Browsing by Author "Kosać, Ana (55786067800)"

Spinal muscular atrophy (SMA) is caused by functional loss of the survival of motor neuron 1 (SMN1) gene. Despite genetic homogeneity, phenotypic variability indicates the involvement of disease modifiers. SMN1 is located in 5q13.2 segmental duplication, enriched in genes and prone to unequal rearrangements, which results in copy number polymorphism (CNP). We examined the influence of CNP of 5q13.2 genes and their joint effect on childhood-onset SMA phenotype. Multiplex ligation-dependent probe amplification (MLPA) was used to construct 5q13.2 alleles and assess copy number of the SMN2, small EDRK-rich factor 1A (SERF1A) and NLR family apoptosis inhibitory protein (NAIP) genes in 99 Serbian patients with SMN1 homozygous absence (23-type I, 37-type II and 39-mild type III) and 122 patients' parents. Spearman rank test was performed to test correlation of individual genes and SMA type. Generalized linear models and backward selection were performed to obtain a model explaining phenotypic variation with the smallest set of variables. 5q13.2 alleles most commonly associated with type I harbored large-scale deletions, while those detected in types II and III originated from conversion of SMN1 to SMN2. Inverse correlation was observed between SMN2, SERF1A and NAIP CNP and SMA type (P=2.2e-16, P=4.264e-10, P=2.722e-8, respectively). The best minimal model describing phenotypic variability included SMN2 (P<2e-16), SERF1A (P<2e-16) and their interaction (P=0.02628). SMN2 and SERF1A have a joint modifying effect on childhood-onset SMA phenotype. © 2015 The Japan Society of Human Genetics All rights reserved.

Spinal muscular atrophy (SMA) is caused by functional loss of the survival of motor neuron 1 (SMN1) gene. Despite genetic homogeneity, phenotypic variability indicates the involvement of disease modifiers. SMN1 is located in 5q13.2 segmental duplication, enriched in genes and prone to unequal rearrangements, which results in copy number polymorphism (CNP). We examined the influence of CNP of 5q13.2 genes and their joint effect on childhood-onset SMA phenotype. Multiplex ligation-dependent probe amplification (MLPA) was used to construct 5q13.2 alleles and assess copy number of the SMN2, small EDRK-rich factor 1A (SERF1A) and NLR family apoptosis inhibitory protein (NAIP) genes in 99 Serbian patients with SMN1 homozygous absence (23-type I, 37-type II and 39-mild type III) and 122 patients' parents. Spearman rank test was performed to test correlation of individual genes and SMA type. Generalized linear models and backward selection were performed to obtain a model explaining phenotypic variation with the smallest set of variables. 5q13.2 alleles most commonly associated with type I harbored large-scale deletions, while those detected in types II and III originated from conversion of SMN1 to SMN2. Inverse correlation was observed between SMN2, SERF1A and NAIP CNP and SMA type (P=2.2e-16, P=4.264e-10, P=2.722e-8, respectively). The best minimal model describing phenotypic variability included SMN2 (P<2e-16), SERF1A (P<2e-16) and their interaction (P=0.02628). SMN2 and SERF1A have a joint modifying effect on childhood-onset SMA phenotype. © 2015 The Japan Society of Human Genetics All rights reserved.

Introduction L-2-Hydroxyglutaric aciduria (L-2-HGA) is an autosomal recessive neurometabolic disease with a slowly progressive course and characterized by increased levels of hydroxyglutaric acid in urine, cerebrospinal fluid and plasma. In this condition clinical features mainly consist of mental deterioration, ataxia and motor deficits. Case Outline The patient is a 16-year-old girl, the first and only child of healthy, non-consanguineous parents of Serbian origin. At the age of 4 years her walk became unsteady and ataxic. Other signs of cerebellar involvement were soon observed. Head circumference was above two standard deviations (55 cm). Mild mental retardation was revealed by formal intelligence testing (IQ 60). MR examination of the brain showed confluent subcortical white matter lesions spread centripetally, and atrophy of the cerebellar vermis with involvement of dentate nuclei, without deep white matter abnormalities. Laboratory investigation revealed increased amounts and a very large peak of HGA in urine and plasma. Enantiomeric analysis confirmed the L-configuration (>90%) establishing the diagnosis of L-2-HGA. The first epileptic seizure, partial with secondary generalization, occurred at age of 8 years. Favorable seizure control was achieved. A slow progression of neurological impairment was noted. Therapeutic trials with oral coenzyme Q10 and with oral riboflavin showed no biochemical and clinical effects. Recently, the diagnosis was proven by the presence of a mutation in the L-2-HGA gene. Conclusion To our knowledge, this is the first report of L-2-HGA in Serbia. L-2-HGA must be considered in the differential diagnosis based on specific findings in cranial MRI. © 2014, Serbia Medical Society. All rights reserved.

