Browsing by Author "Branković, Marija (58122593400)"

Background/Aim. Duchenne muscular dystrophy (DMD) and its allelic form Becker muscular dystrophy (BMD) are X-linked diseases that affect males, characterized by progressive muscle and cardiopulmonary weakness, especially in DMD as a severe form of the disease. They result from mutations in the dystrophin gene, and the most common changes are large intragenic deletions and duplications (80%). One third of patients have de novo mutation and 2/3 of the mothers are estimated as carriers. The aim of the study was to analyze the frequency of duplications versus deletions in the dystrophin gene in patients with dystrophinopathies, as well as to analyze the phenotypic effect of large mutations obtained and to determine the carrier status of female relatives in probands with duplications. Methods. We examined 22 DMD and 35 BMD unrelated patients and 6 female relatives of the probands where duplications were found. We used polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) methods, according to the protocol, to detect or confirm mutations in probands and female carriers. Results. In probands, there were 34 (59.6%) large deletions (mostly affected exons 44–60) and 6 (10.5%) large duplications in 4 DMD and 2 BMD patients. Also, duplications were found in 3 out of 4 (75%) tested mothers. The distribution of duplications was heterogeneous, affecting N-terminal and central rod domain, and included more exons, except for one DMD patient who had duplication of exon 2. An exception from the Monaco rule was present in 9.5% of DMD and 15.8% of BMD probands, i.e. in 12.5% of DMD/BMD cases. Conclusion. In 57 DMD/BMD probands, we found 59.6% of large deletions and 10.5% of large duplications. The most affected region of the DMD gene was the central rod domain. An exception to Monaco's rule was present in 12.5% of DMD/BMD cases. Three out of 4 examined proband's mothers were confirmed as carriers. © 2020 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Background: Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). Methods: Following the MDSGene protocol, we systematically investigated genotype–phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. Results: Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. Conclusions: The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). Methods: Following the MDSGene protocol, we systematically investigated genotype–phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. Results: Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. Conclusions: The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Recent studies explored polymorphisms of multiple genes as contributing to genetic susceptibility to psychosis in Parkinson's disease (PDP). Objective: We aimed to examine the association of seven selected polymorphisms of genes related to dopamine pathways with PDP development. At the same time, demographic and clinical correlates of PDP were assessed. Methods: PD patients (n = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT, rs6277, rs1076560, and rs2283265 in DRD2, and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. Also, variable number of tandem repeats polymorphism in the DAT gene was examined. Each patient underwent comprehensive neurological examination, assessment of psychosis, as defined by the NINDS/NIMH criteria, as well as screening of depression, anxiety, and cognitive status. Results: Diagnostic criteria for PDP were met by 101 (43.2%) patients. They had longer disease duration, were taking higher doses of dopaminergic agents, and had higher scores of the motor and non-motor scales than the non-PDP group. Multivariate regression analysis revealed LEDD≥900 mg, Unified Parkinson's Disease Rating Scale III part score, the Hamilton Depression Rating Scale score≥7, the Hamilton Anxiety Rating Scale score > 14,and GG homozygotes of rs2734849 ANKK1 as independent predictors of the onset of PDP. Conclusion: Besides previous exposure to dopaminergic drugs, impairment of motor status, depression and anxiety, as well-established clinical risk factors for the development of PDP, GG rs2734849 ANKK1 could also be a contributing factor, which requires addressing by future longitudinal studies. © 2021 - IOS Press. All rights reserved.

Background: Recent studies explored polymorphisms of multiple genes as contributing to genetic susceptibility to psychosis in Parkinson's disease (PDP). Objective: We aimed to examine the association of seven selected polymorphisms of genes related to dopamine pathways with PDP development. At the same time, demographic and clinical correlates of PDP were assessed. Methods: PD patients (n = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT, rs6277, rs1076560, and rs2283265 in DRD2, and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. Also, variable number of tandem repeats polymorphism in the DAT gene was examined. Each patient underwent comprehensive neurological examination, assessment of psychosis, as defined by the NINDS/NIMH criteria, as well as screening of depression, anxiety, and cognitive status. Results: Diagnostic criteria for PDP were met by 101 (43.2%) patients. They had longer disease duration, were taking higher doses of dopaminergic agents, and had higher scores of the motor and non-motor scales than the non-PDP group. Multivariate regression analysis revealed LEDD≥900 mg, Unified Parkinson's Disease Rating Scale III part score, the Hamilton Depression Rating Scale score≥7, the Hamilton Anxiety Rating Scale score > 14,and GG homozygotes of rs2734849 ANKK1 as independent predictors of the onset of PDP. Conclusion: Besides previous exposure to dopaminergic drugs, impairment of motor status, depression and anxiety, as well-established clinical risk factors for the development of PDP, GG rs2734849 ANKK1 could also be a contributing factor, which requires addressing by future longitudinal studies. © 2021 - IOS Press. All rights reserved.

