Anni Saarela, Oskari Timonen, Jarkko Kirjavainen, Yawu Liu, Katri Silvennoinen, Esa Mervaala, Reetta Kälviäinen
{"title":"芬兰人群中富集的新型 LAMC3 致病变体会导致大脑皮层发育畸形和严重癫痫。","authors":"Anni Saarela, Oskari Timonen, Jarkko Kirjavainen, Yawu Liu, Katri Silvennoinen, Esa Mervaala, Reetta Kälviäinen","doi":"10.1002/epd2.20244","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objective</h3>\n \n <p>Recessive <i>LAMC3</i> mutations are recognized to cause epilepsy with cortical malformations characterized by polymicrogyria and pachygyria. The objective of this study was to describe the clinical picture and epilepsy phenotype of four patients with a previously undescribed <i>LAMC3</i> variant.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>All epilepsy patients treated in Kuopio Epilepsy Center (located in Kuopio, Finland) are offered the possibility to participate in a scientific study investigating biomarkers in epilepsy (Epibiomarker study). We have collected a comprehensive database of the study population, and are currently re-evaluating our database regarding the patients with developmental and/or epileptic encephalopathy (DEE). If the etiology of epilepsy remains unknown in the clinical setting, we are performing whole exome sequencing to recognize the genetic causes.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Among our study population of 323 DEE patients we recognized three patients with similar homozygous <i>LAMC3</i> c.1866del (p.(Phe623Serfs*10)) frameshift variant and one patient with a compound heterozygous mutation where the same frameshift variant was combined with an intronic <i>LAMC3</i> c.4231-12C>G variant on another allele. All these patients have severe epilepsy and either bilateral agyria-pachygyria or bilateral polymicrogyria in their clinical MRI scanning. Cortical malformations involve the occipital lobes in all our patients. Epilepsy phenotype is variable as two of our patients have DEE with epileptic spasms progressing to Lennox–Gastaut syndrome and intellectual disability. The other two patients have focal epilepsy without marked cognitive deficit. The four patients are unrelated. <i>LAMC3</i> c.1866del p.(Phe623Serfs*10) frameshift variant is enriched in the Finnish population.</p>\n </section>\n \n <section>\n \n <h3> Significance</h3>\n \n <p>Only a few patients with epilepsy caused by <i>LAMC3</i> homozygous or compound heterozygous mutations have been described in the literature. To our knowledge, the variants discovered in our patients have not previously been published. Clinical phenotype appears to be more varied than previously assumed and patients with a milder phenotype and normal cognition have probably remained unrecognized.</p>\n </section>\n </div>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":null,"pages":null},"PeriodicalIF":16.4000,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/epd2.20244","citationCount":"0","resultStr":"{\"title\":\"Novel LAMC3 pathogenic variant enriched in Finnish population causes malformations of cortical development and severe epilepsy\",\"authors\":\"Anni Saarela, Oskari Timonen, Jarkko Kirjavainen, Yawu Liu, Katri Silvennoinen, Esa Mervaala, Reetta Kälviäinen\",\"doi\":\"10.1002/epd2.20244\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>Recessive <i>LAMC3</i> mutations are recognized to cause epilepsy with cortical malformations characterized by polymicrogyria and pachygyria. The objective of this study was to describe the clinical picture and epilepsy phenotype of four patients with a previously undescribed <i>LAMC3</i> variant.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>All epilepsy patients treated in Kuopio Epilepsy Center (located in Kuopio, Finland) are offered the possibility to participate in a scientific study investigating biomarkers in epilepsy (Epibiomarker study). We have collected a comprehensive database of the study population, and are currently re-evaluating our database regarding the patients with developmental and/or epileptic encephalopathy (DEE). If the etiology of epilepsy remains unknown in the clinical setting, we are performing whole exome sequencing to recognize the genetic causes.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Among our study population of 323 DEE patients we recognized three patients with similar homozygous <i>LAMC3</i> c.1866del (p.(Phe623Serfs*10)) frameshift variant and one patient with a compound heterozygous mutation where the same frameshift variant was combined with an intronic <i>LAMC3</i> c.4231-12C>G variant on another allele. All these patients have severe epilepsy and either bilateral agyria-pachygyria or bilateral polymicrogyria in their clinical MRI scanning. Cortical malformations involve the occipital lobes in all our patients. Epilepsy phenotype is variable as two of our patients have DEE with epileptic spasms progressing to Lennox–Gastaut syndrome and intellectual disability. The other two patients have focal epilepsy without marked cognitive deficit. The four patients are unrelated. <i>LAMC3</i> c.1866del p.(Phe623Serfs*10) frameshift variant is enriched in the Finnish population.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Significance</h3>\\n \\n <p>Only a few patients with epilepsy caused by <i>LAMC3</i> homozygous or compound heterozygous mutations have been described in the literature. To our knowledge, the variants discovered in our patients have not previously been published. Clinical phenotype appears to be more varied than previously assumed and patients with a milder phenotype and normal cognition have probably remained unrecognized.</p>\\n </section>\\n </div>\",\"PeriodicalId\":1,\"journal\":{\"name\":\"Accounts of Chemical Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":16.4000,\"publicationDate\":\"2024-05-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/epd2.20244\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Accounts of Chemical Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/epd2.20244\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/epd2.20244","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Novel LAMC3 pathogenic variant enriched in Finnish population causes malformations of cortical development and severe epilepsy
Objective
Recessive LAMC3 mutations are recognized to cause epilepsy with cortical malformations characterized by polymicrogyria and pachygyria. The objective of this study was to describe the clinical picture and epilepsy phenotype of four patients with a previously undescribed LAMC3 variant.
Methods
All epilepsy patients treated in Kuopio Epilepsy Center (located in Kuopio, Finland) are offered the possibility to participate in a scientific study investigating biomarkers in epilepsy (Epibiomarker study). We have collected a comprehensive database of the study population, and are currently re-evaluating our database regarding the patients with developmental and/or epileptic encephalopathy (DEE). If the etiology of epilepsy remains unknown in the clinical setting, we are performing whole exome sequencing to recognize the genetic causes.
Results
Among our study population of 323 DEE patients we recognized three patients with similar homozygous LAMC3 c.1866del (p.(Phe623Serfs*10)) frameshift variant and one patient with a compound heterozygous mutation where the same frameshift variant was combined with an intronic LAMC3 c.4231-12C>G variant on another allele. All these patients have severe epilepsy and either bilateral agyria-pachygyria or bilateral polymicrogyria in their clinical MRI scanning. Cortical malformations involve the occipital lobes in all our patients. Epilepsy phenotype is variable as two of our patients have DEE with epileptic spasms progressing to Lennox–Gastaut syndrome and intellectual disability. The other two patients have focal epilepsy without marked cognitive deficit. The four patients are unrelated. LAMC3 c.1866del p.(Phe623Serfs*10) frameshift variant is enriched in the Finnish population.
Significance
Only a few patients with epilepsy caused by LAMC3 homozygous or compound heterozygous mutations have been described in the literature. To our knowledge, the variants discovered in our patients have not previously been published. Clinical phenotype appears to be more varied than previously assumed and patients with a milder phenotype and normal cognition have probably remained unrecognized.
期刊介绍：
Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance.
Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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