Neurogenetics最新文献_第5页

Whole exome sequencing in Serbian patients with hereditary spastic paraplegia. 塞尔维亚遗传性痉挛性截瘫患者的全外显子组测序。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-03-19 DOI: 10.1007/s10048-024-00755-x

Marija Brankovic, Vukan Ivanovic, Ivana Basta, Rin Khang, Eugene Lee, Zorica Stevic, Branislav Ralic, Radoje Tubic, GoHun Seo, Vladana Markovic, Ivo Bozovic, Marina Svetel, Ana Marjanovic, Nikola Veselinovic, Sarlota Mesaros, Milena Jankovic, Dusanka Savic-Pavicevic, Zita Jovin, Ivana Novakovic, Hane Lee, Stojan Peric

{"title":"Whole exome sequencing in Serbian patients with hereditary spastic paraplegia.","authors":"Marija Brankovic, Vukan Ivanovic, Ivana Basta, Rin Khang, Eugene Lee, Zorica Stevic, Branislav Ralic, Radoje Tubic, GoHun Seo, Vladana Markovic, Ivo Bozovic, Marina Svetel, Ana Marjanovic, Nikola Veselinovic, Sarlota Mesaros, Milena Jankovic, Dusanka Savic-Pavicevic, Zita Jovin, Ivana Novakovic, Hane Lee, Stojan Peric","doi":"10.1007/s10048-024-00755-x","DOIUrl":"10.1007/s10048-024-00755-x","url":null,"abstract":"Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with a high genetic and clinical heterogeneity. Numerous HSP patients remain genetically undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel variants and genes is needed. Our previous study analyzed 74 adult Serbian HSP patients from 65 families using panel of the 13 most common HSP genes in combination with a copy number variation analysis. Conclusive genetic findings were established in 23 patients from 19 families (29%). In the present study, nine patients from nine families previously negative on the HSP gene panel were selected for the whole exome sequencing (WES). Further, 44 newly diagnosed adult HSP patients from 44 families were sent to WES directly, since many studies showed WES may be used as the first step in HSP diagnosis. WES analysis of cohort 1 revealed a likely genetic cause in five (56%) of nine HSP families, including variants in the ETHE1, ZFYVE26, RNF170, CAPN1, and WASHC5 genes. In cohort 2, possible causative variants were found in seven (16%) of 44 patients (later updated to 27% when other diagnosis were excluded), comprising six different genes: SPAST, SPG11, WASCH5, KIF1A, KIF5A, and ABCD1. These results expand the genetic spectrum of HSP patients in Serbia and the region with implications for molecular genetic diagnosis and future causative therapies. Wide HSP panel can be the first step in diagnosis, alongside with the copy number variation (CNV) analysis, while WES should be performed after.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"165-177"},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hitting Epstein Barr virus where it hurts: computational methods exploration for siRNA therapy in alleviating Epstein Barr virus-induced multiple sclerosis. 直击爱泼斯坦-巴氏病毒要害：探索 siRNA 治疗缓解爱泼斯坦-巴氏病毒诱发的多发性硬化症的计算方法。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-05-29 DOI: 10.1007/s10048-024-00764-w

Taiwo Ooreoluwa Ojo, Oluwabamise Emmanuel Elegbeleye, Olawale Quadri Bolaji, Temitope Isaac Adelusi, Elijah Kolawole Oladipo, Matthew Oluwaseun Olawuyi, Bukola Oluwafunmilayo Afolayan, Adegboye Oyewole Oyaronbi, Taiwo Temitope Ogunjobi, Moyosoluwa Precious Oyewole, Kolade Pelumi Folorunso, Abdeen Tunde Ogunlana

