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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.
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Proteína C9orf72 , Demencia Frontotemporal , Progranulinas , Proteínas tau , Humanos , Proteínas tau/genética , Proteína C9orf72/genética , Progranulinas/genética , Femenino , Masculino , Anciano , Demencia Frontotemporal/genética , Persona de Mediana Edad , Serbia/epidemiología , Expansión de las Repeticiones de ADN/genética , Disfunción Cognitiva/genética , Disfunción Cognitiva/epidemiología , Enfermedad de Alzheimer/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Anciano de 80 o más AñosRESUMEN
Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with a high genetic and clinical heterogeneity. Numerous HSP patients remain genetically undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel variants and genes is needed. Our previous study analyzed 74 adult Serbian HSP patients from 65 families using panel of the 13 most common HSP genes in combination with a copy number variation analysis. Conclusive genetic findings were established in 23 patients from 19 families (29%). In the present study, nine patients from nine families previously negative on the HSP gene panel were selected for the whole exome sequencing (WES). Further, 44 newly diagnosed adult HSP patients from 44 families were sent to WES directly, since many studies showed WES may be used as the first step in HSP diagnosis. WES analysis of cohort 1 revealed a likely genetic cause in five (56%) of nine HSP families, including variants in the ETHE1, ZFYVE26, RNF170, CAPN1, and WASHC5 genes. In cohort 2, possible causative variants were found in seven (16%) of 44 patients (later updated to 27% when other diagnosis were excluded), comprising six different genes: SPAST, SPG11, WASCH5, KIF1A, KIF5A, and ABCD1. These results expand the genetic spectrum of HSP patients in Serbia and the region with implications for molecular genetic diagnosis and future causative therapies. Wide HSP panel can be the first step in diagnosis, alongside with the copy number variation (CNV) analysis, while WES should be performed after.
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Secuenciación del Exoma , Paraplejía Espástica Hereditaria , Humanos , Paraplejía Espástica Hereditaria/genética , Masculino , Serbia , Femenino , Secuenciación del Exoma/métodos , Adulto , Persona de Mediana Edad , Variaciones en el Número de Copia de ADN , Linaje , Adulto Joven , Mutación , Estudios de CohortesRESUMEN
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.
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Ataxia Cerebelosa , Factores de Crecimiento de Fibroblastos , Proteína de Replicación C , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ataxia Cerebelosa/genética , Expansión de las Repeticiones de ADN/genética , Factores de Crecimiento de Fibroblastos/genética , Proteína de Replicación C/genética , SerbiaRESUMEN
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.
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Anoctaminas , Ataxias Espinocerebelosas , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Edad de Inicio , Anoctaminas/genética , Estudios de Asociación Genética , Ataxias Espinocerebelosas/genética , AncianoRESUMEN
BACKGROUND: Clinical-related risk factors to freezing of gait (FOG) in Parkinson's disease (PD) have been identified. Still, the influence of genetic variations on the FOG occurrence has been poorly studied thus far. AIM: We aimed to evaluate the association of six selected polymorphisms of DRD2, ANKK1, and COMT genes with the FOG occurrence and explore the influence of ANNK1/DRD2 haplotypes on the onset of FOG in the group of PD patients. METHOD: 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. FOG was evaluated by posing a direct question. In addition, a comprehensive set of clinical scales was applied to all patients. RESULTS: FOG occurred in 132 (56.4%) PD patients in our cohort. Freezers were younger at PD onset, had longer disease duration, used higher levodopa daily doses and dopaminergic agents, and had higher motor and non-motor scales scores than non-freezers. FOG was more frequent among AA rs4680 COMT carriers than AG and GG rs4680 COMT carriers. Independent predictors of FOG were: disease duration of more than ten years, levodopa daily dose higher than 500 mg/day, motor status, and COMT AA genotype. AGGAA and GGAAA haplotypes were revealed as protective and vulnerability factors for FOG occurrence. CONCLUSION: In addition to previously identified disease- and therapy-related risk factors, our results suggested a possible contribution of dopamine-related genes to the FOG occurrence.
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Catecol O-Metiltransferasa , Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Antiparkinsonianos/uso terapéutico , Catecol O-Metiltransferasa/genética , Marcha/genética , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/genética , Humanos , Levodopa/uso terapéutico , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores de Dopamina D2/genéticaRESUMEN
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.
