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Impact of Genetic Testing in Epilepsy and Other Neurological Conditions
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Impact of Genetic Testing in Epilepsy and Other Neurological Conditions

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 November 2024) | Viewed by 15882

Special Issue Editors

Dr. Tugce B. Balci

E-Mail Website
Guest Editor
1. Schulich School of Medicine, Western University, London, ON N6A 3K7, Canada
2. Division of Clinical Genetics, Department of Pediatrics, London Health Sciences Centre, London, ON N6A 5W9, Canada
Interests: genetics; epilepsy; novel gene discovery; zebrafish; genome wide sequencing
Dr. Maryam N. Nouri

E-Mail Website
Guest Editor
1. Schulich School of Medicine, Western University, London, ON N6A 3K7, Canada
2. Division of Pediatric Neurology, Department of Pediatrics, London Health Sciences Centre, London, ON N6A 5W9, Canada
Interests: epilepsy; autoimmune epilepsy; epilepsy surgery; neuroimaging; genetic epilepsy

Special Issue Information

Dear Colleagues, 

Neurology has historically been the specialty most associated with medical genetics. Many neurological conditions have a genetic basis, and epilepsy likely takes up the biggest portion of the pie. Genetic testing has become part of the diagnostic toolbox of almost every neurologist, especially in the last 10 years, as genetic testing technologies have advanced. The integration and the increasing use of genome-wide sequencing (such as exome sequencing) in the neurology clinic has led to many families receiving a diagnosis, sometimes after struggling for many years with a debilitating, undiagnosed condition. A genetic diagnosis can be uncovered in about a quarter of all epilepsy patients, with much higher yields in the pediatric population. Many movement disorders, neuromuscular conditions, neurodegenerative conditions and certain types of strokes and dementias have also been found to be associated with heritable single gene defects, both in children and in adults. The benefits of genetic testing and counselling in neurological conditions are undeniable. A confirmed molecular diagnosis of an epilepsy subtype can guide neurologists to alter treatments or management to specifically target the defect (e.g., sodium channel blockers in channelopathies, a ketogenic diet in GLUT1 transporter deficiency, etc.). This can improve outcomes, not to mention the benefits of providing accurate genetic counselling to family members and having the option of presymptomatic genetic testing for at-risk individuals (e.g., of hereditary ataxias) or of prenatal diagnosis for conditions with a high recurrence risk (e.g., autosomal recessive neurodegenerative conditions).

This Special Issue of Genes will focus on new developments in and impacts of genetic testing in neurological conditions, including but not limited to epilepsy, neuromuscular disorders, neurodegenerative conditions and movement disorders.

We are extending an invitation for reviews on the current state of genetic testing and counselling in epilepsy and other neurological conditions, as well as original research articles that focus on the discovery of genetic variations or mutations which could be used to distinguish clinically relevant disease or predict therapeutic efficacies and outcomes. We strongly encourage contributors to send an abstract of their proposed manuscript to the Guest Editors (Drs. Balci and Nouri) for an assessment of its suitability for this Special Issue. We look forward to your contributions.

Dr. Tugce B. Balci
Dr. Maryam N. Nouri
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • genetic epilepsies
  • neuromuscular disorders
  • neurodegenerative conditions
  • genetic movement disorders
  • next generation sequencing
  • exome sequencing
  • genetic counselling
  • neurogenetics

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Published Papers (4 papers)

