Browsing by Author "Novakovic, Ivana (6603235567)"

Brain-derived neurotrophic factor (BDNF) modulates neuroplasticity. A functional polymorphism [Val66Met (G196A)] in BDNF has been reported to modify cortical plasticity in humans. Physiologic investigations have revealed that dystonia might be a consequence of the pathologic plasticity of the sensorimotor cortex. We aimed to investigate the role of the Val66Met polymorphism in a cohort of Serbian patients with adult-onset primary focal and segmental dystonia (PTD). One hundred and forty-nine patients with primary adult-onset PTD, 194 patients with Parkinson's disease (PD), and 366 healthy control subjects were recruited for the study. Patients with PTD and PD, as well as healthy controls had a similar distribution of genotypes and allele frequencies. There was no any significant difference in the allelic distribution at the Val66Met SNP of the BDNF gene among patients with adult-onset PTD, PD, and healthy volunteers from the same geographic areas. In addition, the presence of the Met allele did not influence the clinical characteristics of PTD patients. Patients with the Met variant did not differ by age at onset, number of affected regions, and efficacy of a sensory trick. Met66Met is not associated with an increased risk of dystonia. © 2013 Belgian Neurological Society.

Parkinson’s disease (PD) guidelines lack clear criteria for genetic evaluation. We assessed the yield and rationale of genetic testing for PD in a routine clinical setting on a multicenter cohort of 149 early-onset and familial patients by exome sequencing and semi-quantitative multiplex ligation-dependent probe amplification of evidence-based PD-associated gene panel. We show that genetic testing for PD should be considered for both early-onset and familial patients alike, and a clinical yield of about 10% in the Caucasian population can be expected. © 2022, The Author(s).

Parkinson’s disease (PD) guidelines lack clear criteria for genetic evaluation. We assessed the yield and rationale of genetic testing for PD in a routine clinical setting on a multicenter cohort of 149 early-onset and familial patients by exome sequencing and semi-quantitative multiplex ligation-dependent probe amplification of evidence-based PD-associated gene panel. We show that genetic testing for PD should be considered for both early-onset and familial patients alike, and a clinical yield of about 10% in the Caucasian population can be expected. © 2022, The Author(s).

Background Hypo/anechogenicity of the brainstem raphe (BR) structures has been suggested as a possible transcranial parenchymal sonography (TCS) marker associated with depression. Aim The aim of this study was to analyze possible association of the abnormal BR echogenicity in patients with major depression when compared to healthy controls, and to evaluate its clinical and genetic correlates. Methods TCS was performed in 53 patients diagnosed as major depressive disorder (MDD) without psychotic symptoms and in 54 healthy matched controls. Results: The TCS detected BR abnormalities were significantly more frequent in MDD patients (35 out of 53; 66%) in comparison to matched controls (5 out of 56; 9%). The prevalence of short allele (s) homozygocity in the length polymorphism of the promoter region of the serotonin transporter gene (5-HTTLPR) was significantly higher in MDD patients relative to those with normal BR echogenicity. A stepwise statistical discriminant analysis revealed statistically significant separation between MDD patients with and without BR abnormalities groups based on the four predictors combined: the Hamilton Anxiety Rating Scale item 5 („difficulty in concentration, poor memory“), presence of social phobia, s allele homozygocity of the 5-HTTLPR polymorphism, and presence of generalized anxiety disorder. Limitations Cross-sectional design and heterogenous treatment of depressed patients. Conclusions Reduced BR echogenicity in at least a subgroup of MDD patients may reflect a particular phenotype, characterized by more prevalent comorbid anxiety disorders, associated with particular genetic polymorphisms and neurotransmitter(s) deficits, most probably altered serotonergic mechanisms. © 2016 Elsevier B.V.

Background Hypo/anechogenicity of the brainstem raphe (BR) structures has been suggested as a possible transcranial parenchymal sonography (TCS) marker associated with depression. Aim The aim of this study was to analyze possible association of the abnormal BR echogenicity in patients with major depression when compared to healthy controls, and to evaluate its clinical and genetic correlates. Methods TCS was performed in 53 patients diagnosed as major depressive disorder (MDD) without psychotic symptoms and in 54 healthy matched controls. Results: The TCS detected BR abnormalities were significantly more frequent in MDD patients (35 out of 53; 66%) in comparison to matched controls (5 out of 56; 9%). The prevalence of short allele (s) homozygocity in the length polymorphism of the promoter region of the serotonin transporter gene (5-HTTLPR) was significantly higher in MDD patients relative to those with normal BR echogenicity. A stepwise statistical discriminant analysis revealed statistically significant separation between MDD patients with and without BR abnormalities groups based on the four predictors combined: the Hamilton Anxiety Rating Scale item 5 („difficulty in concentration, poor memory“), presence of social phobia, s allele homozygocity of the 5-HTTLPR polymorphism, and presence of generalized anxiety disorder. Limitations Cross-sectional design and heterogenous treatment of depressed patients. Conclusions Reduced BR echogenicity in at least a subgroup of MDD patients may reflect a particular phenotype, characterized by more prevalent comorbid anxiety disorders, associated with particular genetic polymorphisms and neurotransmitter(s) deficits, most probably altered serotonergic mechanisms. © 2016 Elsevier B.V.

