Search

Completed suicide accounts for over 700,000 deaths worldwide annually, while attempted suicide is 20 times more frequent. Genetic background is an important factor contributing to suicidal behavior, including candidate genes in glutamate, γ-aminobutyric acid (GABA), and polyamine systems. Our aim was to differentiate genetic predispositions underlying different types of suicidal behavior, attempted and completed suicide, in two Balkan populations. Analysis of variants in the genes GRIN2B (rs2268115 and rs220557), GABRG2 (rs424740), and ODC1 (rs1049500 and rs2302614) was performed on a study sample including 173 suicide attempters with comorbid psychiatric disorders, 216 non-suicidal psychiatric patients and 172 healthy controls from Serbia, and 333 suicide completers and 356 non-suicidal autopsy controls from Slovenia. CA genotype of rs220557 in GRIN2B gene increased the risk for completed suicide (P = 0.021), and violent suicide (P = 0.037), compared to controls. In ODC1 gene, CA genotype of rs2302614 decreased the risk for completed suicide compared to suicide attempt (P = 0.012). Marginally, AC haplotype for variants rs1049500-rs2302614 in ODC1 gene decreased the risk for completed suicide compared to suicide attempt (P = 0.052). Specific genetic variants of glutamate and polyamine systems are differently distributed among diverse suicidal phenotypes, providing further information on the implication of these systems in suicidality., (© 2024. The Author(s).)

Innovative treatments for spinal muscular atrophy (SMA) yield the utmost advantages only within the presymptomatic phase, underlining the significance of newborn screening (NBS). We aimed to establish statewide NBS for SMA in Serbia. Our stepwise implementation process involved technical validation of a screening assay, collaboration with patient organizations and medical professionals, a feasibility study, and negotiation with public health representatives. Over 12,000 newborns were tested during the 17-month feasibility study, revealing two unrelated SMA infants and one older sibling. All three children received therapeutic interventions during the presymptomatic phase and have shown no signs of SMA. No false-negative results were found among the negative test results. As frontrunners in this field in Serbia, we established screening and diagnostic algorithms and follow-up protocols and raised awareness among stakeholders about the importance of early disease detection, leading to the incorporation of NBS for SMA into the national program on 15 September 2023. Since then, 54,393 newborns have been tested, identifying six SMA cases and enabling timely treatment. Our study demonstrates that effective collaborations between academia, non-profit organizations, and industry are crucial in bringing innovative healthcare initiatives to fruition, and highlights the potential of NBS to revolutionize healthcare outcomes for presymptomatic SMA infants and their families.

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

Suicidal behavior has been associated with a deficient serotonin neurotransmission which is likely a consequence of individual genetic architecture, exposure to environmental factors and interactions of those factors. We examined whether the interaction of child abuse, TPH2 (tryptophan hydroxylase 2) variant rs4290270, affecting alternative splicing and editing of TPH2 pre-mRNAs, and ADARB1 (adenosine deaminase acting on RNA B1) variants rs4819035 and rs9983925 may influence the risk for suicide attempt in psychiatric patients. TPH2 rs4290270 was genotyped in 165 suicide attempters and 188 suicide non-attempters diagnosed with major depressive disorder, bipolar disorder and schizophrenia. Genotyping data for ADARB1 variants were taken over from our previous study. Child abuse before the age of 18 years was assessed using the Early Trauma Inventory-Self Report. Generalized linear models and backward selection were applied to identify the main and interacting effects of environmental and genetic factors, including psychiatric diagnoses, patients' gender and age as covariates. Childhood general traumas were independently associated with suicide attempt. Two-way interaction between TPH2 rs4290270 and general traumas revealed that TT homozygotes with a history of general traumas had an increased risk for suicide attempt. Three-way interaction of general traumas, TPH2 rs4290270 and ADARB1 rs4819035 indicated that the highest predisposition to suicide attempt was observed in individuals who experienced general traumas and were TT homozygote for rs4290270 and TT homozygote for rs4819035. Our findings suggest that the risk for suicide attempt in psychiatric patients exposed to an adverse childhood environment may depend on TPH2 and ADARB1 variants.

Tryptophan hydroxylase 1 (TPH1) gene, coding for serotonin synthesizing enzyme, and recent stressful life events (SLEs) have been commonly associated with suicidal behavior. TPH1 has been also hypothesized to be involved in stress-response mechanisms. The aim of this study was to assess TPH1 variant rs1800532 and its possible interaction with recent SLEs as risk factors for suicide attempt (SA) in Serbian psychiatric patients, including 165 suicide attempters and 188 suicide nonattempters. rs1800532 and recent SLEs were independently associated with SA, while rs1800532 did not moderate the effect of recent SLEs on SA vulnerability among Serbian psychiatric patients., (© 2016 The American Association of Suicidology.)

Objectives: Adenosine to inosine RNA editing, serotonin 2C receptor (HTR2C), and stressful life events (SLEs) have all been implicated in suicidal behaviour. We examined the main and moderating effects of RNA editing (ADAR, ADARB1) and HTR2C genes, childhood trauma (CT), recent SLEs and psychiatric disorders as contributors to suicide attempt (SA) vulnerability., Methods: Study included 165 suicide attempters and 188 suicide non-attempters, all diagnosed with one of major psychiatric disorders. CT and recent SLEs were assessed using Early Trauma Inventory-Self Report and List of Threatening Experiences Questionnaire, respectively. Selected ADAR and ADARB1 tag-variants, and HTR2C rs6318 were pre-screened for association with SA, while generalized linear models and backward selection were applied to identify individual and interacting SA risk factors., Results: ADARB1 rs9983925 and rs4819035 and HTR2C rs6318 were associated with SA. The best minimal model found emotional abuse, recent SLEs, rs9983925 and rs6318 as independent SA risk factors, and general traumas as a factor moderating the effect of psychiatric disorders and emotional abuse., Conclusions: SA vulnerability in psychiatric patients is related to the joint effect of ADARB1 and HTR2C variants, the existing mood disorder and the cumulative exposures to a various childhood and recent stressful experiences.