{"title":"Hitting Epstein Barr virus where it hurts: computational methods exploration for siRNA therapy in alleviating Epstein Barr virus-induced multiple sclerosis.","authors":"Taiwo Ooreoluwa Ojo, Oluwabamise Emmanuel Elegbeleye, Olawale Quadri Bolaji, Temitope Isaac Adelusi, Elijah Kolawole Oladipo, Matthew Oluwaseun Olawuyi, Bukola Oluwafunmilayo Afolayan, Adegboye Oyewole Oyaronbi, Taiwo Temitope Ogunjobi, Moyosoluwa Precious Oyewole, Kolade Pelumi Folorunso, Abdeen Tunde Ogunlana","doi":"10.1007/s10048-024-00764-w","DOIUrl":"10.1007/s10048-024-00764-w","url":null,"abstract":"Multiple sclerosis (MS), an intricate neurological disorder, continues to challenge our understanding of the pivotal interplay between the immune system and the central nervous system (CNS). This condition arises from the immune system's misdirected attack on nerve fiber protection, known as myelin sheath, alongside nerve fibers themselves. This enigmatic condition, characterized by demyelination and varied clinical manifestations, prompts exploration into its multifaceted etiology and potential therapeutic avenues. Research has revealed a potential connection between Epstein Barr virus (EBV), specifically Epstein Barr Nuclear Antigen 1 (EBNA-1), and MS. The immune response to EBNA-1 antigen triggers the production of anti-EBNA-1 molecules, including IgG that identify a similar amino acid sequence to EBNA-1 in myelin, inadvertently targeting myelin sheath and contributing to MS progression. Currently, no treatment exists for EBNA-1-induced MS apart from symptom management. Addressing this, a novel potential therapeutic avenue utilizing small interference RNAs (siRNA) has been designed. By targeting the conserved EBNA-1 gene sequences in EBV types 1 and 2, five potential siRNAs were identified in our analysis. Thorough evaluations encompassing off-target binding, thermodynamics and secondary structure elucidation, efficacy prediction, siRNA-mRNA sequence binding affinity exploration, melting temperature, and docking of siRNAs with human argonaute protein 2 (AGO2) were conducted to elucidate the siRNAs efficiency. These designed siRNA molecules harnessed promising silencing activity in the EBNA-1 gene encoding the EBNA-1 antigen protein and thus have the potential to mitigate the severity of this dangerous virus.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"263-275"},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of established and novel extracellular matrix components in glioblastoma as targets for angiogenesis and prognosis. 鉴定胶质母细胞瘤中作为血管生成和预后靶点的既有和新型细胞外基质成分。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-05-22 DOI: 10.1007/s10048-024-00763-x

Lucas Cunha Barbosa, Gabriel Cardoso Machado, Manoela Heringer, Valéria Pereira Ferrer

{"title":"Identification of established and novel extracellular matrix components in glioblastoma as targets for angiogenesis and prognosis.","authors":"Lucas Cunha Barbosa, Gabriel Cardoso Machado, Manoela Heringer, Valéria Pereira Ferrer","doi":"10.1007/s10048-024-00763-x","DOIUrl":"10.1007/s10048-024-00763-x","url":null,"abstract":"Glioblastomas (GBM) are aggressive tumors known for their heterogeneity, rapid proliferation, treatment resistance, and extensive vasculature. Angiogenesis, the formation of new vessels, involves endothelial cell (EC) migration and proliferation. Various extracellular matrix (ECM) molecules regulate EC survival, migration, and proliferation. Culturing human brain EC (HBMEC) on GBM-derived ECM revealed a decrease in EC numbers compared to controls. Through in silico analysis, we explored ECM gene expression differences between GBM and brain normal glia cells and the impact of GBM microenvironment on EC ECM transcripts. ECM molecules such as collagen alpha chains (COL4A1, COL4A2, p < 0.0001); laminin alpha (LAMA4), beta (LAMB2), and gamma (LAMC1) chains (p < 0.0005); neurocan (NCAN), brevican (BCAN) and versican (VCAN) (p < 0.0005); hyaluronan synthase (HAS) 2 and metalloprotease (MMP) 2 (p < 0.005); MMP inhibitors (TIMP1-4, p < 0.0005), transforming growth factor beta-1 (TGFB1) and integrin alpha (ITGA3/5) (p < 0.05) and beta (ITGB1, p < 0.0005) chains showed increased expression in GBM. Additionally, GBM-influenced EC exhibited elevated expression of COL5A3, COL6A1, COL22A1 and COL27A1 (p < 0.01); LAMA1, LAMB1 (p < 0.001); fibulins (FBLN1/2, p < 0.01); MMP9, HAS1, ITGA3, TGFB1, and wingless-related integration site 9B (WNT9B) (p < 0.01) compared to normal EC. Some of these molecules: COL5A1/3, COL6A1, COL22/27A1, FBLN1/2, ITGA3/5, ITGB1 and LAMA1/B1 (p < 0.01); NCAN, HAS1, MMP2/9, TIMP1/2 and TGFB1 (p < 0.05) correlated with GBM patient survival. In conclusion, this study identified both established and novel ECM molecules regulating GBM angiogenesis, suggesting NCAN and COL27A1 are new potential prognostic biomarkers for GBM.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"249-262"},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Next generation sequencing panel as an effective approach to genetic testing in patients with a highly variable phenotype of neuromuscular disorders. 下一代测序面板是对表型千变万化的神经肌肉疾病患者进行基因检测的有效方法。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-05-17 DOI: 10.1007/s10048-024-00762-y

