EEFSEC deficiency: A selenopathy with early-onset neurodegeneration.

Inborn errors of selenoprotein expression arise from deleterious variants in genes encoding selenoproteins or selenoprotein biosynthetic factors, some of which are associated with neurodegenerative disorders. This study shows that bi-allelic selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC) variants cause selenoprotein deficiency, leading to progressive neurodegeneration. EEFSEC deficiency, an autosomal recessive disorder, manifests with global developmental delay, progressive spasticity, ataxia, and seizures.

Basic Science and Pathogenesis.

Background: Numerous studies have highlighted the role of oxidative stress in Alzheimer's disease (AD) development. Yet, the alignment of systemic and central oxidative stress biomarkers is unclear across diverse populations in the AD continuum. This study aims to assess protein damage levels in plasma and cerebrospinal fluid (CSF) within the AD continuum.

Clinical Manifestations.

Background: The Montreal Cognitive Assessment (MoCA) stands as a prominent cognitive impairment screening tool, finding widespread use globally and existing in official versions across 14 languages, including Spanish. Despite this, the challenges emerge due to the extensive variations within the Spanish language, which is not only the fourth most spoken language worldwide but also possesses significant geographic diversity, particularly evident in regions like Peru. Here, the intersection of regional nuances, low educational backgrounds, and culturally distinct tasks complicates the application of a standard MoCA version.

Fast activity chirp patterns in focal seizures from patients and animal models.

Time-frequency analysis of focal seizure electroencephalographic signals performed with depth electrodes in human temporal lobe structures has revealed the occurrence at onset of oscillations at approximately 30-100 Hz that feature a monotonic rapid decay in frequency content. This seizure onset pattern, referred to as chirp, has been identified as a highly specific and sensitive marker of focal seizures that are characterized by low-voltage fast activity. We report that this chirp pattern is also observed in animal models of temporal lobe epilepsy in both in vivo and in vitro preparations.

Identification of a Founder GLDN Variant Associated With "Lethal" Arthrogryposis in Nunavik Inuit: Implications for Obstetrical and Long-Term Survivors' Management.

Biallelic variants in GLDN have recently been associated with lethal congenital contracture syndrome 11 (LCCS11), a form of fetal akinesia deformation sequence (FADS) with high neonatal mortality. In this report, we describe five individuals from two Canadian Inuit families originating from different communities in Nunavik all affected with FADS and harboring a rare homozygous missense variant, [NM_181789.4:c.

Discovery of MDI-114215: A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome.

LIMKs are serine/threonine and tyrosine kinases responsible for controlling cytoskeletal dynamics as key regulators of actin stability, ensuring synaptic health through normal synaptic bouton structure and function. However, LIMK1 overactivation results in abnormal dendritic synaptic development that characterizes the pathogenesis of Fragile X Syndrome (FXS). As a result, the development of LIMK inhibitors represents an emerging disease-modifying therapeutic approach for FXS.

Measurement Properties of the Dysphagiameter for the Assessment of Dysphagia in Oculopharyngeal Muscular Dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a rare late-onset muscle disease with progressive dysphagia as a major symptom. The Dysphagiameter is a newly developed patient-reported outcome measure (PROM) to assess the severity of dysphagia and its impact in patients with OPMD. This article reports on item reduction and a first assessment of the Dysphagiameter's psychometrics properties, in a French and English-speaking population of individuals with OPMD.

Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus.

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males.

Machine learning prediction of brain metastasis invasion pattern on brain magnetic resonance imaging scans.

Background: Brain metastasis invasion pattern (BMIP) is an emerging biomarker associated with recurrence-free and overall survival in patients, and differential response to therapy in preclinical models. Currently, BMIP can only be determined from the histopathological examination of surgical specimens, precluding its use as a biomarker prior to therapy initiation. The aim of this study was to investigate the potential of machine learning (ML) approaches to develop a noninvasive magnetic resonance imaging (MRI)-based biomarker for BMIP determination.

repeat expansion creates the unstable folate-sensitive fragile site FRA9A.

The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and , is linked to multiple diseases. (GGGGCC)n expansions (Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown.

Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open.

Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public-private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents.

Homocysteine, neurodegenerative biomarkers, and APOE ε4 in neurodegenerative diseases.

Introduction: Elevated plasma homocysteine (Hcy) is associated with an increased risk of developing neurodegenerative diseases; however, its relationship with the apolipoprotein E (APOE) ε4 allele has not been well characterized.

Methods: Participants clinically diagnosed with Alzheimer's disease or mild cognitive impairment (AD/MCI), frontotemporal dementia, Parkinson's disease, or cerebrovascular disease were stratified by the presence of the APOE ε4 allele. Volumetric magnetic resonance imaging, plasma amyloid/tau/neurodegeneration biomarkers, and cognitive performance were quantified.

Enhancing variant of uncertain significance (VUS) interpretation in neurogenetics: collaborative experiences from a tertiary care centre.

Background: The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population.

Methods: VUS Rounds brought together genetic counsellors, molecular geneticists and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification of 'VUS Hot', 'True VUS' or 'VUS Cold', corresponding to potential pathogenicity.

Multicentre analysis of seizure outcome predicted by removal of high frequency oscillations.

In drug-resistant focal epilepsy, planning surgical resection may involve presurgical intracranial EEG recordings (iEEG) to detect seizures and other iEEG patterns to improve postsurgical seizure outcome. We hypothesized that resection of tissue generating interictal high frequency oscillations (HFOs, 80-500 Hz) in the iEEG predicts surgical outcome. Eight international epilepsy centres recorded iEEG during the patients' pre-surgical evaluation.

Follow the CSF flow: probing multiciliated ependymal cells in brain pathology.

Multiciliated ependymal cells regulate cerebrospinal fluid (CSF) microcirculation and form a dynamic CSF-brain interface. Emerging evidence suggests that ependymal cells enter reactive states in response to pathology that are associated with ciliary and junctional protein alterations. The drivers of these alterations, likely from both acquired and inherited mechanisms, remain elusive.

GBA1 T369M and Parkinson's disease - Further evidence of a lack of association in the Swedish population.

Variants in GBA1 are important genetic risk factors in Parkinson's disease (PD). GBA1 T369M has been linked to an ∼80 % increased PD risk but the reports are conflicting and the relevance of GBA1 variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation.

How the prospect of a clinical trial impacts decision-making for predictive genetic testing in ALS.

Genetic testing practices are rapidly evolving for people living with, or at-risk for, amyotrophic lateral sclerosis (ALS), due to emerging genotype-driven therapies. This study explored how individuals at-risk for familial ALS (fALS) perceive the opportunity to participate in a clinical trial, and to better understand how that may influence the decision-making process for predictive genetic testing. This study used both quantitative and qualitative data analyses.

Are rare heterozygous SYNJ1 variants associated with Parkinson's disease?

Previous studies have established that rare biallelic SYNJ1 mutations cause autosomal recessive parkinsonism and Parkinson's disease (PD). We analyzed 8165 PD cases, 818 early-onset-PD (EOPD, < 50 years) and 70,363 controls. Burden meta-analysis revealed an association between rare nonsynonymous variants and variants with high Combined Annotation-Dependent Depletion score (> 20) in the Sac1 SYNJ1 domain and PD (Pfdr = 0.