Abstract Objective To determine if the co-presence of genetic polymorphisms related to ALS has additive effects on the course of the disease in a population-based cohort of Italian patients. Methods The study population includes 1245 ALS patients identified through the Piemonte Register for ALS, diagnosed between 2007 and 2016 and not carrying SOD1, TARDBP and FUS mutations. Controls were 766 age, sex, and geographically matched Italian subjects. We considered UNC13A ( rs12608932), CAMTA1 ( rs2412208), SLC112A ( rs407135) and ZNF512B (ZNF512B) polymorphisms, as well as ATXN2 polyQ intermediate repeats and C9ORF72 GGGGCC intronic expansion. Results The variants in C9orf72 (p=0.016), ATXN2 (p<0.001) and UNC13A (p<0.001) were significantly related to survival in univariate analysis, while the other considered variants did not influence ALS outcome. However, in the Cox multivariable analysis, also CAMTA1 emerged to be independently related to survival. When assessing the interaction by pairs of genes, we found that the presence of both detrimental alleles/expansion was correlated with significantly shorter survival compared to subjects non-carrying both detrimental alleles/expansions. Each association of pairs of detrimental alleles was characterized by specific clinical phenotypes. Conclusions we demonstrated that gene polymorphisms acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common polymorphism or repeat expansion, highlighting the clinical impact of our findings. In addition, the identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity and should be considered in designing and interpreting clinical trials. Key messages What is already known on this topic Besides the disease-causing genes, several other genes have been reported to act as modifiers of ALS phenotype, especially patients’ survival. However, the interactions of these genes at clinical level have never been explored. What this study adds We demonstrated that gene polymorphisms and expansions acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental allele at common polymorphism or repeat expansion, highlighting the clinical impact of our findings. How this study might affect research, practice, or polic The identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity, will have deep effects on clinical trial design and interpretation and support the inclusion of these polymorphisms in ALS genetic panels.
An Infectious Disease vaccine specialist joined our institution's Cochlear Implant Team in 2010 in order to address the high percentage of non-compliance to immunization prior to surgery identified previously from an internal review. The purpose of this study was to (1) review the immunization status of cochlear implant recipients in 2010-2014, (2) assess if introducing a vaccine specialist made a significant change in vaccination compliance and (3) elucidate any barriers to vaccination compliance.Retrospective chart review and a telephone survey. Medical records of 116 cochlear implant recipients between 2010 and 2014 were reviewed. A telephone survey was conducted to obtain the current vaccination status in children who required post-operative vaccinations with incomplete records on chart review and, if applicable, the reason for non-compliance.Between 2010 and 2014, 98% of children were up-to-date at the time of surgery, compared to 67% up-to-date at the time of surgery between 2002 and 2007. 27 children were included in our post-operative immunization analysis. 29.6% (8/27) failed to receive necessary vaccinations post-surgery. Pneumovax-23, a vaccine for high-risk patients (such as cochlear implant candidates) was missed in all cases.Pre-operative vaccination for cochlear implant recipients improved dramatically with the addition of a vaccine specialist. However, a significant proportion of patients requiring vaccinations post-surgery did not receive them. The main reason for non-compliance was due to parents being unaware that their children required this vaccine postoperatively by being "high-risk". Although improvement was demonstrated, a communication gap continued to impede the adequacy of vaccination uptake in pediatric cochlear implant recipients following surgery at age 2 when the high-risk vaccine was due.
Since the discovery that mutations in the enzyme SOD1 are causative in human amyotrophic lateral sclerosis (ALS), many strategies have been employed to elucidate the toxic properties of this ubiquitously expressed mutant protein, including the generation of GFP-SOD1 chimaeric proteins for studies in protein localization by direct visualization using fluorescence microscopy. However, little is known about the biochemical and physical properties of these chimaeric proteins, and whether they behave similarly to their untagged SOD1 counterparts.Here we compare the physicochemical properties of SOD1 and the effects of GFP-tagging on its intracellular behaviour. Immunostaining demonstrated that SOD1 alone and GFP-SOD1 have an indistinguishable intracellular distribution in PC12 cells. Cultured primary motor neurons expressing GFP or GFP-SOD1 showed identical patterns of cytoplasmic expression and of movement within the axon. However, GFP tagging of SOD1 was found to alter some of the intrinsic properties of SOD1, including stability and specific activity. Evaluation of wildtype and mutant SOD1, tagged at either the N- or C-terminus with GFP, in PC12 cells demonstrated that some chimaeric proteins were degraded to the individual proteins, SOD1 and GFP.Our findings indicate that most, but not all, properties of SOD1 remain the same with a GFP tag.