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Enfermedad de Niemann-Pick Tipo C , Variación Biológica Poblacional , Diagnóstico Tardío , Humanos , Mutación/genética , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Enfermedad de Niemann-Pick Tipo C/genética , Fenotipo , Serbia/epidemiologíaRESUMEN
Mitochondrial encephalomyopathies (MEMP) are heterogeneous multisystem disorders frequently associated with mitochondrial DNA (mtDNA) mutations. Clinical presentation varies considerably in age of onset, course, and severity up to death in early childhood. In this study, we performed molecular genetic analysis for mtDNA pathogenic mutation detection in Serbian children, preliminary diagnosed clinically, biochemically and by brain imaging for mitochondrial encephalomyopathies disorders. Sanger sequencing analysis in three Serbian probands revealed two known pathogenic mutations. Two probands had a heteroplasmic point mutation m.3243A>G in the MT-TL1 gene, which confirmed mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome (MELAS), while a single case clinically manifested for Leigh syndrome had an almost homoplasmic (close to 100%) m.8993T>G mutation in the MT-ATP6 gene. After full mtDNA MITOMASTER analysis and PhyloTree build 17, we report MELAS' association with haplogroups U and H (U2e and H15 subclades); likewise, the mtDNA-associated Leigh syndrome proband shows a preference for haplogroup H (H34 subclade). Based on clinical-genetic correlation, we suggest that haplogroup H may contribute to the mitochondrial encephalomyopathies' phenotypic variability of the patients in our study. We conclude that genetic studies for the distinctive mitochondrial encephalomyopathies should be well-considered for realizing clinical severity and possible outcomes.
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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 (nâ=â234), 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≥900âmg, Unified Parkinson's Disease Rating Scale III part score, the Hamilton Depression Rating Scale score≥7, the Hamilton Anxiety Rating Scale score >â14,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.
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Enfermedad de Parkinson , Trastornos Psicóticos , Predisposición Genética a la Enfermedad , Humanos , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Polimorfismo Genético , Proteínas Serina-Treonina Quinasas/genética , Trastornos Psicóticos/genéticaRESUMEN
Rapid and efficient diagnostics is crucial for newborns with congenital heart defects (CHD) in intensive care unit (ICU) but is often challenging. Given that genetic factors play a role in 20-30% cases of CHD, it is likely that genetic tests could improve both its speed and efficiency. We aimed to analyze the utility of rapid and cost-effective multiplex ligation dependent probe amplification analysis (MLPA) for chromosomal analysis in newborns with critical CHD. One hundred consecutive newborns admitted with critical CHD to the ICU were included in the study. Those with normal MLPA findings were further tested by chromosomal microarray and clinical exome sequencing. Overall, pathogenic/likely pathogenic variants were determined in ten (10%) newborns by MLPA, three (3%) by chromosomal microarray, and three (3%) by clinical exome sequencing. The most common variant detected was deletion of 22q11.2 region.Conclusion: MLPA is fast and cost-effective analysis that could be used as the first-tier test in newborns with critical CHD admitted to the ICU. What is Known: ⢠MLPA is an established method for chromosome analysis in patients with CHD, but detection rate in newborns with critical CHD is unknown. What is New: ⢠Study suggests that detection rate of casual variants using MLPA in newborns with critical CHD is 10%.
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Cardiopatías Congénitas , Pruebas Genéticas , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Humanos , Recién Nacido , Unidades de Cuidados Intensivos , Análisis por Micromatrices , Reacción en Cadena de la Polimerasa MultiplexRESUMEN
Introduction: Although one of the most common monogenic late-onset neurodegenerative disorders, fragile-X-associated tremor/ataxia syndrome (FXTAS) is still underdiagnosed. The aim of the present study was to estimate the frequency of premutation carriers in patients with unexplained degenerative ataxias, action tremor or parkinsonism, and action tremor with or without associated cognitive impairment.Methods: The study comprised 100 consecutive patients with the disease onset >49 years who had any form of unexplained action tremor, cerebellar ataxia, followed by parkinsonism with or without incipient dementia, and in whom the FMR1 repeats size was determined.Results: Premutation in the FMR1 was identified in two patients (2%): the first, male patient had 83 CGG repeats and the second, female patient had 32 and 58 CGG repeats.Discussion/Conclusion: FXTAS was relatively rare among older patients with unexplained ataxia and action tremor, with or without parkinsonism and/or cognitive impairment. Tremor and ataxia were major clinical features in our two patients, although parkinsonism, autonomic dysfunction and psychiatric problems might be an important part of the spectrum. Probable FXTAS should be considered in the differential diagnosis of patients with unexplained action tremor and ataxia, and undetermined parkinsonism, especially when there was a positive family history for involuntary movement disorders in other family members and/or autism spectrum disorders in younger cousins.