Wiktoria Radziwonik-Fraczyk, Ewelina Elert-Dobkowska, Marek Karpinski, Jacek Pilch, Karolina Ziora-Jakutowicz, Jolanta Kubalska, Dominika Szczesniak, Iwona Stepniak, Jacek Zaremba, Anna Sulek

{"title":"Next generation sequencing panel as an effective approach to genetic testing in patients with a highly variable phenotype of neuromuscular disorders.","authors":"Wiktoria Radziwonik-Fraczyk, Ewelina Elert-Dobkowska, Marek Karpinski, Jacek Pilch, Karolina Ziora-Jakutowicz, Jolanta Kubalska, Dominika Szczesniak, Iwona Stepniak, Jacek Zaremba, Anna Sulek","doi":"10.1007/s10048-024-00762-y","DOIUrl":"10.1007/s10048-024-00762-y","url":null,"abstract":"Neuromuscular disorders (NMDs) include a wide range of diseases affecting the peripheral nervous system. The genetic diagnoses are increasingly obtained with using the next generation sequencing (NGS). We applied the custom-design targeted NGS panel including 89 genes, together with genotyping and multiplex ligation-dependent probe amplification (MLPA) to identify a genetic spectrum of NMDs in 52 Polish patients. As a result, the genetic diagnosis was determined by NGS panel in 29 patients so its diagnostic utility is estimated at 55.8%. The most pathogenic variants were found in CLCN1, followed by CAPN3, SCN4A, and SGCA genes. Genotyping of myotonic dystrophy type 1 and 2 (DM1 and DM2) as a secondary approach has been performed. The co-occurrence of CAPN3 and CNBP mutations in one patient as well as DYSF and CNBP mutations in another suggests possibly more complex inheritance as well as expression of a phenotype. In 7 individuals with single nucleotide variant found in NGS testing, the MLPA of the CAPN3 gene was performed detecting the deletion encompassing exons 2-8 in the CAPN3 gene in one patient, confirming recessive limb-girdle muscular dystrophy type 1 (LGMDR1). Thirty patients obtained a genetic diagnosis (57.7%) after using NGS testing, genotyping and MLPA analysis. The study allowed for the identification of 27 known and 4 novel pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) associated with NMDs.In conclusion, the diagnostic approach with diverse molecular techniques enables to broaden the mutational spectrum and maximizes the diagnostic yield. Furthermore, the co-occurrence of DM2 and LGMD has been detected in 2 individuals.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"233-247"},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical genomics expands the link between erroneous cell division, primary microcephaly and intellectual disability. 临床基因组学拓展了错误细胞分裂、原发性小头畸形和智力残疾之间的联系。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-07-01 Epub Date: 2024-05-25 DOI: 10.1007/s10048-024-00759-7

Saima, Amjad Khan, Sajid Ali, Jiuhong Jiang, Zhichao Miao, Atif Kamil, Shahid Niaz Khan, Stefan T Arold

{"title":"Clinical genomics expands the link between erroneous cell division, primary microcephaly and intellectual disability.","authors":"Saima, Amjad Khan, Sajid Ali, Jiuhong Jiang, Zhichao Miao, Atif Kamil, Shahid Niaz Khan, Stefan T Arold","doi":"10.1007/s10048-024-00759-7","DOIUrl":"10.1007/s10048-024-00759-7","url":null,"abstract":"Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935 T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) and CEP135 (NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"179-191"},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141097003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Apo gene's genetic variants: hidden role in Asian vascular risk 载脂蛋白基因的遗传变异：在亚洲人血管风险中的隐性作用

IF 2.2 4区医学

Neurogenetics Pub Date : 2024-04-16 DOI: 10.1007/s10048-024-00757-9

Valentinus Besin, Farizky Martriano Humardani, Trilis Yulianti, Sulistyo Emantoko Dwi Putra, Rina Triana, Matthew Justyn

