Neurogenetics最新文献

Idiopathic Parkinson's disease (PD) constitutes a complex trait influenced by genetic, environmental, and lifestyle factors, with an estimated heritability of nearly 30%. However, a large proportion of the heritable variation linked to PD remains uncertain, partly due to ancestral bias. Expanding research into Hispanic populations can contribute to address this gap. To review the evidence of genetic variants associated with idiopathic PD in Latin America. A PRISMA-compliant systematic review was conducted in MEDLINE, EMBASE and LILACS, compiling studies published up to February 7, 2025. Nineteen case-control studies were included. Two hypothesis-free studies identified rs525496 near H2BW1 as a protective factor and rs356182 in SNCA as a risk factor through XWAS and GWAS, respectively. Seventeen hypothesis-driven studies examined over three hundred variants, identifying nineteen genetic markers; risk factors included one INDEL in NR4A2, CNV burdens in PRKN, SNCA, and PLA2G6, along with fourteen variants in six loci including GBA, APOEε4, MTHFR, LRRK2, and SNCA. Three SNPs in the PICALM, ALDH1A1, and APOE-ε3 loci were identified as protective factors. Additionally, six SNCA variant haplotypes appear to increase PD risk, while two NR4A2 INDELs haplotypes showed mixed effects. This review summarized genetic loci associated with idiopathic PD in Latin American populations evidencing an overlap with European findings as well as novel loci, although awaiting replication and validation. These observations contribute to the understanding of genetic configuration of the disease and highlight the need for further genomic research in underrepresented groups that include local ancestry analysis within admixed cohorts to guide development of personalized treatments and population-specific interventions.

Epilepsy is one of the most common neurological afflictions worldwide, with one-third of patients exhibiting resistance to treatment. It has been speculated that the polymorphisms of the sodium channel alpha subunit 1 (SCN1A) gene are associated with both the occurrence of epilepsy and its resistance to treatment. The aim of this study is to systematically review the literature and conduct meta-analyses revealing the associations of the SCN1A polymorphisms with epilepsy and resistance to treatment. We conducted a search of Pubmed, Web of Science, and Scopus, and if more than two studies investigated a polymorphism, odds ratios for association with epilepsy and/or resistance to treatment were calculated in three allelic, homozygous, and recessive genetic models. The initial search yielded 4106 items, and a total of 64 articles met the final inclusion criteria. With respect to the occurrence of epilepsy, the rs2298771 polymorphism was revealed to be negatively associated in the recessive model, while the associations of other polymorphisms were not statistically significant. With regard to resistance to treatment, rs2298771 was revealed to be positively associated across all three models, and rs10167228 was positively associated in the allelic and homozygous models, but not the recessive model. Other polymorphisms were not shown to be associated with resistance to treatment. In conclusion, we demonstrated that the rs2298771 polymorphism had a significant and negative association with the occurrence of epilepsy. Furthermore, rs2298771 and rs10167228 polymorphisms had positive associations with resistance to treatment. Further studies are needed to explore these associations among other polymorphisms.