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Ataxia/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Mutación/genética , Trastornos Parkinsonianos/genética , Temblor/genética , Anciano , Anciano de 80 o más Años , Ataxia/diagnóstico , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Diagnóstico Diferencial , Femenino , Síndrome del Cromosoma X Frágil/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico , Serbia/epidemiología , Temblor/diagnósticoRESUMEN
Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder that affects central vision in young adults and is typically associated with mitochondrial DNA (mtDNA) mutations. This study is based on a mutational screening of entire mtDNA in eight Serbian probands clinically and genetically diagnosed with LHON and four of their family members, who are asymptomatic mutation carriers. All obtained sequence variants were compared to human mtDNA databases, and their potential pathogenic characteristics were assessed by bioinformatics tools. Mitochondrial haplogroup analysis was performed by MITOMASTER. Our study revealed two well-known primary LHON mutations, m.11778G>A and m.3460G>A, and one rare LHON mutation, m.8836A>G. Various secondary mutations were detected in association with the primary mutations. MITOMASTER analysis showed that the two well-known primary mutations belong to the R haplogroup, while the rare LHON m.8836A>G was detected within the N1b haplogroup. Our results support the need for further studies of genetic background and its role in the penetrance and severity of LHON.
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Genoma Mitocondrial/genética , Mitocondrias/genética , Atrofia Óptica Hereditaria de Leber/genética , Adolescente , Adulto , Niño , Preescolar , Biología Computacional/métodos , ADN Mitocondrial/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Penetrancia , Adulto JovenRESUMEN
INTRODUCTION: Hereditary neuropathy with liability to pressure palsies (HNPP) is a rare neuromuscular disorder, mostly caused by PMP22 deletion. AIM: To determine a yield of the genetic analysis of PMP22 gene deletion in patients with compression neuropathies. METHOD: We included 112 patients with clinical suspicion of HNPP diagnosis. Nerve conduction studies (NCS) were performed for motor and sensory nerves bilaterally. Number of the PMP22 gene copies was determined using a real-time polymerase chain reaction (RT-PCR). RESULTS: PMP22 deletion was found in 34 (30.3%) patients. Patients with genetically confirmed HNPP had 12 years earlier disease onset compared to other patients with compression neuropathies (p < 0.01), more nerves affected during lifespan (5.5 ± 3.5 vs. 3.0 ± 2.0, p < 0.01) and at the time of referral (2.7 ± 2.5 vs. 2.0 ± 1.9, p < 0.05). HNPP patients had positive family history more frequently (p < 0.01). Foot deformities (pes cavus and hammertoe), symmetric muscle atrophy in lower legs and absent muscle reflexes in lower limbs were more common in HNPP patients. NCS abnormalities were also more common in HNPP group. Multiple linear regression analysis identified positive family history (ß = + 0.35, p < 0.01) and decreased sensory conduction velocity in at least three sensory nerves (ß = + 0.40, p < 0.01) as independent predictors of the PMP22 deletion. CONCLUSION: Among patients with compression neuropathies, those with a positive family history, earlier symptom onset and NCS abnormalities had a higher chance to have PMP22 deletion.
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Artrogriposis , Enfermedad de Charcot-Marie-Tooth , Neuropatía Hereditaria Motora y Sensorial , Síndromes de Compresión Nerviosa , Artrogriposis/genética , Enfermedad de Charcot-Marie-Tooth/genética , Eliminación de Gen , Neuropatía Hereditaria Motora y Sensorial/genética , Humanos , Proteínas de la Mielina/genéticaRESUMEN
BACKGROUND: Only several studies analyzed the characteristics of neuropathic pain (NeP) more extensively in patients with Charcot-Marie-Tooth type 1A (CMT1A). Therefore, we sought to determine the frequency and features of NeP in CMT1A patients and to assess the association between NeP and sociodemographic and clinical characteristics of patients with CMT1A. METHODS: Our research included 51 genetically diagnosed CMT1A patients. The International Association for the Study of Pain (IASP) criteria were used for diagnosis of NeP. PainDETECT questionnaire (PD-Q) was used to assess NeP features. The Medical Research Council (MRC) Sum Score, CMT Neuropathy Score (CMTNS), Overall Neuropathy Limitation Scale (ONLS) score, and Beck Depression Inventory were also used. RESULTS: NeP was present in 15 (29.4%) patients with CMT1A. The average intensity of pain was 5.7 ± 2.2 out of 10. The most sensitive neuropathic symptoms were numbness, then tingling, and burning sensations, while the most specific symptom was allodynia. Patients with NeP more frequently reported pain in the back (p < 0.01) and the trunk (p < 0.05). Patients with NeP had more pronounced disability of the upper extremities and overall disability, as assessed by the ONLS score (p < 0.05). Depression was more frequent in patients with NeP compared with patients without NeP (66.7 to 13.9%, p < 0.01). CONCLUSION: NeP was present in almost one-third of the patients with CMT1A and it was moderate on average. Presence of NeP was associated with worse functional disability and depression.