{"title":"The Apo gene's genetic variants: hidden role in Asian vascular risk","authors":"Valentinus Besin, Farizky Martriano Humardani, Trilis Yulianti, Sulistyo Emantoko Dwi Putra, Rina Triana, Matthew Justyn","doi":"10.1007/s10048-024-00757-9","DOIUrl":"https://doi.org/10.1007/s10048-024-00757-9","url":null,"abstract":"Vascular risk factors, including diabetes, hypertension, hyperlipidemia, and obesity, pose significant health threats with implications extending to neuropsychiatric disorders such as stroke and Alzheimer's disease. The Asian population, in particular, appears to be disproportionately affected due to unique genetic predispositions, as well as epigenetic factors such as dietary patterns and lifestyle habits. Existing management strategies often fall short of addressing these specific needs, leading to greater challenges in prevention and treatment. This review highlights a significant gap in our understanding of the impact of genetic screening in the early detection and tailored treatment of vascular risk factors among the Asian population. Apolipoprotein, a key player in cholesterol metabolism, is primarily associated with dyslipidemia, yet emerging evidence suggests its involvement in conditions such as diabetes, hypertension, and obesity. While genetic variants of vascular risk are ethnic-dependent, current evidence indicates that epigenetics also exhibits ethnic specificity. Understanding the interplay between Apolipoprotein and genetics, particularly within diverse ethnic backgrounds, has the potential to refine risk stratification and enhance precision in management. For Caucasian carrying the APOA5 rs662799 C variant, pharmacological interventions are recommended, as dietary interventions may not be sufficient. In contrast, for Asian populations with the same genetic variant, dietary modifications are initially advised. Should dyslipidemia persist, the consideration of pharmaceutical agents such as statins is recommended.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":"49 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140566343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Two more families supporting the existence of monogenic spinocerebellar ataxia 48 又有两个家族支持单基因脊髓小脑共济失调症的存在 48

IF 2.2 4区医学

Neurogenetics Pub Date : 2024-04-16 DOI: 10.1007/s10048-024-00758-8

Flavia Palombo, Alessandro Vaisfeld, Valentina Concetta Tropeano, Danara Ormanbekova, Isabelle Bacchi, Claudio Fiorini, Adelaide Peruzzi, Luca Morandi, Rocco Liguori, Valerio Carelli, Giovanni Rizzo

引用次数: 0

Identification of a Novel Homozygous GLS Gene Variant Associated with Developmental and Epileptic Encephalopathy (DEE) Type 71 与发育性癫痫性脑病 (DEE) 71 型有关的新型同卵 GLS 基因变异的鉴定

IF 2.2 4区医学

Neurogenetics Pub Date : 2024-04-15 DOI: 10.1007/s10048-024-00753-z

Afsaneh Bazgir, Mehdi Agha Gholizadeh, Seyyed Mohammad Kahani, Ali Reza Tavasoli, Masoud Garshasbi

{"title":"Identification of a Novel Homozygous GLS Gene Variant Associated with Developmental and Epileptic Encephalopathy (DEE) Type 71","authors":"Afsaneh Bazgir, Mehdi Agha Gholizadeh, Seyyed Mohammad Kahani, Ali Reza Tavasoli, Masoud Garshasbi","doi":"10.1007/s10048-024-00753-z","DOIUrl":"https://doi.org/10.1007/s10048-024-00753-z","url":null,"abstract":"Developmental and epileptic encephalopathy (DEEs) (OMIM#618,328) is characterized by seizures, hypotonia, and brain abnormalities, often arising from mutations in genes crucial for brain function. Among these genes, GLS stands out due to its vital role in the central nervous system (CNS), with homozygous variants potentially causing DEE type 71. Using Whole Exome Sequencing (WES) on a patient exhibiting symptoms of epileptic encephalopathy, we identified a novel homozygous variant, NM_014905.5:c.1849G > T; p.(Asp617Tyr), in the GLS gene. The 5-year-old patient, born to consanguineous parents, presented with developmental delay, encephalopathy, frequent seizures, and hypotonia. Sanger sequencing further validated the GLS gene variant in both the patient and his family. Furthermore, our bioinformatics analysis indicated that this missense variant could lead to alteration of splicing, resulting in the activation of a cryptic donor site and potentially causing loss of protein function. Our finding highlights the pathogenic significance of the GLS gene, particularly in the context of brain disorders, specifically DEE71.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":"9 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140565542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical and neuroimaging characterization of the first frontotemporal dementia family carrying the MAPT p.K298E mutation 首个携带 MAPT p.K298E 突变的额颞叶痴呆症家族的临床和神经影像学特征分析

IF 2.2 4区医学

Neurogenetics Pub Date : 2024-04-09 DOI: 10.1007/s10048-024-00756-w

Federico Emanuele Pozzi, Vittoria Aprea, Ginevra Giovannelli, Francesca Lattuada, Cinzia Crivellaro, Francesca Bertola, Veronica Castelnovo, Elisa Canu, Massimo Filippi, Ildebrando Appollonio, Carlo Ferrarese, Federica Agosta, Lucio Tremolizzo