Introduction: Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. Methods: We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). Results: SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Conclusion: Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration. Copyright © 2024 Brkušanin, Kosać, Branković-Srećković, Jovanović, Perić, Karanović, Matijašević Joković, Garai, Pešović, Nikolić, Stević, Brajušković, Milić-Rašić and Savić-Pavićević.

Introduction: Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. Methods: We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). Results: SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Conclusion: Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration. Copyright © 2024 Brkušanin, Kosać, Branković-Srećković, Jovanović, Perić, Karanović, Matijašević Joković, Garai, Pešović, Nikolić, Stević, Brajušković, Milić-Rašić and Savić-Pavićević.

Introduction: There are rising evidences that subcortical structures, including the basal ganglia, are affected in patients with epilepsy. These structures are thought to influence the modulation and phenotypic expression of epileptic seizures. Our study aimed to evaluate the presence of structural abnormalities in subcortical structures in patients with juvenile myoclonic epilepsy (JME). Methods: This cross-sectional study included 51 patients who were diagnosed with JME and who were monitored on an outpatient basis at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade from January 1985 to October 2017. All patients underwent transcranial parenchymal sonography (TCS) from October 2015 to October 2017. Relation of clinical parameters (seizure control andcognitive functioning,) with TCS results was assessed. Results: Hyperechogenicity of the substantia nigra (SN) was detected in 37.2% of JME subjects and it was significantly more common in patients with JME than in the control group. The marked echogenicity of the red nucleus (RN) was detected in 17.6% of cases, while 11.8% of subjects had hyperechogenic RN. The presence of hyperechogenic RN (both right and left) was significantly more frequent in the group of patients with JME compared to the control group. The third ventricle diameter was larger in patients with JME than in controls. Conclusion: Structural changes of certain subcortical structures, primarily SN and RN, detected in JME patients indicate additional non-lesional abnormalities of the basal ganglia and midbrain structures in these patients. © The Author(s) under exclusive licence to Belgian Neurological Society 2024.

BackgroundAim. Common features of tuberous sclerosis complex (TSC) arise from the formation of hamartomas both in the brain and multiple organ systems, mainly due to a mutation in one of two genes, TSC1 or TSC2, with well described inter- and intrafamilial different phenotypic outcomes. The aim of this work was to make a synthesis of the patients data with diagnosed tuberous sclerosis in order to better understand the disease in our environment. Methods. We reviewed retrospectively the clinical records of all patients with TSC, diagnosed and regularly followed at the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade, Serbia during the period of more than two decades. Statistical analyses were performed using descriptive statistics as well as the Fisher's exact test. Results. Cohort of 44 patients with the diagnosis of definitive TSC were included. The mean age at last follow-up was 19.4 years [age range 1-58, standard deviation (SD) 11.8]. Family history for TSC was noted in 25% of patients. Dermatological manifestations were described in 93.2%, retinal astrocytoma and cardiac rhabdomyomas was found in 36.4% each, nephrological manifestations in 34.1% and lymphangioleiomyomatosis was diagnosed in two female patients. All patients presented with the structural lesions of central nervous system; epilepsy was diagnosed in 88.6%, out of whom 59 % of patients had seizure onset in the first year of life. The West syndrome was diagnosed in 27.3% of patients. Complete seizure control was achieved in 30.8%, in a majority with valproic acid or cabamazepine, but also with topiramate, lamotrigine and vigabatrin. At least two antiepileptic drugs were administered in 82% of patients. Mental retardation was noted in 50% of patients. Psychiatric manifestations were found in 40.9%, with attention deficit hyperactivity disorder diagnosed in 27.3%, autism spectrum disorder in 13.6 %, and psychosis and depression observed in 11.4% each. Conclusion. This kind of synthesis of the data certainly contributes to better understanding of the disease in our environment, as TSC, although well-known disease, still remains diagnostic and therapeutic challenge in daily clinical practice. © 2019 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.