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Enfermedad de Charcot-Marie-Tooth , Depresión , Neuralgia , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Enfermedad de Charcot-Marie-Tooth/psicología , Depresión/etiología , Depresión/fisiopatología , Personas con Discapacidad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neuralgia/etiología , Neuralgia/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
Limb-girdle muscular dystrophy (LGMD) type 2A (calpainopathy) is an autosomal recessive disease caused by mutation in the CAPN3 gene. The aim of this study was to examine genetic and phenotypic features of Serbian patients with calpainopathy. The study comprised 19 patients with genetically confirmed calpainopathy diagnosed at the Neurology Clinic, Clinical Center of Serbia and the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia during a ten-year period. Eighteen patients in this cohort had c.550delA mutation, with nine of them being homozygous. In majority of the patients, disease started in childhood or early adulthood. The disease affected shoulder girdle - upper arm and pelvic girdle - thigh muscles with similar frequency, with muscles of lower extremities being more severely impaired. Facial and bulbar muscles were spared. All patients in this cohort, except two, remained ambulant. None of the patients had cardiomyopathy, while 21% showed mild conduction defects. Respiratory function was mildly impaired in 21% of patients. Standard muscle histopathology showed myopathic and dystrophic pattern. In conclusion, the majority of Serbian LGMD2A patients have the same mutation and similar phenotype.
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Calpaína/genética , Proteínas Musculares/genética , Distrofia Muscular de Cinturas/genética , Adolescente , Adulto , Edad de Inicio , Alelos , Biopsia , Niño , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Distrofia Muscular de Cinturas/diagnóstico por imagen , Distrofia Muscular de Cinturas/epidemiología , Distrofia Muscular de Cinturas/fisiopatología , Mutación , Fenotipo , Serbia/epidemiologíaRESUMEN
BACKGROUND: Myotonic dystrophy type 2 (DM2) is a multisystem disorder, mostly presented with mild but heterogeneous spectrum of symptoms. OBJECTIVE: The aim of this research was to provide detailed sociodemographic, clinical and laboratory data of a large DM2 cohort from the Serbian registry. METHODS: In 2008, we started to prospectively enter data of all DM patients. We also retrospectively collected data of patients hospitalized from 1990 until 2008. RESULTS: At the end of 2017, registry comprised 87 (68%) of 128 genetically confirmed DM2 patients in Serbia, i.e. 1.2 registered cases per 100,000 inhabitants. Female subjects were more prevalent (63%). The diagnostic delay was 11.8±11.3 years. The most common first symptoms in our patients were lower limb weakness, handgrip myotonia and limb pain, although some percentage of patients presented with cataracts or extrapyramidal symptoms and signs. Lens opacities were present in 75% of patients. Severe ECG abnormalities were noted in 8% and pacemaker was implanted in 5% of DM2 subjects. Pulmonary restriction was observed in 10% of DM2 patients. Insulin resistance and diabetes mellitus were frequent in our cohort (21% and 17%, respectively). Male subjects more frequently had snoring, baldness, sterility, polyneuropathy, lower HDL and higher glycaemia, while waddling gait and increased muscle reflexes were more common in females. CONCLUSIONS: This registry offers a spectrum of different features presented in Serbian DM2 population, which could be at service of earlier diagnosis and better treatment.