[No abstract available]

[No abstract available]

Most of the heritability in frontotemporal dementia (FTD) is accounted for by autosomal dominant hexanucleotide expansion in the chromosome 9 open reading frame 72 (C9orf72), pathogenic/likely pathogenic variants in progranulin (GRN), and microtubule-associated protein tau (MAPT) genes. Until now, there has been no systematic analysis of these genes in the Serbian population. Herein, we assessed the frequency of the C9orf72 expansion, pathogenic/likely pathogenic variants in GRN and MAPT in a well-characterized group of 472 subjects (FTD, Alzheimer’s disease - AD, mild cognitive impairment - MCI, and unspecified dementia - UnD), recruited in the Memory Center, Neurology Clinic, University Clinical Center of Serbia. The C9orf72 repeat expansion was detected in 6.98% of FTD cases (13.46% familial; 2.6% sporadic). In the UnD subgroup, C9orf72 repeat expansions were detected in 4.08% (8% familial) individuals. Pathogenic variants in the GRN were found in 2.85% of familial FTD cases. Interestingly, no MAPT pathogenic/likely pathogenic variants were detected, suggesting possible geographical specificity. Our findings highlight the importance of wider implementation of genetic testing in neurological and psychiatric practice managing patients with cognitive-behavioral and motor symptoms. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.

Most of the heritability in frontotemporal dementia (FTD) is accounted for by autosomal dominant hexanucleotide expansion in the chromosome 9 open reading frame 72 (C9orf72), pathogenic/likely pathogenic variants in progranulin (GRN), and microtubule-associated protein tau (MAPT) genes. Until now, there has been no systematic analysis of these genes in the Serbian population. Herein, we assessed the frequency of the C9orf72 expansion, pathogenic/likely pathogenic variants in GRN and MAPT in a well-characterized group of 472 subjects (FTD, Alzheimer’s disease - AD, mild cognitive impairment - MCI, and unspecified dementia - UnD), recruited in the Memory Center, Neurology Clinic, University Clinical Center of Serbia. The C9orf72 repeat expansion was detected in 6.98% of FTD cases (13.46% familial; 2.6% sporadic). In the UnD subgroup, C9orf72 repeat expansions were detected in 4.08% (8% familial) individuals. Pathogenic variants in the GRN were found in 2.85% of familial FTD cases. Interestingly, no MAPT pathogenic/likely pathogenic variants were detected, suggesting possible geographical specificity. Our findings highlight the importance of wider implementation of genetic testing in neurological and psychiatric practice managing patients with cognitive-behavioral and motor symptoms. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.

Background: Niemann Pick type C is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 and NPC2 genes. It is a neuro-visceral disease with a heterogeneous phenotype. Clinical features depend on the age at onset. Visceral manifestations are more prominent in the early onset (infantile) form, while neuro-psychiatric symptoms are more prominent in the late disease onset (juvenile and adult forms). Methods: A total number of 150 patients have been screened for changes in NPC1 and NPC2 gene at the Neurology Clinic, University Clinical Centre of Serbia in the period 2012–2020. Clinical data were extracted for patients with biallelic mutations. Results: Fifteen patients carried biallelic mutations in the NPC1. Out of eight different reported NPC1 variants, four are novel (c.1204_1205TT>GC, p.F402A; c.2486T>G, p.L829R; c.2795+5 G>C; c.3722T>A, p.L1241*). The mean age at the disease onset was 20.3 ± 11.9 years with the average diagnostic delay of 7.7 ± 4.3 years. Movement disorders and psychiatric or cognitive disturbances were the most common initial symptoms (in 33% and 28% patients, respectively). The average age at the first neurological manifestation was 21 ± 12.0 years. At the last examination, eye movement abnormalities (vertical slow saccades or vertical supranuclear gaze palsy), and ataxia were present in all patients, while dystonia was common (in 78.6% of patients). Presence of c.2861C>T, p.S954L mutation in homozygous state was associated with older age at the neurological symptom onset. Conclusions: Clinical findings were in line with the expected, but the diagnostic delay was common. We hypothesize that the presence of c.2861C>T, p.S954L mutation may contribute to the phenotype attenuation. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.

