Frequency of C9orf72, GRN, and MAPT pathogenic variants in patients recruited at the Belgrade Memory Center.

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.

Whole exome sequencing in Serbian patients with hereditary spastic paraplegia.

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.

ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series.

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.

Earlier age of symptom onset in younger generation of familial cases of multiple sclerosis.

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.

Physical activity and mental health of medical students.

OBJECTIVE: Medical students usually do not meet the recommendations on the minimum level of physical activity, despite knowing the impact that physical activity has on the prevention and treatment of various diseases. Medical students are considered to be insufficiently physically active. The aim of this study is to determine the prevalence of physically active fifth-year medical students at five universities in Serbia, as well as to identify factors associated with insufficient physical activity of students. METHODS: A cross-sectional study was performed in the population of fifth-year medical students from five different universities in Serbia. The research instrument was a questionnaire specially designed based on similar research. Descriptive and analytical statistics methods were used in statistical analysis. RESULTS: The study included a total of 573 fifth-year medical students from five universities in Serbia: 311 (54.3%) Belgrade; 86 (15.0%) Kragujevac; 58 (10.1%) Nis; 66 (11.5%) Kosovska Mitrovica; 52 (9.1%) Novi Sad. Insufficient physical activity was statistically significantly associated with studying at the University of Kosovska Mitrovica (OR = 3.98, 95% CI: 1.83-8.57). There was a statistically significant difference in the frequency of anti-anxiety medications use in the last 12 months between students with sufficient and insufficient physical activity (p = 0.040) as well as in the average number of cigarettes smoked per day between students with sufficient and those with insufficient physical activity (2.82 ± 6.35 vs. 4.50 ± 8.29, p = 0.043). There was also a statistically significant difference in the average score on the Beck's depression scale between students with sufficient and students with insufficient physical activity (6.51 ± 6.59 vs. 10.03 ± 9.37, p < 0.001) and in the average score on Zung's anxiety scale (34.86 ± 8.18 vs. 38.07 ± 8.71, p = 0.003). CONCLUSION: A high percentage of medical faculty students (86.6%) are physically active. Differences in the level of physical activity were observed between students of these five universities as well as between students with different levels of physical activity.

Galectin 3 rs4644 gene polymorphism is associated with metabolic traits in Serbian adolescent population.

Background: Among many genes which have been analyzed to understand obesity and related metabolic traits among children and adolescents, not many studies are conducted on LGALS3 gene, especially in population of children. A positive correlation of circulating galectin 3 serum levels with impaired blood glucose, high blood pressure and higher values of serum lipids and was found in general population. The aim was to investigate possible association of rs4644 with body mass index, glycaemia, and lipid profile in Serbian adolescents. Methods: The study included 72 boys and 79 girls, 14-15 years of age. Among boys 51 (67.1%) had normal values of BMI, 11 (14.5%) were overweight, and 14 (18.4%) were obese. Among girls, 53 (63.9%) had normal BMI, 16 (19.3%) were overweight, and 14 (16.9%) were obese. Diabetes type 1 or 2, genetic syndromes, generalized inflammation, cardiovascular and malignant diseases were criteria for exclusion. Genotyping was performed by Real time PCR.

Exclusive breastfeeding may be a protective factor in individuals with familial multiple sclerosis. A population registry-based case-control study.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease that affects the central nervous system, which most likely results from the interplay between environmental and genetic factors. The aim of our study was to assess the effect of breastfeeding on the risk of developing familial multiple sclerosis (fMS) in persons with positive MS history, being the first such investigation performed in fMS cohort. METHODS: A case-control study based on the Belgrade population MS Registry was conducted. Cases for the sporadic MS (sMS) control group were randomly selected from the Registry, and matched with individuals with fMS at a ratio of 1:1. Spouses of the persons with fMS were included as a healthy control (HC) group. A specific questionnaire that was previously validated was used to obtain the data. To evaluate risk factors associated with breastfeeding for fMS occurrence compared with sMS and HC, multinomial regression analysis was performed to compute the relative risk ratios (RRR) along with 95% confidence intervals (95% CI). The analysis was afterwards repeated, stratified by sex. Both models were adjusted for potential confounding factors. RESULTS: A total of 393 participants were included in our case-control study, 131 per group. There were more individuals who were exclusively breastfed longer than six months in the sMS group compared to fMS group (RRR 2.01, 95% CI 1.22-3.32). After stratification by sex, exclusive breastfeeding was shown to be a protective factor for fMS only in male population, for individuals breastfed ≥4 months. The results of both the main and stratified analysis remained robust after adjustment. CONCLUSION: Our study findings indicate that breastfeeding reduces the risk of MS in infants with family history of the disease, although this protective effect may be limited to the male population. Further investigation into the differences in risk factors between fMS and sMS is warranted to gain a more comprehensive understanding of the disease.