Hereditary neurological disorders (HNDs) are a group of heterogeneous disorders characterized by significant genetic and clinical variability. HNDs are caused by dysfunction of the central or peripheral nervous system due to aberrant electrical impulses. More than 600 types of HNDs have been documented, and overall, these are the second leading cause of death worldwide. This systematic review is based on a retrospective analysis of research articles reporting HNDs diagnosed using whole exome sequencing in Pakistani families from 2014 to November 2024. Original research articles were retrieved through online surveys, notably Google Scholar, PubMed, and the Web of Science. Based on stringent selection criteria, 89 research articles and 188 variants published around 10 years were considered. Variants and research articles were cross-checked and further validated in different online databases/resources to confirm their genomic nomenclature and pathogenicity according to the ACMG guidelines. A total of 188 variants in 143 distinct genes in Pakistani families identified through whole exome sequencing have been reported to date that caused genetic and clinically heterogeneous HNDs. Consanguineous parentage was found in around 90% of cases, and approximately 91% of causative alleles were reported in homozygous state showing a predominant burden of HNDs because of blood-related marriages. The most frequent type of pathogenic variants were single nucleotide substitutions (92 missense and 39 nonsense). Among 188 variants, 76 variants were reported in 2024 and 44 variants were observed in 2023. Pakistan is the fifth most populous country in the world having an extreme prevalence of consanguinity resulting in the expression of pathogenic variants due to homozygosity. Therefore, there is a prevalence of genetic disorders particularly rare monogenic or Mendelian disorders. Next-generation sequencing approach is strongly recommended for diagnosis, early therapeutic intervention and genetic counselling.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation, neurofibrillary tangles, neuroinflammation, and progressive cognitive decline, posing a significant global health challenge. Growing evidence suggests that dietary polyphenols may reduce the risk and progression of AD through multifaceted neuroprotective mechanisms. Polyphenols regulate amyloid proteostasis by inhibiting β/γ-secretase activity, preventing Aβ aggregation, and enhancing clearance pathways. Their strong antioxidant properties neutralize reactive oxygen species, chelate redox-active metals, and activate cytoprotective enzymes via Nrf2 signaling. This review examines the potential therapeutic targets, signaling pathways, and molecular mechanisms by which dietary polyphenols exert neuroprotective effects in AD, focusing on their roles in modulating amyloid proteostasis, oxidative stress, neuroinflammation, and cerebrovascular health. Polyphenols mitigate neuroinflammation by suppressing NF-κB signaling and upregulating brain-derived neurotrophic factor, supporting neuroplasticity and neurogenesis. They also enhance cerebrovascular health by improving cerebral blood flow, maintaining blood-brain barrier integrity, and modulating angiogenesis. This review examines the molecular and cellular pathways through which polyphenols exert neuroprotective effects, focusing on their antioxidant, anti-inflammatory, and amyloid-modulating roles. We also discuss their influence on key AD pathologies, including Aβ deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Insights from clinical and preclinical studies highlight the potential of polyphenols in preventing or slowing AD progression. Future research should explore personalized dietary strategies that integrate genetic and lifestyle factors to optimize the neuroprotective effects of polyphenols.

Mutations in mitochondrial DNA play a crucial role in several diseases, but interpreting the clinical significance of mitochondrial DNA variants is challenging due to heteroplasmy, age-related loss of variants and evolving phenotypes. The aim of study was to identify mitochondrial pathogenic variants and explore their potential future association with specific phenotypes in patients during their lifetime, for both known and novel variants. We used a Python pipeline to analyse exome sequencing data from 418 patients (median age: 15 years; 52.9% males and 47.1% females), mostly diagnosed with neurological disorders, developmental and intellectual disabilities, behavioural and sensory disorders, cardiovascular and metabolic abnormalities, renal diseases and others. Screening identified 1,000 unique variants with heteroplasmy levels greater than 10% and 192 unique variants with 1-10% heteroplasmy, excluding hypervariable regions. Among these variants, four confirmed pathogenic variants were detected according to MITOMAP (m.1555 A > G, m.3243 A > G, m.9035T > C, and m.11778G > A), each identified in one patient. The application of pathogenicity and frequency criteria led to the identification of three unique variants and one in monozygotic twin sister with low levels of heteroplasmy, which were confirmed by next-generation sequencing. Finally, one of them, the variant m.15897G > A, was recognised as likely pathogenic (PP3, PS2). Our study highlights the complexity of diagnosing mitochondrial diseases associated with mtDNA mutations and emphasises the need for a comprehensive genotype-phenotype approach to correctly identify causal variants.

We describe a unique patient who had been diagnosed with inflammatory demyelinating polyneuropathy (CIDP) for 13 years with frequent clear responses to immunotherapies and was finally diagnosed with Charcot-Marie-Tooth disease (CMT) with a rare point mutation in PMP22 (c.320G > A, p.G107D). Some patients diagnosed with young-onset CIDP may have underlying CMT, and extensive genetic testing including point mutations of PMP22 gene is required not to miss the diagnosis.

Mutations in the DEPDC5 gene are inherited in an autosomal dominant manner and can lead to various clinical phenotypes, including focal seizures. While numerous case reports on DEPDC5 mutations exist, functional validation studies remain scarce. We analyzed seven cases of epilepsy or developmental disorders caused by DEPDC5 mutations, summarizing their clinical manifestations and conducting genetic analysis of the mutation sites. The age of onset in the seven patients ranged from 2 months to 4 years. Six mutation sites were identified, including three nonsense mutations: c.1443del (p.C481X), c.2512 C > T (p.R838X), and c.2620 C > T (p.R874X); one missense mutation: c.1140 C > A (p.F380L); and two splice-site mutations: c.2802-13 C > G (splicing) and c.4034-2 A > G (splicing). Among these, c.2512 C > T (p.R838X) and c.2620 C > T (p.R874X) had been previously reported, while the remaining mutations were novel. Minigene experiments confirmed that the c.4034-2 A > G mutation resulted in a slightly truncated protein.Focal seizures were the predominant symptom in six cases. Among the four patients with nonsense mutations, three (Cases 2, 4, and 5) exhibited drug-resistant epilepsy. Four out of seven patients responded effectively to lacosamide treatment. DEPDC5 mutations can cause focal seizures, with truncating mutations associated with more severe symptoms. Lacosamide may offer better therapeutic outcomes. The intronic mutation c.463 + 4 A > G (splicing) led to protein truncation and was determined to be pathogenic.