Background: Niemann Pick type C is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 and NPC2 genes. It is a neuro-visceral disease with a heterogeneous phenotype. Clinical features depend on the age at onset. Visceral manifestations are more prominent in the early onset (infantile) form, while neuro-psychiatric symptoms are more prominent in the late disease onset (juvenile and adult forms). Methods: A total number of 150 patients have been screened for changes in NPC1 and NPC2 gene at the Neurology Clinic, University Clinical Centre of Serbia in the period 2012–2020. Clinical data were extracted for patients with biallelic mutations. Results: Fifteen patients carried biallelic mutations in the NPC1. Out of eight different reported NPC1 variants, four are novel (c.1204_1205TT>GC, p.F402A; c.2486T>G, p.L829R; c.2795+5 G>C; c.3722T>A, p.L1241*). The mean age at the disease onset was 20.3 ± 11.9 years with the average diagnostic delay of 7.7 ± 4.3 years. Movement disorders and psychiatric or cognitive disturbances were the most common initial symptoms (in 33% and 28% patients, respectively). The average age at the first neurological manifestation was 21 ± 12.0 years. At the last examination, eye movement abnormalities (vertical slow saccades or vertical supranuclear gaze palsy), and ataxia were present in all patients, while dystonia was common (in 78.6% of patients). Presence of c.2861C>T, p.S954L mutation in homozygous state was associated with older age at the neurological symptom onset. Conclusions: Clinical findings were in line with the expected, but the diagnostic delay was common. We hypothesize that the presence of c.2861C>T, p.S954L mutation may contribute to the phenotype attenuation. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.

Introduction. GLUT1 deficiency syndrome (GLUT1 DS, OMIM 606777) is a metabolic brain disorder caused by mutations in SLC2A1 gene (chromosome 1) encoding glucose transporter type 1 located on blood-brain membrane. The “classic” phenotype in children includes early onset generalized farmacoresistant epilepsy, developmental delay, complex movement disorders and acquired microcephaly. However, there are milder phenotypes without epilepsy which could be seen in older children. The ketogenic diet is a treatment of choice. Case report. We present a four-year- old female patient with farmacoresistant generalized epilepsy, paroxysmal dystonic posturing, ataxia, hypotonia, developmental delay (motor, attention and speech disturbances), and microcephaly. The genetic testing revealed a novel point mutation at c.156T > A (p.Y52X) in exon 3 of SLC2A1 gene. The patient responded excellent on ketogenic diet. Conclusion. GLUT1 DS is treatable, and likely to be under-diagnosed neurological disorder. The ketogenic diet is resulting in good control of seizures in the patients, and it has certain benefit for the neurodevelopmental disability. Apstrakt Uvod. GLUT1 sindrom deficijencije (GLUT1 DS, OMIM 606777) je metaboličko oboljenje mozga uzrokovano mutacijom u SLC2A1 genu (hromozom 1) koji kodira transporter glukoze tip 1 lokalizovan na krvno-moždanoj barijeri. “Klasični” fenotip kod dece uključuje ranu pojavu generalizovane farmakorezistentne epilepsije, usporen psihomotorni razvoj, poremećaje pokreta i stečenu mikrocefaliju. Međutim, blaži fenotipovi bez pojave epilepsije mogu se videti i u kasnijem uzrastu. Ketogena dijeta je terapija izbora. Prikaz bolesnika. U radu je prikazana devojčica, uzrasta četiri godine sa farmakorezistentnom generalizovanom epilepsijom, paroksizmalnim distonijama, ataksijom, hipotonijom, usporenim razvojem (poremećajima motorike, pažnje i govora) i mikrocefalijom. Genetsko testiranje je otkrilo novu tačkastu mutaciju u c.156T > A (p.Y52X) na egzonu 3 SLC2A1 gena. Kod bolesnice je primećeno poboljšanje u kliničkom nalazu na primenu ketogene dijete. Zaključak. GLUT1 DS je lečiva neurološka bolest, koja je verovatno nedovoljno prepoznata. Ketogena dijeta dovodi do povoljne kontrole napada kod dece, a doprinosi izvesnom poboljšanju u neurološkom nalazu. © 2019, Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Introduction: Next generation sequencing (NGS) has greatly expanded our understanding of genetic contributors in multiple epilepsy syndromes, including focal epilepsy. Describing the genetic architecture of common syndromes promises to facilitate the diagnostic process as well as aid in the identification of patients who stand to benefit from genetic testing, but most studies to date have been limited to examining children or adults with intellectual disability. Our aim was to determine the yield of targeted sequencing of 5 established epilepsy genes (DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19) in an extensively phenotyped cohort of focal epilepsy patients with normal intellectual function or mild intellectual disability, as well as describe novel variants and determine the characteristics of variant carriers. Patients and methods: Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria. Results: Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1. Conclusion: Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability. © 2023