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Research

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10 pages, 1362 KiB  
Article
From Alpha-Thalassemia Trait to NPRL3-Related Epilepsy: A Genomic Diagnostic Odyssey
by Maryam Nabavi Nouri, Lama Alandijani, Kalene van Engelen, Soumitra Tole, Emilie Lalonde and Tugce B. Balci
Genes 2024, 15(7), 836; https://doi.org/10.3390/genes15070836 - 25 Jun 2024
Viewed by 1899
Abstract
Introduction: The NPRL3 gene is a critical component of the GATOR1 complex, which negatively regulates the mTORC1 pathway, essential for neurogenesis and brain development. Located on chromosome 16p13.3, NPRL3 is situated near the α-globin gene cluster. Haploinsufficiency of NPRL3, either by [...] Read more.
Introduction: The NPRL3 gene is a critical component of the GATOR1 complex, which negatively regulates the mTORC1 pathway, essential for neurogenesis and brain development. Located on chromosome 16p13.3, NPRL3 is situated near the α-globin gene cluster. Haploinsufficiency of NPRL3, either by deletion or a pathogenic variant, is associated with a variable phenotype of focal epilepsy, with or without malformations of cortical development, with known decreased penetrance. Case Description: This work details the diagnostic odyssey of a neurotypical 10-year-old boy who presented at age 2 with unusual nocturnal episodes and a history of microcytic anemia, as well as a review of the existing literature on NPRL3-related epilepsy, with an emphasis on individuals with deletions who also present with α-thalassemia trait. The proband’s episodes were mistaken for gastroesophageal reflux disease for several years. He had molecular testing for his α-thalassemia trait and was noted to carry a deletion encompassing the regulatory region of the α-thalassemia gene cluster. Following the onset of overt focal motor seizures, genetic testing revealed a heterozygous loss of NPRL3, within a 106 kb microdeletion on chromosome 16p13.3, inherited from his mother. This deletion encompassed the entire NPRL3 gene, which overlaps the regulatory region of the α-globin gene cluster, giving him the dual diagnosis of NPRL3-related epilepsy and α-thalassemia trait. Brain imaging postprocessing showed left hippocampal sclerosis and mid-posterior para-hippocampal focal cortical dysplasia, leading to the consideration of epilepsy surgery. Conclusions: This case underscores the necessity of early and comprehensive genetic assessments in children with epilepsy accompanied by systemic features, even in the absence of a family history of epilepsy or a developmental delay. Recognizing phenotypic overlaps is crucial to avoid diagnostic delays. Our findings also highlight the impact of disruptions in regulatory regions in genetic disorders: any individual with full gene deletion of NPRL3 would have, at a minimum, α-thalassemia trait, due to the presence of the major regulatory element of α-globin genes overlapping the gene’s introns. Full article
(This article belongs to the Special Issue Impact of Genetic Testing in Epilepsy and Other Neurological Conditions)
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Review

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21 pages, 373 KiB  
Review
The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions
by Alice Man, Matteo Di Scipio, Shan Grewal, Yujin Suk, Elisabetta Trinari, Resham Ejaz and Robyn Whitney
Genes 2024, 15(3), 332; https://doi.org/10.3390/genes15030332 - 4 Mar 2024
Cited by 17 | Viewed by 4411
Abstract
The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous [...] Read more.
The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype–phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition. Full article
(This article belongs to the Special Issue Impact of Genetic Testing in Epilepsy and Other Neurological Conditions)
24 pages, 752 KiB  
Review
Progressive Myoclonus Epilepsy: A Scoping Review of Diagnostic, Phenotypic and Therapeutic Advances
by Vincent Zimmern and Berge Minassian
Genes 2024, 15(2), 171; https://doi.org/10.3390/genes15020171 - 27 Jan 2024
Cited by 8 | Viewed by 4366
Abstract
The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy [...] Read more.
The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy and myoclonus cases that are seen in tertiary care centers. The last decade has seen substantial progress in our understanding of the pathophysiology, diagnosis, prognosis, and, in select disorders, therapies of these diseases. In this scoping review, we examine English language publications from the past decade that address diagnostic, phenotypic, and therapeutic advances in all PMEs. We then highlight the major lessons that have been learned and point out avenues for future investigation that seem promising. Full article
(This article belongs to the Special Issue Impact of Genetic Testing in Epilepsy and Other Neurological Conditions)
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15 pages, 917 KiB  
Review
STXBP1-Related Disorders: Clinical Presentation, Molecular Function, Treatment, and Future Directions
by Alexander Freibauer, Mikayla Wohlleben and Cyrus Boelman
Genes 2023, 14(12), 2179; https://doi.org/10.3390/genes14122179 - 5 Dec 2023
Cited by 8 | Viewed by 4516
Abstract
In recent years, the affordability and availability of genetic testing have led to its increased use in clinical care. The increased frequency of testing has led to STXBP1 variants being identified as one of the more common variants associated with neurological disorders. In [...] Read more.
In recent years, the affordability and availability of genetic testing have led to its increased use in clinical care. The increased frequency of testing has led to STXBP1 variants being identified as one of the more common variants associated with neurological disorders. In this review, we aim to summarize the common clinical phenotypes associated with STXBP1 pathogenic variants, provide an overview of their known natural history, and discuss current research into the genotype to phenotype correlation. We will also provide an overview of the suspected normal function of the STXBP1-encoded Munc18-1 protein, animal models, and experimental techniques that have been developed to study its function and use this information to try to explain the diverse phenotypes associated with STXBP1-related disorders. Finally, we will explore current therapies for STXBP1 disorders, including an overview of treatment goals for STXBP1-related disorders, a discussion of the current evidence for therapies, and future directions of personalized medications for STXBP1-related disorders. Full article
(This article belongs to the Special Issue Impact of Genetic Testing in Epilepsy and Other Neurological Conditions)
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