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.

For sexually reproducing animals, selecting optimal mates is important for maximizing reproductive fitness. In the nematode C. elegans, populations reproduce largely by hermaphrodite self-fertilization, but the cross-fertilization of hermaphrodites by males also occurs. Males\' ability to recognize hermaphrodites involves several sensory cues, but an integrated view of the ways males use these cues in their native context to assess characteristics of potential mates has been elusive. Here, we examine the mate-preference behavior of C. elegans males evoked by natively produced cues. We find that males use a combination of volatile sex pheromones (VSPs), ascaroside sex pheromones, surface-associated cues, and other signals to assess multiple features of potential mates. Specific aspects of mate preference are communicated by distinct signals: developmental stage and sex are signaled by ascaroside pheromones and surface cues, whereas the presence of a self-sperm-depleted hermaphrodite is likely signaled by VSPs. Furthermore, males prefer to interact with virgin over mated, and well-fed over food-deprived, hermaphrodites; these preferences are likely adaptive and are also mediated by ascarosides and other cues. Sex-typical mate-preference behavior depends on the sexual state of the nervous system, such that pan-neuronal genetic masculinization in hermaphrodites generates male-typical social behavior. We also identify an unexpected role for the sex-shared ASH sensory neurons in male attraction to ascaroside sex pheromones. Our findings lead to an integrated view in which the distinct physical properties of various mate-preference cues guide a flexible, stepwise behavioral program by which males assess multiple features of potential mates to optimize mate preference.

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Correlation between blood-oxygen-level-dependent (BOLD) and cerebral blood flow (CBF) has been used as an index of neurovascular coupling. Hippocampal BOLD-CBF correlation is associated with neurocognition, and the reduced correlation is associated with neuropsychiatric disorders. We conducted the first genome-wide association study of the hippocampal BOLD-CBF correlation in 4,832 Chinese Han subjects. The hippocampal BOLD-CBF correlation had an estimated heritability of 16.2-23.9% and showed reliable genome-wide significant association with a locus at 3q28, in which many variants have been linked to neuroimaging and cerebrospinal fluid markers of Alzheimer\'s disease. Gene-based association analyses showed four significant genes (GMNC, CRTC2, DENND4B, and GATAD2B) and revealed enrichment for mast cell calcium mobilization, microglial cell proliferation, and ubiquitin-related proteolysis pathways that regulate different cellular components of the neurovascular unit. This is the first unbiased identification of the association of hippocampal BOLD-CBF correlation, providing fresh insights into the genetic architecture of hippocampal neurovascular coupling.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord. The causes of ALS are not fully understood. About 10% of ALS cases were associated with genetic factors. Since the discovery of the first familial ALS pathogenic gene SOD1 in 1993 and with the technology advancement, now over 40 ALS genes have been found. Recent studies have identified ALS related genes including ANXA11, ARPP21, CAV1, C21ORF2, CCNF, DNAJC7, GLT8D1, KIF5A, NEK1, SPTLC1, TIA1, and WDR7. These genetic discoveries contribute to a better understanding of ALS and show the potential to aid the development of better ALS treatments. Besides, several genes appear to be associated with other neurological disorders, such as CCNF and ANXA11 linked to FTD. With the deepening understanding of the classic ALS genes, rapid progress has been made in gene therapies. In this review, we summarize the latest progress on classical ALS genes and clinical trials for these gene therapies, as well as recent findings on newly discovered ALS genes.

