Neurogenetics最新文献

Migraine is a highly prevalent neurological disorder that imposes significant personal and economic burdens worldwide. However, the causal relationships between these biological factors and migraine remain poorly understood. This study aimed to investigate these causal relationships using robust genetic epidemiological methods to identify potential therapeutic targets for improved migraine management. A two-sample Mendelian randomization (MR) approach was used to assess the causal roles of three major categories of biological factors: metabolites (metabolites, blood and urine biomarkers), immune (inflammatory factors and immune cells), and microbiota (intestinal and skin flora). Genetic instruments were derived from large-scale genome-wide association studies. Bayesian weighted MR (BWMR) analyses were conducted to validate the robustness of findings. Colocalization analyses were performed to determine whether significant associations were mediated through known migraine-related pathogenic or therapeutic genes. The study identified 30 putative causal factors for migraine, including 16 metabolites, 5 immune cell profiles, 3 inflammatory markers, 5 intestinal floras, and 1 skin floras. Among the metabolites, the alpha-ketoglutarate to ornithine ratio and the spermidine to choline ratio were significant risk factors, whereas alliin and (2,4 or 2,5)-dimethylphenol sulfate were identified as protective factors. No significant associations were observed for blood and urine biomarkers. Colocalization analyses indicated that these factors influence migraine risk through pathways independent of known pathogenic or therapeutic genes. This study provides novel genetic evidence supporting the causal roles of metabolites, inflammatory markers, immune cell profiles, and microbiota in migraine etiology. The findings highlight potential biomarkers and therapeutic targets for migraine management.

This study aims to investigate the clinical baseline characteristics and HbA1c variability in elderly patients with mild cognitive impairment (MCI) associated with type 2 diabetes mellitus (T2DM), as well as the synergistic relationship between these factors and dementia progression. A total of 186 elderly patients with T2DM with MCI were enrolled and stratified into 94 with normolipidemia and 92 with dyslipidemia. The patients' demographics, baseline characteristics, lipid levels, baseline HbA1c, and Montreal cognitive assessment scale scores were recorded. Patients were followed up for at least 36 months, with a maximum follow-up period of 48 months. Patients in the dyslipidemia group had a longer duration of DM and had significantly higher total cholesterol, triglycerides, and low-density lipoprotein cholesterol than those in the normolipidemia group. Thirty-five patients progressed to dementia, with 25% (23/92) in the dyslipidemia group compared to 12.77% (12/94) in the normolipidemia group. Patients in the dyslipidemia group had significantly higher HbA1c variability than those in the normolipidemia group. Furthermore, the group progressing to dementia exhibited advanced age, prolonged DM duration, shorter years of education, and abnormal lipid levels, as well as greater HbA1c variability. Dyslipidemia under the association with the glycemic variability profile (HbA1c variability ≥ 10.49%) was also strongly associated with the degree of MCI in patients with dementia. Multivariable logistic regression confirmed that both dyslipidemia (OR = 2.05, P = 0.015) and high HbA1c variability (OR = 3.56, P = 0.010) were independent risk factors, with a significant interaction between them (OR = 3.15, P = 0.046). Dyslipidemia and glycemic variability are not only correlates of cognitive decline in patients with T2DM, but may also act synergistically to accelerate the process of MCI to dementia. The stratification by lipid status effectively identifies patient subgroups at differential risk, highlighting the combined impact of these metabolic factors.

NOTCH3, a key regulator of vascular smooth muscle cell function within the Notch signaling pathway, is essential for maintaining small artery integrity, especially in cerebral microvasculature. Pathogenic heterozygous missense variants in NOTCH3 cause CADASIL, an autosomal dominant small-vessel disease marked by extracellular domain aggregation, granular osmiophilic material deposition, and vascular smooth muscle cell dysfunction, leading to early-onset ischemic strokes, migraine with aura, and progressive cognitive decline. We report a 12-year-old Moroccan girl, born to first-degree consanguineous parents, presenting with global developmental delay, spastic tetraparesis, epilepsy, and bilateral periventricular white matter abnormalities. Whole-exome sequencing identified a novel homozygous frameshift variant in NOTCH3 (NM_000435.3:c.2985_2991del; NP_000426.2:p.(Gln996ArgfsTer274)), confirmed by Sanger sequencing, with heterozygous carrier parents. Emerging evidence shows that biallelic loss-of-function variants, unlike the gain-of-function variants underlying CADASIL, define a distinct autosomal recessive leukodystrophy characterized by early-onset pyramidal signs, epilepsy, and white matter abnormalities, thereby expanding the phenotypic and molecular spectrum of NOTCH3-related disorders. This work highlights the functional divergence between dominant and recessive NOTCH3 variants and supports the inclusion of NOTCH3 in gene panels for early-onset leukodystrophies, especially in consanguineous populations.

MYBPC3 (Myosin-binding site protein C3) alterations are associated with hypertrophic cardiomyopathy (HCM). However, the neuroimaging features of these patients are not well-described in the literature. We present a unique case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)-like neuroimaging features in a middle-aged female, who harbors a heterozygous likely pathogenic splice site variant [c.26-2 A > G] in MYBPC3 [NM_000256.3]. The patient had negative genetic and electron microscopy test results for CADASIL. Our observations suggest that CADASIL-like cerebral vasculopathy may occur in MYBPC3-related disorders, thus highlighting the need for further characterization of neuroimaging features of patients with MYBPC3-related disorders.