Introduction: Next generation sequencing (NGS) has greatly expanded our understanding of genetic contributors in multiple epilepsy syndromes, including focal epilepsy. Describing the genetic architecture of common syndromes promises to facilitate the diagnostic process as well as aid in the identification of patients who stand to benefit from genetic testing, but most studies to date have been limited to examining children or adults with intellectual disability. Our aim was to determine the yield of targeted sequencing of 5 established epilepsy genes (DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19) in an extensively phenotyped cohort of focal epilepsy patients with normal intellectual function or mild intellectual disability, as well as describe novel variants and determine the characteristics of variant carriers. Patients and methods: Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria. Results: Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1. Conclusion: Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability. © 2023

[No abstract available]

[No abstract available]

Background: The newly discovered intronic repeat expansions in the genes encoding replication factor C subunit 1 (RFC1) and fibroblast growth factor 14 (FGF14) frequently cause late-onset cerebellar ataxia. Objectives: To investigate the presence of RFC1 and FGF14 pathogenic repeat expansions in Serbian patients with adult-onset cerebellar ataxia. Methods: The study included 167 unrelated patients with sporadic or familial cerebellar ataxia. The RFC1 repeat expansion analysis was performed by duplex PCR and Sanger sequencing, while the FGF14 repeat expansion was tested for by long-range PCR, repeat-primed PCR, and Sanger sequencing. Results: We identified pathogenic repeat expansions in RFC1 in seven patients (7/167; 4.2%) with late-onset sporadic ataxia with neuropathy and chronic cough. Two patients also had bilateral vestibulopathy. Repeat expansions in FGF14 were found in nine unrelated patients (9/167; 5.4%) with ataxia, less than half of whom presented with neuropathy and two-thirds with global brain atrophy. Tremor and episodic features were the most frequent additional characteristics in carriers of uninterrupted FGF14 repeat expansions. Among the 122 sporadic cases, 12 (9.8%) carried an expansion in either RFC1 or FGF14, comparable to 4/45 (8.9%) among the patients with a positive family history. Conclusions: Pathogenic repeat expansions in RFC1 and FGF14 are relatively frequent causes of adult-onset cerebellar ataxia, especially among sporadic patients, indicating that family history should not be considered when prioritizing ataxia patients for testing of RFC1 or FGF14 repeat expansions. © 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: The newly discovered intronic repeat expansions in the genes encoding replication factor C subunit 1 (RFC1) and fibroblast growth factor 14 (FGF14) frequently cause late-onset cerebellar ataxia. Objectives: To investigate the presence of RFC1 and FGF14 pathogenic repeat expansions in Serbian patients with adult-onset cerebellar ataxia. Methods: The study included 167 unrelated patients with sporadic or familial cerebellar ataxia. The RFC1 repeat expansion analysis was performed by duplex PCR and Sanger sequencing, while the FGF14 repeat expansion was tested for by long-range PCR, repeat-primed PCR, and Sanger sequencing. Results: We identified pathogenic repeat expansions in RFC1 in seven patients (7/167; 4.2%) with late-onset sporadic ataxia with neuropathy and chronic cough. Two patients also had bilateral vestibulopathy. Repeat expansions in FGF14 were found in nine unrelated patients (9/167; 5.4%) with ataxia, less than half of whom presented with neuropathy and two-thirds with global brain atrophy. Tremor and episodic features were the most frequent additional characteristics in carriers of uninterrupted FGF14 repeat expansions. Among the 122 sporadic cases, 12 (9.8%) carried an expansion in either RFC1 or FGF14, comparable to 4/45 (8.9%) among the patients with a positive family history. Conclusions: Pathogenic repeat expansions in RFC1 and FGF14 are relatively frequent causes of adult-onset cerebellar ataxia, especially among sporadic patients, indicating that family history should not be considered when prioritizing ataxia patients for testing of RFC1 or FGF14 repeat expansions. © 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.