{"title":"Clinical and neuroimaging characterization of the first frontotemporal dementia family carrying the MAPT p.K298E mutation","authors":"Federico Emanuele Pozzi, Vittoria Aprea, Ginevra Giovannelli, Francesca Lattuada, Cinzia Crivellaro, Francesca Bertola, Veronica Castelnovo, Elisa Canu, Massimo Filippi, Ildebrando Appollonio, Carlo Ferrarese, Federica Agosta, Lucio Tremolizzo","doi":"10.1007/s10048-024-00756-w","DOIUrl":"https://doi.org/10.1007/s10048-024-00756-w","url":null,"abstract":"We present an in-depth clinical and neuroimaging analysis of a family carrying the MAPT K298E mutation associated with frontotemporal dementia (FTD). Initial identification of this mutation in a single clinical case led to a comprehensive investigation involving four affected siblings allowing to elucidate the mutation's phenotypic expression.A 60-year-old male presented with significant behavioral changes and progressed rapidly, exhibiting speech difficulties and cognitive decline. Neuroimaging via FDG-PET revealed asymmetrical frontotemporal hypometabolism. Three siblings subsequently showed varied but consistent clinical manifestations, including abnormal behavior, speech impairments, memory deficits, and motor symptoms correlating with asymmetric frontotemporal atrophy observed in MRI scans.Based on the genotype–phenotype correlation, we propose that the p.K298E mutation results in early-onset behavioral variant FTD, accompanied by a various constellation of speech and motor impairment.This detailed characterization expands the understanding of the p.K298E mutation's clinical and neuroimaging features, underlining its role in the pathogenesis of FTD. Further research is crucial to comprehensively delineate the clinical and epidemiological implications of the MAPT p.K298E mutation.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":"18 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140566236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic blueprint of congenital muscular dystrophies with brain malformations in Egypt: A report of 11 families. 埃及先天性肌肉萎缩症伴有脑畸形的遗传蓝图：11 个家庭的报告。

IF 1.6 4区医学

Neurogenetics Pub Date : 2024-04-01 Epub Date: 2024-02-01 DOI: 10.1007/s10048-024-00745-z

Sylvia Safwat, Kyle P Flannery, Ahmed A El Beheiry, Mohamed M Mokhtar, Ebtesam Abdalla, M Chiara Manzini

{"title":"Genetic blueprint of congenital muscular dystrophies with brain malformations in Egypt: A report of 11 families.","authors":"Sylvia Safwat, Kyle P Flannery, Ahmed A El Beheiry, Mohamed M Mokhtar, Ebtesam Abdalla, M Chiara Manzini","doi":"10.1007/s10048-024-00745-z","DOIUrl":"10.1007/s10048-024-00745-z","url":null,"abstract":"Congenital muscular dystrophies (CMDs) are a group of rare muscle disorders characterized by early onset hypotonia and motor developmental delay associated with brain malformations with or without eye anomalies in the most severe cases. In this study, we aimed to uncover the genetic basis of severe CMD in Egypt and to determine the efficacy of whole exome sequencing (WES)-based genetic diagnosis in this population. We recruited twelve individuals from eleven families with a clinical diagnosis of CMD with brain malformations that fell into two groups: seven patients with suspected dystroglycanopathy and five patients with suspected merosin-deficient CMD. WES was analyzed by variant filtering using multiple approaches including splicing and copy number variant (CNV) analysis. We identified likely pathogenic variants in FKRP in two cases and variants in POMT1, POMK, and B3GALNT2 in three individuals. All individuals with merosin-deficient CMD had truncating variants in LAMA2. Further analysis in one of the two unsolved cases showed a homozygous protein-truncating variant in Feline Leukemia Virus subgroup C Receptor 1 (FLVCR1). FLVCR1 loss of function has never been previously reported. Yet, loss of function of its paralog, FLVCR2, causes lethal hydranencephaly-hydrocephaly syndrome (Fowler Syndrome) which should be considered in the differential diagnosis for dystroglycanopathy. Overall, we reached a diagnostic rate of 86% (6/7) for dystroglycanopathies and 100% (5/5) for merosinopathy. In conclusion, our results provide further evidence that WES is an important diagnostic method in CMD in developing countries to improve the diagnostic rate, management plan, and genetic counseling for these disorders.","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"93-102"},"PeriodicalIF":1.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11076401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139652285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0