Neurogenetics最新文献

Intermediate CAG repeats from 29 to 33 in the ATXN2 gene contributes to the risk of amyotrophic lateral sclerosis (ALS) in European and Asian populations. In this study, 148 ALS patients of multiethnic descent: Chinese (56.1%), Malay (24.3%), Indian (12.8%), others (6.8%) and 100 neurologically normal controls were screened for the ATXN2 CAG repeat expansion. The most common repeat length in both the controls and patients was 22. No familial ALS patients were positive for the intermediate repeat sizes (29-33), while four sporadic patients (2.8%) were positive, with one harbouring a rare ATXN2 homozygous 32 repeat expansion, and a likely pathogenic variant in SPAST. All four patients had limb-onset ALS. Despite representing the smallest ethnic group in our patient cohort, three of the four patients with intermediate repeat sizes were of Indian ancestry. This study, which is the first in Malaysia and Southeast Asia, shows that ATXN2 intermediate risk expansions are relevant to ALS in these populations and will help to inform future genetic testing strategies in the clinic.

Schizophrenia (SZ) is a complex, chronic mental disorder characterized by positive symptoms (such as delusions and hallucinations), negative symptoms (including anhedonia, alogia, avolition, and social withdrawal), and cognitive deficits (affecting attention, processing speed, verbal and visuospatial learning, problem-solving, working memory, and mental flexibility). Extensive animal and clinical studies have emphasized the NMDAR hypofunction hypothesis of SZ. Glycine plays a crucial role as an agonist of NMDAR, enhancing the receptor's affinity for glutamate and supporting normal synaptic function and plasticity, that is, signal transmission between neurons. In the absence of glycine or any other co-agonists (serine and D-cycloserine), NMDAR responsiveness to glutamate decreases, reducing its likelihood to open and allow ion flow, which leads to impaired synaptic plasticity and neurotransmission. Current antipsychotic treatments are severely limited, as they only address positive symptoms, can lead to significant neurological and metabolic side effects such as sexual dysfunction, and are effective in only about half of SZ patients. Similarly, direct glycine-site modulators have shown considerable side-effects due to high-dose usage, such as nausea, nephrotoxicity, anxiety, depression, and hyperexcitability resulting from the external administration of glycine, serine, and D-cycloserine. To this effect, the current study considers glycine-like compounds with improved BBB permeability directly targeting the Glycine modulatory site (GMS). A thorough evaluation encompassing ADMET analysis, virtual screening, and molecular dynamics was used to screen the glycine-like library. Data collected revealed Compound_8, Compound_15, and Compound_945 as promising agonists. Further experimental validation is needed to confirm their preclinical relevance as SZ treatment.

Background: Mutations in the LARS2 gene are correlated with Perrault syndrome, a rare autosomal recessive genetic disorder, that is typically characterized by sensorineural hearing loss and ovarian insufficiency.

Methods: Whole-exome sequencing and mutational analysis were employed to identify hearing loss-causing genes in a Chinese family from the Guangxi Zhuang Autonomous Region. Clinical phenotypes, audiological data, and color Doppler ultrasound of the family were collected, and a series of computer software were used to analyze the impact of genetic variations on protein structure and function.

Results: Novel compound heterozygous LARS2 variants, c.604G > A and c.703C > T, were linked to hearing loss in the family, the latter of which has not been reported in any public database. The proband and her brother in this family presented with hearing loss, while the parents had normal hearing. Additionally, the c.703C > T mutation is a nonsense mutation, leading to a significant loss of amino acids, while the c.604G > A mutation affects the secondary structure and side-chain structure of the protein.

Conclusion: These mutations expand the LARS2 mutation spectrum and provide a basis for the genetic diagnosis of Perrault syndrome and related hearing loss.

In most cases there is a single etiological factor causing neuromotor developmental delay and epilepsy while sometimes more than one gene may be involved. These include the autosomal recessive inherited CAMSAP1 gene, which is associated with cortical developmental malformations such as pachygyria and lissencephaly and the autosomal dominant inherited NBEA gene, which plays crucial roles in vesicle trafficking as well as synapse structure and function. Loss of function of both genes together is a well-known disease mechanism. We report a 7-year-old girl with early-onset epilepsy, severe neuromotor developmental delay and brain malformation. Whole exome analysis of the patient revealed c.1153C > T p.Gln385* nonsense homozygous likely pathogenic variant in CAMSAP1 gene and c.6867G > A p.Trp2289* nonsense heterozygous pathogenic de novo variant in NBEA gene. A small number of cases associated with these genes have been reported. We report the 8th case reported in the CAMSAP1 gene and the overlapping phenotype in these two genes.

To investigate the causal relationships between cerebrospinal fluid (CSF) metabolites and various neurodegenerative diseases (NDDs), we conducted a two-sample Mendelian randomization (MR) analysis. This study utilized summary statistics from genome-wide association studies (GWAS) of CSF metabolites and four common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). MR methods were employed to determine causal associations, with the inverse variance weighted method as the primary approach. Additionally, different GWAS summary data for NDDs were used to validate the initial results and perform sensitivity analyses to enhance the robustness of the findings. Finally, reverse MR analyses were conducted to assess the possibility of reverse causation. Combining results from the initial and replication phases of MR analysis, we identified potential causal relationships between various CSF metabolites and different NDDs. Specifically, we found potential causal relationships between five CSF metabolites and AD, six CSF metabolites and MS, and thirteen CSF metabolites and ALS. Further sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis indicated causal effects of AD on glucuronate and ALS on acetylcarnitine (C2). Our study, through genetic means, demonstrates close causal associations between the specific types of CSF metabolites and the risk of NDDS (AD, PD, MS, and ALS), providing useful guidance for future clinical researches.