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease caused by conformational alteration of the ubiquitous prion protein. Sporadic CJD appears to progress faster if the basal ganglia are shown to be affected on magnetic resonance imaging. Transcranial B-mode sonography (TCS) enables visualization of differences in tissue echogenicity, which can be associated with changes in the cerebral metabolism of various metals. These metabolic changes are considered 1 of the potential mechanisms of the brain damage in CJD; TCS hyperechogenicity may reflect changes in metal homeostasis in CJD. We report a 63-year-old woman who presented with typical sporadic CJD. One month after she fell ill, a magnetic resonance imaging scan of her brain showed diffuse cortical but no obvious basal ganglia involvement. However, TCS revealed moderate hyperechogenicity of both lentiform nuclei. The patient's disease progressed quickly and she died 2 months later. TCS may show basal ganglia alteration early in the disease course of patients with quickly progressing CJD, thus aiding in premortem diagnosis. © 2014 by Lippincott Williams and Wilkins.

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease caused by conformational alteration of the ubiquitous prion protein. Sporadic CJD appears to progress faster if the basal ganglia are shown to be affected on magnetic resonance imaging. Transcranial B-mode sonography (TCS) enables visualization of differences in tissue echogenicity, which can be associated with changes in the cerebral metabolism of various metals. These metabolic changes are considered 1 of the potential mechanisms of the brain damage in CJD; TCS hyperechogenicity may reflect changes in metal homeostasis in CJD. We report a 63-year-old woman who presented with typical sporadic CJD. One month after she fell ill, a magnetic resonance imaging scan of her brain showed diffuse cortical but no obvious basal ganglia involvement. However, TCS revealed moderate hyperechogenicity of both lentiform nuclei. The patient's disease progressed quickly and she died 2 months later. TCS may show basal ganglia alteration early in the disease course of patients with quickly progressing CJD, thus aiding in premortem diagnosis. © 2014 by Lippincott Williams and Wilkins.

Purpose: Treatment of Ischemic stroke (IS) in acute phase is based on the use of thrombolytic rt-PA therapy. We aimed to determine whether different alleles and genotypes of I/D ACE gene and 4G/5G PAI-1 gene polymorphisms may influence outcome of rt-PA therapy in patients with IS and the occurrence of haemorrhagic transformation (HT). Methods: Our study included 94 consecutive patients with IS treated with rt-PA. Modified Rankin Scale (mRS) at 3rd month after IS was used to determine the stroke outcome, with scores 0-1 defining the favourable outcome, and scores 2-6 defining poor outcome. Genotypisation of the ACE-1 I/D polymorphism was performed by polymerase chain reaction and of the PAI-1 4G/5G polymorphism by polymerase chain reaction - restriction fragment length analysis. Results: Regarding PAI-I 4G/5G polymorphism, 44 patients (46.8%) were heterozygotes, and the number of 4G/4G and 5G/5G homozygotes was the same – 25 each (26.6%). Number of heterozygotes for the ACE I/D polymorphism was 54 (57.4%), 9 patients (9.6%) had II, and 31 (33%) DD genotypes. A favourable outcome was recorded in 26 (28.0%) and the poor outcome in 67 (72.0%) patients. Favourable and poor outcome groups did not differ significantly in PAI-1 4G/5G and ACE I/D polymorphisms genotype or allele frequencies. There was a statistically significant difference in the occurrence of HT between patients with ACE II and patients with ACE ID or DD genotypes (p=0.035). Conclusion: Results of our study suggest that stroke patients with ACE II genotype, treated with rt-PA, may be at risk of HT. © 2019, MDPI AG. All rights reserved.