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Distrofia Miotónica/epidemiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distrofia Miotónica/fisiopatología , Prevalencia , Sistema de Registros , Serbia/epidemiologíaRESUMEN
PURPOSE: Renal cell carcinoma (RCC) is the most common renal cancer in adults and includes several subtypes that may be distinguished by their histology, genetic background, clinical course and responses to treatment. Human telomerase reverse transcriptase (hTERT), a crucial enzyme for telomere maintenance, has been linked to RCC development. The purpose of this study was to search for genetic and epigenetic alterations in hTERT (promoter mutations and methylation and gene amplification), and to establish a possible association between molecular and clinico-pathological characteristics of RCC. METHODS: DNA was extracted from 31 formalin-fixed, paraffin-embedded tumor samples and 23 blood samples from 54 patients with RCC. Polymerase chain reaction (PCR) products were sequenced and analyzed using the Sequencher software. HTERT amplification was determined by quantitative PCR, while the promoter methylation status was assessed by methylation specific PCR. Statistical analysis was performed using SPSS. RESULTS: No mutations could be detected in the hTERT promoter but only a single nucleotide polymorphism (SNP) (-245 T>C). In 54 analyzed RCC cases, the variant allele C was present in homozygous or heterozygous form in 48% of the patients. The C allele was significantly more frequent in low grade tumors (p=0.046). Gene amplification was detected in 19.4% of the 31 RCCs and hTERT methylation in 54.8% of the 31 samples. An association was established between methylation and histological type of RCC (p=0.047). CONCLUSIONS: HTERT seems to be implicated in RCC pathogenesis since the promoter polymorphism exerts a modulation effect on tumor behavior. In addition, hTERT promoter methylation status is related to RCC histology.
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Biomarcadores de Tumor/genética , Carcinoma de Células Renales/patología , Metilación de ADN , Neoplasias Renales/patología , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Telomerasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/epidemiología , Neoplasias Renales/genética , Masculino , Persona de Mediana Edad , Mutación , Prevalencia , Pronóstico , Estudios Retrospectivos , SerbiaRESUMEN
Safe and successful bioapplications of metallic nanoparticles depend on their physicochemical characteristics, in particular their surface properties. This study aimed to investigate how different surface functionalization of silver nanoparticles (AgNP) affect their interaction with mammalian liver cells with regard to cytotoxicity, genotoxicity and mechanism of cellular uptake. Differentially coated AgNP were prepared by surface functionalization using sodium bis(2-ethylhexyl)-sulfosuccinate (AOTAgNP), cetyltrimethylammonium bromide (CTABAgNP), poly(vinylpyrrolidone) (PVPAgNP), poly-l-lysine (PLLAgNP), and bovine serum albumin (BSAAgNP). Data showed varying toxic potential of differentially coated AgNP. All AgNP types demonstrated concentration dependent effects on cytotoxicity and genotoxicity in HepG2 cells. Cytotoxic potential of differentially coated AgNP followed the order of BSAAgNP > PLLAgNP > CTABAgNP > AOTAgNP > PVPAgNP. Exposure of HepG2 cells to non-cytotoxic concentrations (up to 10 mg Ag/L) of AgNP for 24 h induced primary DNA damage as evaluated by alkaline comet assay. The highest increase in both comet tail length and tail intensity was produced by PLLAgNP followed by AOTAgNP, while CTABAgNP appeared to be least damaging. The main uptake mechanisms of AgNP were macropinocytosis and clathrin-mediated endocytosis. The study findings contribute to the criteria that should be considered in evaluating the biocompatibility and safety of novel nanomaterials.
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Nanopartículas del Metal/toxicidad , Plata/metabolismo , Ensayo Cometa , Daño del ADN/efectos de los fármacos , Endocitosis , Células Hep G2 , Humanos , Nanopartículas del Metal/química , Tamaño de la Partícula , Plata/química , Plata/toxicidad , Propiedades de SuperficieRESUMEN
This study evaluated the cyto- and genotoxic effects of three pesticides: α-cypermethrin, chlorpyrifos and imidacloprid applied in vitro to human lymphocytes and HepG2 cells for exposure times of 4 and 24 h at concentrations corresponding to OEL, ADI and REL. Assessments were made using oxidative stress biomarkers and the alkaline comet, cytokinesis-block micronucleus cytome and cell viability assays. Low doses of all three pesticides displayed DNA damaging potential, both in lymphocytes and HepG2 cells. At the tested concentrations, all three compounds induced lymphocyte apoptosis, though α-cypermethrin and chlorpyrifos were generally more cyto- and genotoxic than imidacloprid. At the tested concentrations, oxidative stress biomarkers were not significantly altered, and the effects mediated indirectly through free radicals may not have a key role in the formation of DNA damage. It is likely that the DNA damaging effects were caused by direct interactions between the tested compounds and/or their metabolites that destabilized the DNA structure. The tested pesticides had the potential for MN, NB and NPB formation and to disturb cell cycle kinetics in both cell types. There were also indications that exposure to α-cypermethrin led to the formation of crosslinks in DNA, though this would require more detailed study in the future.