The yield of genetic workup for middle-aged and elderly patients with neurological disorders in a real-world setting.

Genetic workup is becoming increasingly common in the clinical assessment of neurological disorders. We evaluated its yield among middle-aged and elderly neurological patients, in a real-world context. This retrospective study included 368 consecutive Israeli patients aged 50 years and older (202 [54.9%] males), who were referred to a single neurogenetics clinic between 2017 and mid-2023. All had neurological disorders, without a previous molecular diagnosis. Demographic, clinical and genetic data were collected from medical records. The mean age at first genetic counseling at the clinic was 62.3 ± 7.8 years (range 50-85 years), and the main indications for referral were neuromuscular, movement and cerebrovascular disorders, as well as cognitive impairment and dementia. Out of the 368 patients, 245 (66.6%) underwent genetic testing that included exome sequencing (ES), analysis of nucleotide repeat expansions, detection of specific mutations, targeted gene panel sequencing or chromosomal microarray analysis. Overall, 80 patients (21.7%) received a molecular diagnosis due to 36 conditions, accounting for 32.7% of the patients who performed genetic testing. The diagnostic rates were highest for neuromuscular (58/186 patients [31.2%] in this group, 39.2% of 148 tested individuals) and movement disorders (14/79 [17.7%] patients, 29.2% of 48 tested), but lower for other disorders. Testing of nucleotide repeat expansions and ES provided a diagnosis to 28/73 (38.4%) and 19/132 (14.4%) individuals, respectively. Based on our findings, genetic workup and testing are useful in the diagnostic process of neurological patients aged ≥50 years, in particular for those with neuromuscular and movement disorders.

Combined central and peripheral demyelination in two siblings, immune mediated or genetic?

We report unusual cases of combined central and peripheral demyelination in two siblings related to pregnancy, each presenting with progressive tetraparesis and cranial nerve palsies. The elder sister had a relapsing-remitting course with optic nerve dysfunction and died during a relapse from respiratory insufficiency. The younger sister presented with disorientation and acute-onset limb and facial weakness. She responded well to corticosteroid therapy. Their clinical presentation, response to immunomodulatory therapy, nerve conduction studies, cerebrospinal fluid and histology supported an acquired demyelinating cause. Whole-exome sequencing identified variants in two genes not previously linked to this clinical phenotype. Serological tests for antibody-mediated demyelination were negative. Despite the undefined pathogenesis, these cases provide a platform to explore the confluence of genetic, immune and environmental factors in the context of acquired demyelination. We discuss the differential diagnosis and a diagnostic approach to such cases from the perspectives of neuroimmunology and neurogenetics.

Shared patterns of glial transcriptional dysregulation link Huntington's disease and schizophrenia.

Huntington's disease and juvenile-onset schizophrenia have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we used comparative correlation network approaches to analyse RNA-sequencing data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between Huntington's disease and schizophrenia hGPCs yet distinct from normal controls that included 174 highly connected genes in the shared disease-associated network, focusing on genes involved in synaptic signalling. These synaptic genes were largely suppressed in both schizophrenia and Huntington's disease hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both schizophrenia and Huntington's disease hGPCs. Chromatin immunoprecipitation sequencing confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signalling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, Huntington's disease and schizophrenia.

Genetic Landscape of Amyotrophic Lateral Sclerosis in Czech Patients.

Background: Genetic factors are involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS) and constitute a link to its association with frontotemporal dementia (FTD). Gene-targeted therapies for some forms of ALS (C9orf72, SOD1) have recently gained momentum. Genetic architecture in Czech ALS patients has not been comprehensively assessed so far. Objective: We aimed to deliver pilot data on the genetic landscape of ALS in our country. Methods: A cohort of patients with ALS (n = 88), recruited from two Czech Neuromuscular Centers, was assessed for hexanucleotide repeat expansion (HRE) in C9orf72 and also for genetic variations in other 36 ALS-linked genes via next-generation sequencing (NGS). Nine patients (10.1%) had a familial ALS. Further, we analyzed two subgroups of sporadic patients - with concomitant FTD (n = 7) and with young-onset of the disease (n = 22). Results: We detected the pathogenic HRE in C9orf72 in 12 patients (13.5%) and three other pathogenic variants in FUS, TARDBP and TBK1, each in one patient. Additional 7 novel and 9 rare known variants with uncertain causal significance have been detected in 15 patients. Three sporadic patients with FTD (42.9%) were harbouring a pathogenic variant (all HRE in C9orf72). Surprisingly, none of the young-onset sporadic patients harboured a pathogenic variant and we detected no pathogenic SOD1 variant in our cohort. Conclusion: Our findings resemble those from other European populations, with the highest prevalence of HRE in the C9orf72 gene. Further, our findings suggest a possibility of a missing genetic variability among young-onset patients.