Methylenetetrahydrofolate reductase (MTHFR) regulates the metabolism of folate and methionine, essential components of DNA synthesis and methylation. Polymorphisms in the MTHFR gene have been associated with susceptibility to some types of cancer. We investigated a possible association of MTHFR polymorphisms (677C>T and 1298A>C) and increased risk for acute lymphoblastic leukemia in 78 affected children. The frequencies of both MTHFR 677 genotypes and alleles were significantly different between patients and controls. A significant association between CT/TT individuals and reduced risk of acute lymphoblastic leukemia was found. The odds ratios were 0.53 (95% confidence interval, 032-0.89) and 0.30 (95% confidence interval, 0.12-0.81). Polymorphism 1298 did not show statistical difference between patients and controls. © 2010 Lippincott Williams & Wilkins, Inc.

Objectives: Identifying genetic predictors of methotrexate (MTX) treatment response in patients with rheumatoid arthritis (RA) may have great importance for optimising drug doses required for clinical benefit without toxicity. In a group of 125 RA patients treated with MTX we investigated whether selected polymorphisms in genes relevant for MTX action (aminoimidazole-4-carboxiamide ribonucleotide transformylase, ATIC, and dihydrofolate reductase, DHFR) modulate disease activity and/or have impact on therapy side effects. Methods: The efficacy of treatment was estimated both by the disease activity score in 28 joints (DAS28), based on EULAR criteria, and relative DAS28 (rDAS28) score. Adverse drug events (ADEs) were also recorded. RA patients were genotyped using the PCR-RFLP method, followed by an association study between ATIC -129T>G, DHFR -216T>C and DHFR -317A>G polymorphisms and the efficacy and toxicity of MTX. Results: According to the EULAR response criteria, 96 RA patients (76.8%) were classified as responders (good/moderate response) and 29 (23.2%) as non-responders (poor response). rDAS28 values ranged from -0.01 to 0.80 (mean value 0.31±0.19). Among 125 patients enrolled in this study 39 experienced at least one side effect. The DHFR -317AA genotype was associated with the less favourable response (reduction in rDAS28 score, p=0.05). None of the analysed polymorphisms was associated with MTX toxicity. Conclusion: RA patients with DHFR-317AA genotype had less favourable response to MTX Further studies in larger patient populations are necessary to confirm the relationship between the analysed polymorphisms and MTX treatment response. © Clinical and Experimental Rheumatology 2012.

Objectives: Identifying genetic predictors of methotrexate (MTX) treatment response in patients with rheumatoid arthritis (RA) may have great importance for optimising drug doses required for clinical benefit without toxicity. In a group of 125 RA patients treated with MTX we investigated whether selected polymorphisms in genes relevant for MTX action (aminoimidazole-4-carboxiamide ribonucleotide transformylase, ATIC, and dihydrofolate reductase, DHFR) modulate disease activity and/or have impact on therapy side effects. Methods: The efficacy of treatment was estimated both by the disease activity score in 28 joints (DAS28), based on EULAR criteria, and relative DAS28 (rDAS28) score. Adverse drug events (ADEs) were also recorded. RA patients were genotyped using the PCR-RFLP method, followed by an association study between ATIC -129T>G, DHFR -216T>C and DHFR -317A>G polymorphisms and the efficacy and toxicity of MTX. Results: According to the EULAR response criteria, 96 RA patients (76.8%) were classified as responders (good/moderate response) and 29 (23.2%) as non-responders (poor response). rDAS28 values ranged from -0.01 to 0.80 (mean value 0.31±0.19). Among 125 patients enrolled in this study 39 experienced at least one side effect. The DHFR -317AA genotype was associated with the less favourable response (reduction in rDAS28 score, p=0.05). None of the analysed polymorphisms was associated with MTX toxicity. Conclusion: RA patients with DHFR-317AA genotype had less favourable response to MTX Further studies in larger patient populations are necessary to confirm the relationship between the analysed polymorphisms and MTX treatment response. © Clinical and Experimental Rheumatology 2012.

Purpose: Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). Methods: The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. Results: According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed. Conclusion: The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients. © 2012 Springer-Verlag.

Purpose: Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). Methods: The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. Results: According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed. Conclusion: The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients. © 2012 Springer-Verlag.

