement therapy in more than a dozen children with GD so far. A fourteen-year-old boy from Serbia developed clinical signs of acute appendicitis six years after the onset of GD type 3 related abdominal lymphadenopathy. Ultrasound examination showed diffuse thickening of the intestinal wall in the ileocoecal region with periappendicular infiltration. An appendectomy was performed four months after conservative treatment with antibiotics. Histopathology revealed macrophages with cytological characteristics of Gaucher cells densely crammed in mesoappendiceal adipose tissue. Also the multifocal replacement of subserosal tissue by Gaucher cells and their infiltration to a variable depth of muscularis propria of the appendix were verified. Frank infiltration of the vermiform appendix with Gaucher cells represents a novel observation in a wide spectrum of manifestations reported in GD. A possible causative relationship of this infiltration with appendicitis is considered. © 2016 Elsevier Inc.

Background: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. Methods: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 μmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. Results: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. Conclusions: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients. © 2018 The Author(s).

Objectives: Primary hyperparathyroidism in juveniles is extremely rare condition, but in the last few decades the incidence is increasing. The aim of this study was to compare biochemical and clinical characteristics of juvenile and adult primary hyperparathyroidism patients. Methods: A retrospective case-control study was conducted from 2004 until 2017 in high volume endocrine surgery center. Juvenile group consisted of all primary hyperparathyroidism patients younger than 20 who have undergone parathyroidectomy, and two-fold more patients older than 20 were classified in control (adult) group. Results: A total of 14 patients with the age ≤20 years were included in the juvenile group, while 28 patients older than 20 were selected for the control group. Female-to-male ratio in juveniles was 1:1, and in adults 8:1 (p = 0.005). The most common form of the disease in juveniles was bone disease (42.9%) and most of adults were asymptomatic (39.3%). Mean preoperative serum calcium level was significantly higher in juveniles than in adults, 3.47 ± 0.74 mmol/L vs. 2.96 ± 0.25 mmol/L, p = 0.025. Mean preoperative PTH level was higher in juveniles than in control group, 572.6 ± 533.3 ng/L vs. 331.8 ± 347.5 ng/L, p = 0.089. Conclusion: Clinical manifestations of primary hyperparathyroidism significantly differ in juvenile and adult patients. Juvenile primary hyperparathyroidism represents more severe form of the disease, often with end-organ damages, and it should be considered in patients with unspecific symptoms. © 2020 Elsevier B.V.

Persistent hypoglycaemia in newborns and infants is most commonly caused by congenital hyperinsulinism (CHI). Most CHI studies report outcomes in children from both consanguineous and non-consanguineous families which can affect the phenotype-genotype analysis. The aim of this study was to analyze characteristics of patients with CHI in 21 non-consanguineous families from Serbia. This retrospective cohort study included a total of 21 patients with CHI treated in the Mother and Child Healthcare Institute of Serbia during the past 20 years. The prevalence of macrosomia at birth was very low in our cohort (4.8%). Median age at presentation was 6 days, with seizures as the presenting symptom in 76% of patients. Only four patients (19%) were diazoxide unresponsive, and eventually underwent pancreatectomy. Genetic testing was performed in 15 patients and genetic diagnosis was confirmed in 60%, with all patients being heterozygous for detected mutations. The ABCC8 gene mutations were detected in 55.6%, GLUD1 in three patients (33.3%) with HIHA syndrome and one patient had HNF4A gene mutation and unusual prolonged hyperglycaemia lasting 6 days after diazoxide cessation. Neurodevelopmental deficits persisted in 33% of patients. Conclusion: This is the first study regarding CHI patients in Serbia. It suggests that in countries with low consanguinity rate, majority of CHI patients are diazoxide responsive. The most common mutations were heterozygous ABCC8, followed by GLUD1 and HNF4A mutations, suggesting the potential benefit of population-tailored genetic analysis approach, targeting the mutations causing CHI via dominant inheritance model in regions with low consanguinity rates.What is Known:• Persistent hypoglycaemia during infancy and early childhood is most commonly caused by congenital hyperinsulinism (CHI).• Consanguinity is a very important factor regarding the genetics and phenotype of CHI, increasing the risk of autosomal recessive genetic disorders, including the severe, diazoxide-unresponsive forms caused by recessive inactivating mutations in ABCC8 and KCNJ11.What is New:• Results of the present study which included CHI patients from 21 non-consanguineous families suggest that in countries with low consanguinity rates, majority of CHI patients can be diazoxide responsive, with most common mutations being heterozygous ABCC8, followed by GLUD1 and HNF4A mutations.• Unusually prolonged hyperglycaemic reaction to diazoxide treatment in a patient with HNF4A mutation was also described in the present study. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly. © 2018, SSIEM.

Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly. © 2018, SSIEM.

Background: In children and adolescents, primary hyperparathyroidism (pHPT) is rare, associated with severe morbidity, and has different clinical characteristics than in adults. The aim of this study was to analyze differences in clinical and laboratory characteristics between children and adolescents with pHPT. Methods: A retrospective cohort study was conducted to analyze pHPT characteristics in young patients, who have been operated at our institution. All patients were divided into two groups: group of patients ≤ 15 years (children) and group of patients > 15 and ≤ 20 years (adolescents). Results: Out of 1363 pHPT patients surgically treated during the study period, 14 patients (1%) were younger than 20 years: 6 children and 8 adolescents. Male-to-female ratio in children was 2:1, and in adolescents 1:1.7. Kidney stones were found in 62.5% of the adolescents and in none of the children patients. Bone form of the disease was the most frequent in children (in 83.1%), while in adolescents the kidney form was the most frequent (in 50%). Only 16.7% of children and 25% of adolescents did not have classical symptoms. All adolescent patients had single parathyroid adenoma, while 4 children patients had single parathyroid adenoma, one patient had hyperplasia, and one had parathyroid carcinoma. Both preoperative serum calcium and PTH levels were higher in children than in adolescents (3.87 mmol/L vs. 3.17 mmol/L; 812 ng/mL vs. 392 ng/mL, respectively). In all patients vitamin D level was low. All patients had normal postoperative values of serum calcium and PTH. Conclusion: There is a significant difference in clinical and biochemical characteristics between children and adolescent pHPT patients. Therefore, these two groups should be analyzed and treated separately. Type of Study: Retrospective comparative study. Level of Evidence: Level III. © 2019 Elsevier Inc.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is considered as the second most common type of hereditary HI. Correlation of genotype and phenotype in HI/HA syndrome has been described in several studies. We present three Serbian patients with HI/HA syndrome with emphasis on a possible correlation between genotype and clinical manifestations. Patient 1 was heterozygous for a de novo mutation p.S445L in the GLUD1 gene, while patients 2 and 3 (son and mother) both carry the p.R221C mutation. Early onset of hypoglycaemia with generalized seizures was recorded in infancy in all three patients. The two male patients had mild developmental delay, while the female patient presented with epilepsy. Analysis of Serbian patients with HI/HA syndrome confirms the association of p.S445L and p.R221C mutations with hypoglycaemic seizures noted within the first three months of life and with subsequent risk for cognitive impairment and/or epilepsy. © Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is considered as the second most common type of hereditary HI. Correlation of genotype and phenotype in HI/HA syndrome has been described in several studies. We present three Serbian patients with HI/HA syndrome with emphasis on a possible correlation between genotype and clinical manifestations. Patient 1 was heterozygous for a de novo mutation p.S445L in the GLUD1 gene, while patients 2 and 3 (son and mother) both carry the p.R221C mutation. Early onset of hypoglycaemia with generalized seizures was recorded in infancy in all three patients. The two male patients had mild developmental delay, while the female patient presented with epilepsy. Analysis of Serbian patients with HI/HA syndrome confirms the association of p.S445L and p.R221C mutations with hypoglycaemic seizures noted within the first three months of life and with subsequent risk for cognitive impairment and/or epilepsy. © Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.

The objective of the study was to evaluate etiology, clinical characteristics and outcome in children with epilepsia partialis continua (EPC).The investigation included 51 children with EPC aged 0.2-18 years treated in the period 1993-2009. The median period from the onset of underlying disorder to EPC was 6 months (0-72 months). EPC was caused by different pathologies: inflammatory and immune-mediated (52%), metabolic (13.7%), structural brain abnormalities (11.8%), cryptogenic (7.8%), vascular (5.9%), dual (5.9%), postoperative (2%). Median duration of EPC was 15 days (1-200 days). EPC involved more frequently the right side of the body comparing to the left one. The outcome was assessed at the end of the follow up period (mean 6.5 years, ranged 0.2-16 years). Unchanged neurological status was observed in 10 (19.6%) children, neurological consequences in 33 (64.7%) children and lethal outcome in 8 (15.7%) children.The most frequent etiology in our cohort was inflammatory and immune-mediated disease of central nerve system including Rasmussen's encephalitis. The duration of EPC was prolonged, most frequently involving the right upper limb. The outcome of EPC in children was unfavorable. © 2012 Elsevier B.V.