Neurodegeneration with brain iron accumulation 5 (NBIA5) is a distinctive type of NBIA phenotype that is caused by mutations in the WDR45 gene. This disorder is inherited in an X-linked manner. Here, we report three Iranian cases affected with this condition. Whole-exome sequencing revealed the following pathogenic variants within WDR45 gene in these cases, respectively: c.697 C > T (p.R233X), c.657_658del (p.F221X) and c.1004_1005del (p.Y335Cfs*5). Hypothyroidism was detected in two cases. Other clinical manifestations did not significantly differ from cases reported in the literature. All cases occurred de novo. Similar mutations have been reported in the literature. The present study broadens the insight about the genetics of this disorder in the mentioned population.

Background: Leigh syndrome is a common mitochondrial disorder caused by gene mutations in the nucleus and mitochondria. When building mitochondrial complex I, the main subunit ND1 combines with the Q module to form a 273 kDa complex, which then adds Ndufa3, Ndufa8, and Ndufa13 to create an intermediate product of about 283 kDa called Q/Pp-a. Although Ndufa8 and Ndufa13 have been linked to mitochondrial diseases, the role of Ndufa3 in disease development is still not fully understood.

Methods: A family suspected of having Leigh syndrome was examined. Subjects (two brothers and a sister) underwent brain imaging, and their clinical symptoms were evaluated. Also, whole exome sequencing and minigene testing were performed by examining peripheral blood samples (2 ml) collected from the proband, his parents, and brothers.

Results: Three affected children showed early-onset symptoms, including abnormalities in muscle tone and delayed motor and language development. Symptoms were relatively mild. The second child of the second pregnancy experienced worsened muscle tone abnormalities after injury, slow wound healing, and sustained increased muscle tone up to a year after wound closure. His brain scans revealed lesions in the basal ganglia and brainstem, consistent with Leigh syndrome diagnosis. Genetic analysis identified compound heterozygous mutations in the Ndufa3 gene in all affected family members.

Conclusion: This is the first report of a family affected by Leigh syndrome associated with mutations in the Ndufa3 gene. Our analyses of clinical symptoms, radiological scans, and genetic investigations broaden our understanding of Ndufa3 gene mutations and their role in the development of Leigh syndrome.

Some subtypes of hereditary spastic paraplegia (HSP), especially with autosomal recessive inheritance (AR-HSP), have been reported rarely. In this study, we report the clinical features and molecular results of three unrelated Iranian patients with rare subtypes of HSP, including SPG76, SPG56, and SPG69; thereafter, we compare them to other reported cases. Three patients who were clinically diagnosed with HSP and born to consanguineous parents underwent molecular assessment by whole-exome sequencing (WES), followed by Sanger sequencing and co-segregation analysis. Two patients carried biallelic pathogenic variants in CAPN1, or CYP2U1, resulting in SPG76, and SPG56, respectively. Additionally, another patient presented with a variant of uncertain significance (VUS) in the gene associated with SPG69, known as RAB3GAP2. Variants of CAPN1 and RAB3GAP2 are novel while the CYP2U1 variant has been previously reported. The patient with the RAB3GAP2 variant is the second reported SPG69 case. Our findings emphasize that the rare forms of AR-HSP may be more prevalent in communities with a high rate of consanguineous marriages, and WES can be a highly effective tool for identifying pathogenic variants in these communities. Also, the CYP2U1 variant seems to be a founder mutation because it was previously reported in 8 patients of three families from the Middle East. These results expand the variant spectrum of the CAPN1 and RAB3GAP2 genes. Also, given the association of variants in CAPN1 and RAB3GAP2 with a diverse array of phenotypes, we propose the use of the terms "CAPN1-related disorders" and "RAB3GAP2-related disorders" as alternatives to HSP76 and HSP69, respectively.

We present a 7.5-year-old boy born to a family from the Iranian Azeri Turkish ethnic group with a consanguineous marriage who presents with a unique set of symptoms, suggesting Giant Axonal Neuropathy. He achieved independent walking at age 3 years, with frequent falling during running. Physical and neurological examinations reveal curly blond hair, generalized muscle atrophy, slow speech and difficulty swallowing solid food, foot drop, pes cavus, hammertoe deformities; reduced deep tendon reflexes, clumsy gait, impaired sense of position, and intention tremors.This comprehensive report significantly expands the clinical and mutational spectrum of Giant Axonal Neuropathy. Whole Exome Sequencing (WES) analysis revealed a novel homozygous variant (NC_000016.10(NM_022041.3):c.2T > C) in the GAN gene, confirmed by Sanger sequencing. Segregation analysis showed that the parents were heterozygous for the variant. The variant was absent in a cohort of 430 healthy individuals from the same ethnic group and in other published population databases such as GenomAD and the 1000 Genome. The clinical manifestations, segregation analysis, population study, and bioinformatics analysis collectively confirm the pathogenicity of variant.

This review article investigates the intricate relationship between nutrigenomics and neurological disorders, highlighting how genetic variations affect an individual's response to nutrients. The study delves into the role of diet-related oxidative stress and the gut-brain axis in the progression and management of brain disorders such as Parkinson's disease, Alzheimer's disease, epilepsy, stroke, migraines, and depression. The review encompasses various clinical trials and introduces new trends and techniques, including omics and artificial intelligence, in identifying and managing neurological disorders. The main findings emphasize that personalized diet recommendations, tailored to an individual's genetic makeup, can significantly improve cognitive health and manage neurological conditions. The study concludes that further research in the field of nutrigenomics is essential to advancing personalized nutrition strategies for better neurological functioning, ultimately linking diet, genes, and brain health.