To determine the incidence of static and dynamic balance dysfunction in a group of children with profound sensorineural hearing loss receiving a cochlear implant and to assess the impact of cochlear implant activation on equilibrium.
Design
Observational cross-sectional study of children with single-sided implants, tested under 2 conditions: (1) implant on and (2) implant off in a random order.
Setting
Ambulatory setting within an academic, tertiary care children's hospital.
Participants
Forty-one children (ages 4-17 years) with cochlear implants comprised the study group. Fourteen children with normal hearing served as controls.
Intervention
All participants performed a standardized test of static and dynamic balance function (Bruininks-Oseretsky Test of Motor Proficiency 2 [BOT2], balance subset). Children with implants performed the BOT2 under the 2 randomized conditions.
Main Outcome Measures
Overall performance on the balance subset of the BOT2 and the influence of implant activation on performance.
Results
The mean (SD) age-adjusted scale score for our control group was 17 (5) points (95% confidence interval [CI], 14-20), which was not significantly different (P = .15) from the published age-adjusted mean for the BOT2 balance subset (15 [5] points). The group that had undergone implantation, however, performed significantly more poorly (12 [ 6] points; 95% CI, 10-14) than either the control group or the published test mean (P = .004). Children with implants performed better with their implants on than with their implants off (mean [SD] difference, 1.3 [2.7] points; 95% CI, 0.3-2.3;P = .01).
Conclusions
Large differences exist in the balance ability of children with sensorineural hearing loss requiring cochlear implantation compared with age-matched controls. Implant activation, however, conferred a slight advantage in accomplishing balance-related tasks. These results substantiate the need to further quantify the baseline vestibular dysfunction of our study population of children with cochlear implants, as well as the impact of implant activation on the input and output of the vestibular system.
The SOD1G93A transgenic mouse strain which carries a human mutant Cu/Zn superoxide dismutase transgene array is a widely studied model of amyotrophic lateral sclerosis. These mice have been used in many breeding experiments to look for interactions with other loci, including transgenic and gene targeted mutations. Therefore, we decided to map the site of the transgene insertion as this may affect the outcome of such breeding experiments. In a fluorescence in situ hybridization experiment we determined that the SOD1G93A transgene insertion site lies on distal mouse chromosome 12. This chromosome also carries the 'Legs at odd angles' locus, which is an entirely unrelated mutation in the dynein heavy chain gene that we have been studying. We have analysed data from a SOD1G93A×Loa cross and determined that the site of the transgene insertion lies proximal of the dynein heavy chain gene on mouse chromosome 12.
Abstract Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.
Various genetic and environmental risk factors have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, the cause of most ALS cases remains obscure. In this review, we describe the current evidence implicating genetic and environmental factors in motor neuron degeneration. While the risk exerted by many environmental factors may appear small, their effect could be magnified by the presence of a genetic predisposition. We postulate that gene-environment interactions account for at least a portion of the unknown etiology in ALS. Climate underlies multiple environmental factors, some of which have been implied in ALS etiology, and the impact of global temperature increase on the gene-environment interactions should be carefully monitored. We describe the main concepts underlying such interactions. Although a lack of large cohorts with detailed genetic and environmental information hampers the search for gene-environment interactions, newer algorithms and machine learning approaches offer an opportunity to break this stalemate. Understanding how genetic and environmental factors interact to cause ALS may ultimately pave the way towards precision medicine becoming an integral part of ALS care.
To characterize the clinical and cognitive behavioral phenotype and brain 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of the UNC13A gene.The study population included 1,409 patients with ALS without C9orf72, SOD1, TARDBP, and FUS mutations identified through a prospective epidemiologic ALS register. Control participants included 1,012 geographically matched, age-matched, and sex-matched participants. Clinical and cognitive differences between patients carrying the C/C rs12608932 genotype and those carrying the A/A + A/C genotype were assessed. A subset of patients underwent 18F-FDG-PET.The C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% confidence interval 1.18-2.01, p = 0.001). Patients with the C/C genotype were older, had more frequent bulbar onset, and manifested a higher rate of weight loss. In addition, they showed significantly reduced performance in the letter fluency test, fluency domain of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and story-based empathy task (reflecting social cognition). Patients with the C/C genotype had a shorter survival (median survival time, C/C 2.25 years, interquartile range [IQR] 1.33-3.92; A/A + C/C: 2.90 years, IQR 1.74-5.41; p = 0.0001). In Cox multivariable analysis, C/C genotype resulted to be an independent prognostic factor. Finally, patients with a C/C genotype had a specific pattern of hypometabolism on brain 18F-FDG-PET extending to frontal and precentral areas of the right hemisphere.C/C rs12608932 genotype of UNC13A is associated with a specific motor and cognitive/behavioral phenotype, which reflects on 18F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 variant in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations.
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