Hyperactive mTORC1 disrupts habenula function and light preference in zebrafish model of Tuberous sclerosis complex.

Mechanistic target of rapamycin complex 1 (mTORC1) is an integration hub for extracellular and intracellular signals necessary for brain development. Hyperactive mTORC1 is found in autism spectrum disorder (ASD) characterized by atypical reactivity to sensory stimuli, among other symptoms. In Tuberous sclerosis complex (TSC) inactivating mutations in the TSC1 or TSC2 genes result in hyperactivation of the mTORC1 pathway and ASD. Here, we show that lack of light preference of the TSC zebrafish model, tsc2 vu242/vu242 is caused by aberrant processing of light stimuli in the left dorsal habenula and tsc2 vu242/vu242 fish have impaired function of the left dorsal habenula, in which neurons exhibited higher activity and lacked habituation to the light stimuli. These characteristics were rescued by rapamycin. We thus discovered that hyperactive mTorC1 caused aberrant habenula function resulting in lack of light preference. Our results suggest that mTORC1 hyperactivity contributes to atypical reactivity to sensory stimuli in ASD.

Linking LRP12 CGG repeat expansion to inherited peripheral neuropathy.

BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions. METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies. RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases. CONCLUSION: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.

Communicating pain: emerging axonal signaling in peripheral neuropathic pain.

Peripheral nerve damage often leads to the onset of neuropathic pain (NeuP). This condition afflicts millions of people, significantly burdening healthcare systems and putting strain on families' financial well-being. Here, we will focus on the role of peripheral sensory neurons, specifically the Dorsal Root Ganglia neurons (DRG neurons) in the development of NeuP. After axotomy, DRG neurons activate regenerative signals of axons-soma communication to promote a gene program that activates an axonal branching and elongation processes. The results of a neuronal morphological cytoskeleton change are not always associated with functional recovery. Moreover, any axonal miss-targeting may contribute to NeuP development. In this review, we will explore the epidemiology of NeuP and its molecular causes at the level of the peripheral nervous system and the target organs, with major focus on the neuronal cross-talk between intrinsic and extrinsic factors. Specifically, we will describe how failures in the neuronal regenerative program can exacerbate NeuP.

Evidence for sodium valproate toxicity in mitochondrial diseases: a systematic analysis.

Background: We aimed to determine whether sodium valproate (VPA) should be contraindicated in all mitochondrial diseases, due to known VPA-induced severe hepatotoxicity in some mitochondrial diseases. Methods: We systematically reviewed the published literature for mitochondrial DNA (mtDNA) and common nuclear genotypes of mitochondrial diseases using PubMed, Ovid Embase, Ovid Medline and MitoPhen databases. We extracted patient-level data from peer-reviewed articles, published until July 2022, using the Human Phenotype Ontology to manually code clinical presentations for 156 patients with genetic diagnoses from 90 publications. Results: There were no fatal adverse drug reactions (ADRs) in the mtDNA disease group (35 patients), and only 1 out of 54 patients with a non-POLG mitochondrial disease developed acute liver failure. There were fatal outcomes in 53/102 (52%) POLG VPA-exposed patients who all harboured recessive mutations. Conclusions: Our findings confirm the high risk of severe ADRs in any patient with recessive POLG variants irrespective of the phenotype, and therefore recommend that VPA is contraindicated in this group. However, there was limited evidence of toxicity to support a similar recommendation in other genotypes of mitochondrial diseases.

Clinical drivers of hospitalisation in patients with mitochondrial diseases.