The objective of the study was to evaluate etiology, clinical characteristics and outcome in children with epilepsia partialis continua (EPC).The investigation included 51 children with EPC aged 0.2-18 years treated in the period 1993-2009. The median period from the onset of underlying disorder to EPC was 6 months (0-72 months). EPC was caused by different pathologies: inflammatory and immune-mediated (52%), metabolic (13.7%), structural brain abnormalities (11.8%), cryptogenic (7.8%), vascular (5.9%), dual (5.9%), postoperative (2%). Median duration of EPC was 15 days (1-200 days). EPC involved more frequently the right side of the body comparing to the left one. The outcome was assessed at the end of the follow up period (mean 6.5 years, ranged 0.2-16 years). Unchanged neurological status was observed in 10 (19.6%) children, neurological consequences in 33 (64.7%) children and lethal outcome in 8 (15.7%) children.The most frequent etiology in our cohort was inflammatory and immune-mediated disease of central nerve system including Rasmussen's encephalitis. The duration of EPC was prolonged, most frequently involving the right upper limb. The outcome of EPC in children was unfavorable. © 2012 Elsevier B.V.

Introduction: We evaluated a novel approach for investigation of lymphocyte dysregulation in Gaucher patients by including determination of IgH and TCR gene rearrangements together with levels of immunoglobulins, natural autoantibodies as well as presence of monoclonal protein. Materials and methods: Measurement of serum immunoglobulins, monoclonal immunoglobulins, selected autoantibodies, as well as analysis of immunoglobulin heavy chain and T cell receptor gene rearrangements. Results: Immunoglobulin disorder was detected in 29.6% patients, 40.7% demonstrated presence of B cell clonality and 44.4% demonstrated presence of autoantibodies. In five patients in our series, the presence of IgH gene rearrangement was the only detectable indicator of B cell dysfunction. TCR gene rearrangements were not found in any of the patients. Conclusion: Based on our results, we propose IgH gene rearrangements as a new biomarker for investigation of B cell dysfunction occurring as a complication of Gaucher disease. © 2012 Elsevier Inc.

Introduction: We evaluated a novel approach for investigation of lymphocyte dysregulation in Gaucher patients by including determination of IgH and TCR gene rearrangements together with levels of immunoglobulins, natural autoantibodies as well as presence of monoclonal protein. Materials and methods: Measurement of serum immunoglobulins, monoclonal immunoglobulins, selected autoantibodies, as well as analysis of immunoglobulin heavy chain and T cell receptor gene rearrangements. Results: Immunoglobulin disorder was detected in 29.6% patients, 40.7% demonstrated presence of B cell clonality and 44.4% demonstrated presence of autoantibodies. In five patients in our series, the presence of IgH gene rearrangement was the only detectable indicator of B cell dysfunction. TCR gene rearrangements were not found in any of the patients. Conclusion: Based on our results, we propose IgH gene rearrangements as a new biomarker for investigation of B cell dysfunction occurring as a complication of Gaucher disease. © 2012 Elsevier Inc.

Background: Glycogen storage disease type Ib (GSD-Ib) is an inherited metabolic disorder caused by autosomal recessive mutations in SLC37A4 coding for the glucose-6-phosphate transporter. Neutropenia represents major feature of GSD-Ib along with metabolic disturbances. Previous research in GSD-Ib patients did not reveal significant genotype-phenotype correlation. Our objective was to explore the frequency and severity of neutropenia and it's complications in relation to genotype of GSD-Ib patients. Methods: We estimated cumulative incidence of neutropenia and severe neutropenia, relation of genotype to absolute neutrophil count (ANC), and dynamics of ANC during serious bacterial infections (SBI) in a cohort of Serbian GSD Ib patients. Impact of genotype on GSD Ib-related inflammatory bowel disease (IBD) was also assessed. Results: Absolute neutrophil count (ANC) < 1500/mm3 was present in all 33 patients, with severe neutropenia (ANC<500/mm3) occurring in 60.6% of patients. The median age at neutropenia onset was 24 months, while severe neutropenia developed at median of 4.5 years. The ANC was elevated during 90.5% episodes of SBI. Genotypes c.81T>A/c.785G>A and c.81T>A/c.1042_1043delCT are associated with earlier onset of neutropenia. Patients carrying c.785G>A mutation express a higher capacity for ANC increase during SBI. Inflammatory bowel disease was diagnosed in 8 patients (24.2% of total) with median age of onset at 7 years. Risk for IBD occurrence was not significantly affected by gender, genotype and severity of neutropenia. Conclusions: We may conclude that certain mutations in SLC37A4 influence the risk for severe neutropenia occurrence but also affect the capacity to increase ANC during SBI. © 2019 Elsevier Masson SAS