Objectives: The presence of cardiovascular risk factors in children may be important in the development of atherosclerosis in adulthood. Adequate control of blood pressure is a cornerstone in atherosclerosis prevention. The aim of the Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD) was to identify risk factors for elevated blood pressure in school children. Methods: The YUSAD study is a multicentre follow-up study comprised of two cross-sectional surveys conducted five years apart. At baseline, 10-year-old children (3226 boys and 3074 girls [n=6300]) were randomly selected during periodical visits to primary health care centres. The risk factors measured were heart rate, weight, body mass index (BMI), waist-to-hip ratio, grade point average and current smoking status. Results: Significant age and sex differences were identified in systolic blood pressure, diastolic blood pressure and all investigated independent variables. In a multivariate analysis, diastolic blood pressure in 10-year-old boys was directly and significantly related to total cholesterol and height, whereas it was inversely related to weight. At follow-up, in the multivariate model, only BMI was a significant predictor of diastolic blood pressure in boys. In girls at baseline in the multivariate regression analysis, the only significant predictor of diastolic blood pressure was total cholesterol. In 15-year-old girls, diastolic blood pressure was significantly and directly related to BMI and heart rate, whereas it was inversely related to weight. For both 10- and 15-year-old male and female participants, none of the variables by multivariate analysis were a significant predictor of systolic blood pressure. Conclusions: Age, sex, heart rate, cholesterol and weight are the most important predictors of blood pressure in school children. © 2006 Pulsus Group Inc. All rights reserved.

Objectives: The presence of cardiovascular risk factors in children may be important in the development of atherosclerosis in adulthood. Adequate control of blood pressure is a cornerstone in atherosclerosis prevention. The aim of the Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD) was to identify risk factors for elevated blood pressure in school children. Methods: The YUSAD study is a multicentre follow-up study comprised of two cross-sectional surveys conducted five years apart. At baseline, 10-year-old children (3226 boys and 3074 girls [n=6300]) were randomly selected during periodical visits to primary health care centres. The risk factors measured were heart rate, weight, body mass index (BMI), waist-to-hip ratio, grade point average and current smoking status. Results: Significant age and sex differences were identified in systolic blood pressure, diastolic blood pressure and all investigated independent variables. In a multivariate analysis, diastolic blood pressure in 10-year-old boys was directly and significantly related to total cholesterol and height, whereas it was inversely related to weight. At follow-up, in the multivariate model, only BMI was a significant predictor of diastolic blood pressure in boys. In girls at baseline in the multivariate regression analysis, the only significant predictor of diastolic blood pressure was total cholesterol. In 15-year-old girls, diastolic blood pressure was significantly and directly related to BMI and heart rate, whereas it was inversely related to weight. For both 10- and 15-year-old male and female participants, none of the variables by multivariate analysis were a significant predictor of systolic blood pressure. Conclusions: Age, sex, heart rate, cholesterol and weight are the most important predictors of blood pressure in school children. © 2006 Pulsus Group Inc. All rights reserved.

Background: Array-based genomic analysis is a gold standard for the detection of copy number variations (CNVs) as an important source of benign as well as pathogenic variations in humans. The introduction of chromosomal microarray (CMA) has led to a significant leap in diagnostics of genetically caused congenital malformations and neurodevelopmental disorders, with an average diagnostic yield of 15%. Here, we present our experience from a single laboratory perspective in four years’ postnatal clinical CMA application. Methods: DNA samples of 430 patients with congenital anomalies and/or neurodevelopmental disorders were analyzed by comparative genome hybridization using oligonucleotide-based microarray platforms. Interpretation of detected CNVs was performed according to current guidelines. The detection rate (DR) of clinically significant findings (pathogenic/likely pathogenic CNVs) was calculated for the whole cohort and isolated or combined phenotypic categories. Results: A total of 140 non-benign CNVs were detected in 113/430 patients (26.5%). In 70 patients at least one CNV was considered clinically significant thus reaching a diagnostic yield of 16.3%. The more complex the phenotype, including developmental delay/intellectual disability (DD/ID) as a prevailing feature, the higher the DR of clinically significant CNVs is obtained. Isolated congenital anomalies had the lowest, while the “dysmorphism plus” category had the highest diagnostic yield. Conclusion: In our study, CMA proved to be a very useful method in the diagnosis of genetically caused congenital anomalies and neurodevelopmental disorders. DD/ID and dysmorphism stand out as important phenotypic features that significantly increase the diagnostic yield of the analysis. © 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.