Background: Mitochondrial diseases in adults are generally chronic conditions with a wide spectrum of severity contributing to disease burden and healthcare resource utilisation. Data on healthcare resource utilisation in mitochondrial diseases are limited. Objectives: We performed a retrospective longitudinal study to investigate the clinical drivers of hospitalisation in adult patients with mitochondrial diseases to better understand healthcare resource utilisation. Methods: We recruited participants from our specialised Mitochondrial Disease Clinic in Sydney, Australia between September 2018 and December 2021. We performed a retrospective chart review for the period 2013-2022 considering emergency department (ED) and/or hospital admission notes, as well as discharge summaries. We used multiple linear regression models to examine the association between the type of presenting symptom(s) and duration of hospital stay and frequency of admissions, while adjusting for relevant covariates. Results: Of the 99 patients considered, the duration of hospitalisation ranged from 0 to 116 days per participant and the number of admissions ranged from 0 to 21 per participant. Participants with one or more mitochondrial disease-associated admissions constituted 52% of the study cohort. 13% of the participants presented to the ED without requiring an admission and 35% never attended the ED or required a hospital admission during this period. Neurological (p<0.0001), gastroenterological (p=0.01) and symptoms categorised as 'other' (p<0.0001) were the main presentations driving the total number of days admitted to hospital. A statistically significant association was evident for the number of admissions and all types of presenting symptoms (p<0.0001). Conclusion: There are variable reasons for hospitalisation in adults with mitochondrial diseases, with neurological and gastroenterological presentations being associated with prolonged and complex hospitalisation. A better understanding of clinical drivers such as these allows for better informed and well-coordinated management aimed at optimising healthcare resource utilisation.

Mechanosensory bristles mediate avoidance behavior by triggering sustained local motor activity in Drosophila melanogaster.

During locomotion, most vertebrates-and invertebrates such as Drosophila melanogaster-are able to quickly adapt to terrain irregularities or avoid physical threats by integrating sensory information along with motor commands. Key to this adaptability are leg mechanosensory structures, which assist in motor coordination by transmitting external cues and proprioceptive information to motor centers in the central nervous system. Nevertheless, how different mechanosensory structures engage these locomotor centers remains poorly understood. Here, we tested the role of mechanosensory structures in movement initiation by optogenetically stimulating specific classes of leg sensory structures. We found that stimulation of leg mechanosensory bristles (MsBs) and the femoral chordotonal organ (ChO) is sufficient to initiate forward movement in immobile animals. While the stimulation of the ChO required brain centers to induce forward movement, unexpectedly, brief stimulation of leg MsBs triggered a fast response and sustained motor activity dependent only on the ventral nerve cord (VNC). Moreover, this leg-MsB-mediated movement lacked inter- and intra-leg coordination but preserved antagonistic muscle activity within joints. Finally, we show that leg-MsB activation mediates strong avoidance behavior away from the stimulus source, which is preserved even in the absence of a central brain. Overall, our data show that mechanosensory stimulation can elicit a fast motor response, independently of central brain commands, to evade potentially harmful stimuli. In addition, it sheds light on how specific sensory circuits modulate motor control, including initiation of movement, allowing a better understanding of how different levels of coordination are controlled by the VNC and central brain locomotor circuits.

Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of KIF5A in Chinese Patients with Familial Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease.

Mitochondrial Parkinsonism: A Practical Guide to Genes and Clinical Diagnosis.

BACKGROUND: Primary mitochondrial diseases (PMDs) are the most common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. They can result from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). These disorders are multisystemic and mainly affect high energy-demanding tissues, such as muscle and the central nervous system (CNS). Among many clinical features of CNS involvement, parkinsonism is one of the most common movement disorders in PMDs. METHODS: This review provides a pragmatic educational overview of the most recent advances in the field of mitochondrial parkinsonism, from pathophysiology and genetic etiologies to phenotype and diagnosis. RESULTS: mtDNA maintenance and mitochondrial dynamics alterations represent the principal mechanisms underlying mitochondrial parkinsonism. It can be present in isolation, alongside other movement disorders or, more commonly, as part of a multisystemic phenotype. Mutations in several nuclear-encoded genes (ie, POLG, TWNK, SPG7, and OPA1) and, more rarely, mtDNA mutations, are responsible for mitochondrial parkinsonism. Progressive external opthalmoplegia and optic atrophy may guide genetic etiology identification. CONCLUSION: A comprehensive deep-phenotyping approach is needed to reach a diagnosis of mitochondrial parkinsonism, which lacks distinctive clinical features and exemplifies the intricate genotype-phenotype interplay of PMDs.