Background: Glycogen storage disease type Ib (GSD-Ib) is an inherited metabolic disorder caused by autosomal recessive mutations in SLC37A4 coding for the glucose-6-phosphate transporter. Neutropenia represents major feature of GSD-Ib along with metabolic disturbances. Previous research in GSD-Ib patients did not reveal significant genotype-phenotype correlation. Our objective was to explore the frequency and severity of neutropenia and it's complications in relation to genotype of GSD-Ib patients. Methods: We estimated cumulative incidence of neutropenia and severe neutropenia, relation of genotype to absolute neutrophil count (ANC), and dynamics of ANC during serious bacterial infections (SBI) in a cohort of Serbian GSD Ib patients. Impact of genotype on GSD Ib-related inflammatory bowel disease (IBD) was also assessed. Results: Absolute neutrophil count (ANC) < 1500/mm3 was present in all 33 patients, with severe neutropenia (ANC<500/mm3) occurring in 60.6% of patients. The median age at neutropenia onset was 24 months, while severe neutropenia developed at median of 4.5 years. The ANC was elevated during 90.5% episodes of SBI. Genotypes c.81T>A/c.785G>A and c.81T>A/c.1042_1043delCT are associated with earlier onset of neutropenia. Patients carrying c.785G>A mutation express a higher capacity for ANC increase during SBI. Inflammatory bowel disease was diagnosed in 8 patients (24.2% of total) with median age of onset at 7 years. Risk for IBD occurrence was not significantly affected by gender, genotype and severity of neutropenia. Conclusions: We may conclude that certain mutations in SLC37A4 influence the risk for severe neutropenia occurrence but also affect the capacity to increase ANC during SBI. © 2019 Elsevier Masson SAS

[No abstract available]

Phenylketonuria (PKU) is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) enzyme. Here, we report the updated spectrum of PAH mutations in 61 Serbian PKU patients. By using both DGGE/DNA sequencing and PCR-RFLP, we identified 26 disease-causing mutations (detection rate 99%). The most frequent ones were p.L48S (31%), p.R408W (16.4%), p.P281L (6%), p.E390G (5.2%), and p.I306V (5.2%). Homozygosity value indicated high heterogeneity of Serbian population. To overcome possible pitfalls of patients’ phenotypic classification, we used two parameters: pretreatment/maximal phenylalanine blood concentration and Phe tolerance. The two phenotypes did not match only for patients with p.L48S. Therefore, we used Mann-Whitney statistical test to compare pretreatment/maximal blood Phe concentration and Phe tolerance detected in patients with p.[L48S];[null] and p.[missense];[null] genotypes. For patients with p.L48S, our results implied that Phe tolerance is a better parameter for phenotypic classification. Also, Fisher’s exact test was used to compare p.L48S effect on phenotype of homozygous and functionally hemizygous patients. Our findings showed that effect of p.L48S was altered in functional hemizygotes. Moreover, phenotypic inconsistency found in homozygotes suggested that interallelic complementation and/or additional factors play a role in genotype-phenotype correlation. Since BH4-supplementation therapy is not available in Serbia, we made the first estimation of its potential benefit based on patients’ genotypes. In the analyzed cohort, the total frequency of BH4-responsive mutations was 52.6%. Furthermore, we found a significant number of genotypes (26.2% BH4-responsive and 51% probably BH4-responsive) that may respond to BH4 therapy. This led us to a conclusion that BH4-supplementation therapy could bring benefit to Serbian PKU patients. © 2012, SSIEM and Springer-Verlag Berlin Heidelberg.