In male mice, courtship behaviors encompass distinct appetitive and consummatory phases, accompanied by ultrasonic vocalizations (USV) that vary with courtship progression and exhibit strain-specific patterns. Despite these differences, how genetics contribute to state- and strain-dependent USV variations remain unclear. We examined USV syllable patterns during courtship in inbred C57BL/6J (B6) and 129S4/SvJae (129) mouse strains, along with their mixed-background F2 offspring. During appetitive behaviors, such as body and anogenital sniffing, B6 and 129 males produced distinct USV. F2 males emitted USV reflecting combinations of B6 and 129 patterns, correlative with the continuous similarity to each strain. In contrast, all groups emitted strikingly similar USV during mounting. These findings suggest that appetitive and consummatory phases are governed by distinct genetic mechanisms, shaped by evolutionary pressures for vocalization diversity during appetitive behaviors and conservation during consummatory behaviors, supporting adaptation to selection pressures that favor flexibility in mate attraction while ensuring consistency in mating success.

Mecasermin, a recombinant analogue of insulin‑like growth factor 1 (IGF‑1), is under investigation as a potential therapy for Rett syndrome (RTT), a neurodevelopmental disorder resulting from mutations in the MECP2 gene. In this systematic review, we assessed the impact of mecasermin on the full spectrum of RTT severity by screening relevant clinical studies identified through MeSH‑based database queries. Evidence indicates that IGF‑1 administration may help preserve social engagement and cognitive function in RTT, although autonomic control and behavioral outcomes have been inconsistent, and electroencephalographic alterations display considerable heterogeneity. Moreover, transcriptomic analyses have uncovered discrete gene‑expression signatures in molecularly defined patient subgroups, suggesting that genetic background modulates therapeutic response. These findings highlight the promise of mecasermin for ameliorating specific RTT features while underscoring the necessity of larger, rigorously designed trials to refine treatment regimens and implement stratified, patient‑specific approaches.

CRISPR-Cas9 technology offers transformative potential in treating Huntington's Disease (HD) by directly addressing its genetic root causes. This manuscript explores the pathophysiological mechanisms of HD, characterized by toxic mutant huntingtin (mHTT) protein resulting from expanded CAG repeats in the HTT gene, and the challenges posed by current therapeutic limitations. We comprehensively review the mechanisms of CRISPR-based therapeutic strategies, including excision of expanded repeats, allele-specific targeting, and epigenome editing, highlighting their efficacy in preclinical studies using animal models and human iPSCs. Delivery methods, such as viral and non-viral vectors, are analysed for their role in optimizing therapeutic outcomes while minimizing off-target effects and immune responses. Ethical and safety considerations, especially regarding precision and long-term impacts, are critically examined alongside emerging strategies to enhance specificity. With ongoing clinical trials and advancements in delivery systems, CRISPR technology represents a paradigm shift in addressing HD and broader neurodegenerative conditions. This review underscores the promise of gene editing in overcoming existing barriers and paving the way for transformative therapeutic approaches.

To investigate a novel NIMA Related Kinase 1 (NEK1) frameshift mutation in amyotrophic lateral sclerosis (ALS), assess its pathogenicity using computational algorithms and genetic databases, and analyze the clinical manifestations of cases carrying the NEK1 genetic mutation. A 65-year-old man with sporadic ALS (sALS) carrying a NEK1 c.2413dup (p.Thr805Asnfs*7) mutation was studied. Clinical and genetic data were evaluated using Mutation Taster and ACMG guidelines. A literature review was conducted in PubMed and CNKI to identify ALS cases with NEK1 mutations. Whole-exome sequencing identified a NEK1 mutation, c.2413dup (p.Thr805Asnfs*7),which is predicted to lead to a truncated protein. A literature review found 19 articles covering 89 mutation sites. Among the recorded cases, sex was reported for 79 cases (47 male,32 female), and age of onset was available for 80 cases, with an average of 56.94 ± 11.88 years. Onset type data were available for 77 cases, of which 49.35% (38/77) had lower motor neuron onset,41.56% (32/77) had upper motor neuron onset, and 9.09% (7/77) had both. Among those with lower motor neuron onset (n = 38),28.95% (11/38) had bulbar onset, and 2.63% (1/38) had respiratory onset. The c.2413dup (p.Thr805Asnfs*7) frameshift mutation in the NEK1 gene is likely pathogenic and may contribute to the onset of ALS. ALS associated with NEK1 mutations appears to be more common in men than women and typically affects individuals in late middle age.

Chorea-Acanthocytosis (ChAc) is a rare genetic disorder characterized by progressive neurodegeneration and acanthocytosis in the bloodstream. Biallelic mutations in the Vacuolar Protein Sorting 13 homolog A (VPS13A) gene have been identified as the cause of ChAc. This study aims to report a novel mutation in VPS13A associated with ChAc in two Iranian brothers. Two brothers from an Iranian family, aged 31 and 32, presented with clinical features suggestive of ChAc, including progressive chorea, cognitive decline, and seizures. Whole exome sequencing revealed a novel homozygous frameshift mutation in exon 47 of VPS13A (NM 0018037. 2: c. 6348delA, p. K2117Nfs*16) in both brothers. However, both parents resulted heterozygous carriers. This report describes a previously unreported homozygous frameshift mutation in VPS13A associated with ChAc. This finding broadens the known mutational landscape of VPS13A in the Iranian population and underscores the value of genetic screening in patients with suspected neuroacanthocytosis syndromes.