In most patients with frontotemporal lobe degeneration (FTLD), the degenerative process begins between the ages 45 and 65 years; onset younger than 45 years is relatively rare and considered very early onset FTLD (VEO-FTLD).
To delineate the clinical, genetic, and pathological features of VEO-FTLD.
A systematic literature review was carried out in PubMed and Embase from inception to September 2021. Patients diagnosed with definite FTLD with onset before age 45 years were included. Patients lacking detailed clinical data or both genetic and neuropathological data were excluded. Phenotypic, genotypic, and pathological data were extracted for further analyses.
Data from 110 patients with VEO-FTLD, reported in a cumulative 70 publications, were included. Age of onset was 35.09 ± 7.04 (14-44) years. Sixty-seven patients were reported age at death of 42.12 ± 7.26 (24-58) years, with a disease course lasting 8.13 ± 4.69 (1-20) years. Behavioural variant frontotemporal dementia (104/110, 94.5%) was the most common clinical subtype, often manifesting as disinhibition (81.8%) and apathy (80.9%), and frequently accompanied by a cognitive deficit (90.9%) and parkinsonism (37.3%). Frequency of familial aggregation was high (familial vs. sporadic, 73/37, 66.4%); most patients carried MAPT gene mutations (72.9% in familial, 40% in sporadic), followed by C9 (18.8% in familial, 10% in sporadic), TARDBP (2.1% in familial), and VCP (2.1% in familial). The most common neuropathology subtype was tau (43.5%), followed by ubiquitin- positive (24.6%), FUS (20.3%), and TDP 43 (2.9%).
VEO-FTLD may have unique clinical, genetic, and neuropathological markers and should be considered in young patients with psycho-behavioral symptoms.

Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China.
Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.
In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.
NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Epilepsy is a neurological network disease with genetics playing a much greater role than was previously appreciated. Unfortunately, the relationship between genetic basis and imaging phenotype is by no means simple. Imaging genetics integrates multidimensional datasets within a unified framework, providing a unique opportunity to pursue a global vision for epilepsy. This review delineates the current knowledge of underlying genetic mechanisms for brain networks in different epilepsy syndromes, particularly from a neural developmental perspective. Further, endophenotypes and their potential value are discussed. Finally, we highlight current challenges and provide perspectives for the future development of imaging genetics in epilepsy.

Continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation technique, can induce long-lasting changes in synaptic plasticity, vital for memory reconsolidation. For this study, a total of 170 participants completed four experiments by a randomized controlled design. Succeeding fear conditioning, the subjects received cTBS over the right dorsolateral prefrontal cortex (dlPFC) or vertex (control) with or without exposure to the conditioned stimulus to reactivate the original fear memory, and then underwent fear response tests. Compared with cTBS over the vertex and without memory reactivation, only cTBS over the right dlPFC after reactivation decreased the fear response for both recent and remote fear memories. This procedure was effective only during the reconsolidation window. The disruptive effect of cTBS over the right dlPFC on fear memory reconsolidation was delay-dependent. These findings demonstrate that cTBS time-dependently and delay-dependently prevents the return of fear and may have clinical potential for treating fear-related disorders.

Gilles de la Tourette syndrome (TS) is a common, childhood-onset psychiatric disorder characterized by persistent motor and vocal tics. It is a heterogeneous disorder in which the phenotypic expression may be affected by environmental factors, such as immune responses. Furthermore, several studies have shown that genetic factors play a vital role in the etiology of TS, as well as its comorbidity with other disorders, including attention deficit hyperactivity disorder, obsessive-compulsive disorder, and autism spectrum disorder. TS has a complex inheritance pattern and, according to various genetic studies, several genes and loci have been correlated with TS. Genome-wide linkage studies have identified Slit and Trk-like 1 (SLITRK1) and histidine decarboxylase (HDC) genes, and candidate gene association studies have extensively investigated the dopamine and serotonin system genes, but there have been no consistent results. Moreover, genome-wide association studies have implicated several genetic loci; however, larger study cohorts are needed to confirm this. Copy number variations, which are polymorphisms in the number of gene copies due to chromosomal deletions or duplications, are considered another significant source of mutations in TS. In the last decade, whole genome/exome sequencing has identified several novel genetic mutations in patients with TS. In conclusion, more studies are needed to reveal the exact mechanisms of underlying TS, which may help to provide more information on the prognosis and therapeutic plans for TS.