Background: Array-based genomic analysis is a gold standard for the detection of copy number variations (CNVs) as an important source of benign as well as pathogenic variations in humans. The introduction of chromosomal microarray (CMA) has led to a significant leap in diagnostics of genetically caused congenital malformations and neurodevelopmental disorders, with an average diagnostic yield of 15%. Here, we present our experience from a single laboratory perspective in four years’ postnatal clinical CMA application. Methods: DNA samples of 430 patients with congenital anomalies and/or neurodevelopmental disorders were analyzed by comparative genome hybridization using oligonucleotide-based microarray platforms. Interpretation of detected CNVs was performed according to current guidelines. The detection rate (DR) of clinically significant findings (pathogenic/likely pathogenic CNVs) was calculated for the whole cohort and isolated or combined phenotypic categories. Results: A total of 140 non-benign CNVs were detected in 113/430 patients (26.5%). In 70 patients at least one CNV was considered clinically significant thus reaching a diagnostic yield of 16.3%. The more complex the phenotype, including developmental delay/intellectual disability (DD/ID) as a prevailing feature, the higher the DR of clinically significant CNVs is obtained. Isolated congenital anomalies had the lowest, while the “dysmorphism plus” category had the highest diagnostic yield. Conclusion: In our study, CMA proved to be a very useful method in the diagnosis of genetically caused congenital anomalies and neurodevelopmental disorders. DD/ID and dysmorphism stand out as important phenotypic features that significantly increase the diagnostic yield of the analysis. © 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.

Purpose: The purpose of this study was to examine wheth er cytomegalovirus (CMV) is present in different histologi cal types of salivary gland cancer (SGC) by detecting CMV immediate-early (IE) and early gene products, and to deter mine the presence of its association with the overexpression of interleukin (IL)-6. Methods: Immunohistochemical analysis of 92 cases of dif ferent histological types of SGC was performed to determine the presence of IL-6 and CMV antigen and its intensity in tumor tissue. Twenty samples of normal salivary gland tis sue obtained during autopsy served as healthy controls. Results: CMV antigens were not found in healthy acinar tissue of salivary glands, but were expressed in epithelium of salivary gland ducts. Negative expression of CMV an tigens was also found in salivary gland tissue surround ing tumors. On the other hand, CMV was detected in 65/92 SGC cases (70.6%). Higher expression of IL-6 was found in SGC (70.7%) than in normal tissue (20%). There was a high association of CMV antigen presence with the presence of IL-6, and with the IL-6 expression intensity. Conclusions: Positive expression of CMV antigens in a high percentage of SGC cells suggests that it might play an important role in carcinogenesis by increasing IL-6 pro duction and leading to inhibition of apoptosis and tumor development.

Purpose: The purpose of this study was to examine wheth er cytomegalovirus (CMV) is present in different histologi cal types of salivary gland cancer (SGC) by detecting CMV immediate-early (IE) and early gene products, and to deter mine the presence of its association with the overexpression of interleukin (IL)-6. Methods: Immunohistochemical analysis of 92 cases of dif ferent histological types of SGC was performed to determine the presence of IL-6 and CMV antigen and its intensity in tumor tissue. Twenty samples of normal salivary gland tis sue obtained during autopsy served as healthy controls. Results: CMV antigens were not found in healthy acinar tissue of salivary glands, but were expressed in epithelium of salivary gland ducts. Negative expression of CMV an tigens was also found in salivary gland tissue surround ing tumors. On the other hand, CMV was detected in 65/92 SGC cases (70.6%). Higher expression of IL-6 was found in SGC (70.7%) than in normal tissue (20%). There was a high association of CMV antigen presence with the presence of IL-6, and with the IL-6 expression intensity. Conclusions: Positive expression of CMV antigens in a high percentage of SGC cells suggests that it might play an important role in carcinogenesis by increasing IL-6 pro duction and leading to inhibition of apoptosis and tumor development.

Aim: The aim of this study was to assess the prevalence of familial MS (fMS) in Belgrade MS population, discern the differences between the persons with fMS and sporadic MS, and to detect the presence of anticipation phenomenon in fMS patients. Methods: The data on the demographic and clinical characteristics of MS patients was obtained from the Belgrade MS population Registry. In cases of vertical transmission of MS, the family members were divided into the younger and older generation, in order to assess the potential presence of anticipation phenomenon. To adjust for follow-up time bias, a secondary analysis including only patients who had the onset of symptoms before 39 years (75.percentile), and those who were 39 + years, was performed. Results: The prevalence of fMS in Belgrade MS population is 6.4%. FMS cases had earlier age at MS symptom onset (30.4 vs. 32.3 years) compared to sporadic MS cohort. When comparing fMS cases across generations, the younger generation had significantly lower age at onset compared with the older one (25.8 vs. 35.7 years, p < 0.001). After adjustment for the different length of the follow-up, the difference in age at symptom onset between the groups was reduced, but it still existed and was statistically significant (30.0 years in younger vs. 36.4 years in older generation, p = 0.040). Conclusion: In our study, the analysis of fMS cases across generations, showed an earlier age of symptom onset in the younger generation, even after adjustment. These results indicate the possibility of existence of anticipation phenomenon. © Fondazione Società Italiana di Neurologia 2024.