Metachromatic Leukodystrophy (MLD) is a rare autosomal recessive lysosomal disorder caused by ARSA gene variants, affecting central and peripheral nervous systems. While ARSA variants are reported globally, data from sub-Saharan Africa (SSA) are limited. We report the first SSA case, a Malian patient with a rare phenotype: predominant tonic seizures without typical peripheral neuropathy signs. The patient harbored a novel ARSA variant (c.191T > C; p.Phe64Ser), predicted deleterious by in silico tools. This case expands the genetic and phenotypic spectrum of MLD, underscoring the need for genetic studies in underrepresented regions.

Schizophrenia (SCZ) is a chronic and severe mental disorder with a complex molecular aetiology. Emerging evidence indicates a potential association between the gut microbiome and the development of SCZ. Considering the under-representation of African populations in SCZ research, this study aimed to explore the association between the gut microbiome and SCZ within a South African cohort. Gut microbial DNA was obtained from 89 participants (n = 41 SCZ cases; n = 48 controls) and underwent 16S rRNA (V4) sequencing. Data preparation and taxa classification were performed with the DADA2 pipeline in R studio followed by diversity analysis using QIIME2. Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC) was utilised to identify differentially abundant taxa. No statistically significant differences were observed between SCZ patients and controls in terms of alpha-diversity (Shannon q = 0.09; Simpson q = 0.174) or beta-diversity (p = 0.547). Five taxa, namely Prevotella (p = 0.037), Faecalibacterium (p = 0.032), Phascolarctobacterium (p = 0.002), Dialister (p = 0.043), and SMB53 (p = 0.012), were differentially abundant in cases compared to controls, but this observation did not survive correction for multiple testing. This exploratory study suggests a potential association between the relative abundance of Prevotella, Faecalibacterium, Phascolarctobacterium, Dialister, and SMB53 with SCZ case-control status. Given the lack of significance after correcting for multiple testing, these results should be interpreted with caution. Mechanistic studies in larger samples are warranted to confirm these findings and better understand the association between the gut microbiome and SCZ.

Mitochondrial Complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is a progressive neurodegenerative disorder characterized by autosomal recessive inheritance and developmental regression, particularly in gross motor skills, which manifests in early childhood. This study aims to present the discovery of a novel variant in four male siblings aged 13 years 9 months to 25 years, making this the fourth family reported globally, while also raising awareness of rare mitochondrial diseases. Four individuals from the same family were retrospectively evaluated based on their demographic, clinical, laboratory, and molecular genetic data. The mutation in the ATP5MK gene was analyzed using the exome sequencing (ES) method. The detected variation was classified according to the criteria American College of Medical Genetics. Four cases, aged between 13 years 9 months and 25 years, were analyzed. All individuals were male. While all four cases had a history of neurodegenerative disease, they also exhibited intellectual disability, muscle weakness, increased deep tendon reflexes in the lower extremities, spasticity, scoliosis, pes cavus deformity, positive Babinski reflex, abnormal gait patterns due to foot deformities, and normal cerebellar tests. Additional findings included geographic tongue (n = 2), strabismus (n = 2), nystagmus (n = 1), ophthalmoplegia (n = 2), hypertrophic upper extremity muscle body build (n = 2), keloid tissue (n = 1), and short stature (n = 3). ES of the first case identified a homozygous splice donor variant (c.87 + 1G > A) in the ATP5MK gene as a novel variant, and family screening revealed the same variant in a biallelic state in the other three siblings. The parents were confirmed as heterozygous carriers, consistent with autosomal recessive inheritance. Mitochondrial diseases can mimic a wide range of neurological disorders. They should be considered as a potential underlying cause when treatment for suspected differential diagnoses proves ineffective.