Neural circuits for taste sensation.

The sense of taste arises from the detection of chemicals in food by taste buds, the peripheral cellular detectors for taste. Although numerous studies have extensively investigated taste buds, research on neural circuits from primary taste neurons innervating taste buds to the central nervous system has only recently begun owing to recent advancements in neuroscience research tools. This minireview focuses primarily on recent reports utilizing advanced neurogenetic tools across relevant brain regions.

Wireless EEG Recording of Audiogenic Seizure Activity in Freely Moving Krushinsky-Molodkina Rats.

This study investigates audiogenic epilepsy in Krushinsky-Molodkina (KM) rats, questioning the efficacy of conventional EEG techniques in capturing seizures during animal restraint. Using a wireless EEG system that allows unrestricted movement, our aim was to gather ecologically valid data. Nine male KM rats, prone to audiogenic seizures, received implants of wireless EEG transmitters that target specific seizure-related brain regions. These regions included the inferior colliculus (IC), pontine reticular nucleus, oral part (PnO), ventrolateral periaqueductal gray (VLPAG), dorsal area of the secondary auditory cortex (AuD), and motor cortex (M1), facilitating seizure observation without movement constraints. Our findings indicate that targeted neural intervention via electrode implantation significantly reduced convulsive seizures in approximately half of the subjects, suggesting therapeutic potential. Furthermore, the amplitude of brain activity in the IC, PnO, and AuD upon audiogenic stimulus onset significantly influenced seizure severity and nature, highlighting these areas as pivotal for epileptic propagation. Severe cases exhibited dual waves of seizure generalization, indicative of intricate neural network interactions. Distinctive interplay between specific brain regions, disrupted during convulsive activity, suggests neural circuit reconfiguration in response to escalating seizure intensity. These discoveries challenge conventional methodologies, opening avenues for novel approaches in epilepsy research and therapeutic interventions.

Genetics of inherited peripheral neuropathies and the next frontier: looking backwards to progress forwards.

Inherited peripheral neuropathies (IPNs) encompass a clinically and genetically heterogeneous group of disorders causing length-dependent degeneration of peripheral autonomic, motor and/or sensory nerves. Despite gold-standard diagnostic testing for pathogenic variants in over 100 known associated genes, many patients with IPN remain genetically unsolved. Providing patients with a diagnosis is critical for reducing their 'diagnostic odyssey', improving clinical care, and for informed genetic counselling. The last decade of massively parallel sequencing technologies has seen a rapid increase in the number of newly described IPN-associated gene variants contributing to IPN pathogenesis. However, the scarcity of additional families and functional data supporting variants in potential novel genes is prolonging patient diagnostic uncertainty and contributing to the missing heritability of IPNs. We review the last decade of IPN disease gene discovery to highlight novel genes, structural variation and short tandem repeat expansions contributing to IPN pathogenesis. From the lessons learnt, we provide our vision for IPN research as we anticipate the future, providing examples of emerging technologies, resources and tools that we propose that will expedite the genetic diagnosis of unsolved IPN families.

Bridging Genetic Insights with Neuroimaging in Autism Spectrum Disorder-A Systematic Review.

Autism Spectrum Disorder (ASD) is an early onset neurodevelopmental disorder characterized by impaired social interaction and communication, and repetitive patterns of behavior. Family studies show that ASD is highly heritable, and hundreds of genes have previously been implicated in the disorder; however, the etiology is still not fully clear. Brain imaging and electroencephalography (EEG) are key techniques that study alterations in brain structure and function. Combined with genetic analysis, these techniques have the potential to help in the clarification of the neurobiological mechanisms contributing to ASD and help in defining novel therapeutic targets. To further understand what is known today regarding the impact of genetic variants in the brain alterations observed in individuals with ASD, a systematic review was carried out using Pubmed and EBSCO databases and following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This review shows that specific genetic variants and altered patterns of gene expression in individuals with ASD may have an effect on brain circuits associated with face processing and social cognition, and contribute to excitation-inhibition imbalances and to anomalies in brain volumes.