New Insights into Genetic Neurological Diseases

A special issue of Neurology International (ISSN 2035-8377).

Deadline for manuscript submissions: 31 July 2024 | Viewed by 6322

Special Issue Editors


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Guest Editor
1. Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
2. Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan
Interests: molecular mechanisms underlying myelination and demyelination; molecular and cellular therapeutic procedures for Charcot–Marie–Tooth diseases; Pelizaeus–Merzbacher disease and hypomyelinating leukodystrophies; frontotemporal dementia
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Laboratory of Ion Channel Pathophysiology, Doshisha University Graduate School of Brain Science, Kyotanabe, Kyoto 610-0394, Japan
Interests: molecular mechanisms underlying myelination and demyelination; molecular and cellular therapeutic procedures for Pelizaeus–Merzbacher disease and hypomyelinating leukodystrophies

E-Mail Website
Guest Editor
Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan
Interests: molecular mechanisms underlying myelination and demyelination; molecular and cellular therapeutic procedures for Charcot–Marie–Tooth diseases; Pelizaeus–Merzbacher disease and hypomyelinating leukodystrophies; frontotemporal dementia

Special Issue Information

Dear Colleagues, 

Significant advances in next-generation nucleic acid sequencing systems have revealed the causes of many neurological disorders and their syndromes due to previously unexpected mutations in protein-encoding genes and non-coding RNAs. In addition, it has been determined familial mutations and fragility mutations in prominent neurological diseases such as Alzheimer’s disease and Parkinson’s disease, as well as tumors derived from ectoderm,  cause these diseases or increase the possibility of developing pathological conditions. Therefore, in this Special Issue, research on the gene mutations and fragility mutations related to the causes of new human neurological diseases, how these gene mutations lead to diseases, or new therapeutic methods for neurological diseases caused by existing mutations will be focused on in vitro studies and reviews using cell lines and disease-derived cells, and in vivo studies and reviews that clarify using experimental animals such as flies, zebrafish, and mice. However, not limited to the scope of these studies, we would like to cover a wide range of research on hereditary mutations.

Prof. Dr. Junji Yamauchi
Dr. Tomohiro Torii
Dr. Yuki Miyamoto
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 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 mutation
  • hereditary disease
  • neuropathy
  • in vitro
  • in vivo
  • mechanism of action
  • therapeutic procedure
  • intracellular signaling
  • extracellular signaling

Published Papers (4 papers)

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Research

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12 pages, 1212 KiB  
Article
Nusinersen Treatment for Spinal Muscular Atrophy: Retrospective Multicenter Study of Pediatric and Adult Patients in Kuwait
by Asma AlTawari, Mohammad Zakaria, Walaa Kamel, Nayera Shaalan, Gamal Ahmed Ismail Elghazawi, Mohamed Esmat Anwar Ali, Dalia Salota, Amr Attia, Ehab Elsayed Ali Elanay, Osama Shalaby, Fatema Alqallaf, Vesna Mitic and Laila Bastaki
Neurol. Int. 2024, 16(3), 631-642; https://doi.org/10.3390/neurolint16030047 - 4 Jun 2024
Viewed by 556
Abstract
Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy approved for the treatment of 5q spinal muscular atrophy in pediatric and adult patients. The objective of this clinical case series is [...] Read more.
Spinal muscular atrophy is a neuromuscular genetic condition associated with progressive muscle weakness and atrophy. Nusinersen is an antisense oligonucleotide therapy approved for the treatment of 5q spinal muscular atrophy in pediatric and adult patients. The objective of this clinical case series is to describe the efficacy and safety of nusinersen in treating spinal muscular atrophy in 20 pediatric and 18 adult patients across six treatment centers in Kuwait. Functional motor assessments (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module) were used to assess changes in motor function following nusinersen treatment. The safety assessment involved clinical monitoring of adverse events. The results demonstrate clinically meaningful or considerable improvement in motor performance for nearly all patients, lasting over 4 years in some cases. A total of 70% of patients in the pediatric cohort and 72% of patients in the adult cohort achieved a clinically meaningful improvement in motor function following nusinersen treatment. Additionally, nusinersen was well-tolerated in both cohorts. These findings add to the growing body of evidence relating to the clinical efficacy and safety of nusinersen. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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19 pages, 8489 KiB  
Article
Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation
by Tomohiro Torii, Remina Shirai, Risa Kiminami, Satoshi Nishino, Takanari Sato, Sui Sawaguchi, Nana Fukushima, Yoichi Seki, Yuki Miyamoto and Junji Yamauchi
Neurol. Int. 2022, 14(4), 1062-1080; https://doi.org/10.3390/neurolint14040085 - 16 Dec 2022
Cited by 3 | Viewed by 2082
Abstract
Hypomyelinating leukodystrophy 10 (HLD10) is an autosomal recessive disease related to myelin sheaths in the central nervous system (CNS). In the CNS, myelin sheaths are derived from differentiated plasma membranes of oligodendrocytes (oligodendroglial cells) and surround neuronal axons to achieve neuronal functions. Nucleotide [...] Read more.
Hypomyelinating leukodystrophy 10 (HLD10) is an autosomal recessive disease related to myelin sheaths in the central nervous system (CNS). In the CNS, myelin sheaths are derived from differentiated plasma membranes of oligodendrocytes (oligodendroglial cells) and surround neuronal axons to achieve neuronal functions. Nucleotide mutations of the pyrroline-5-carboxylate reductase 2 (PYCR2) gene are associated with HLD10, likely due to PYCR2’s loss-of-function. PYCR2 is a mitochondrial residential protein and catalyzes pyrroline-5-carboxylate to an amino acid proline. Here, we describe how each of the HLD10-associated missense mutations, Arg119-to-Cys [R119C] and Arg251-to-Cys [R251C], lead to forming large size mitochondria in the FBD-102b cell line, which is used as an oligodendroglial cell differentiation model. In contrast, the wild type proteins did not participate in the formation of large size mitochondria. Expression of each of the mutated R119C and R251C proteins in cells increased the fusion abilities in mitochondria and decreased their fission abilities relatively. The respective mutant proteins, but not wild type proteins also decreased the activities of mitochondria. While cells expressing the wild type proteins exhibited differentiated phenotypes with widespread membranes and increased expression levels of differentiation marker proteins following the induction of differentiation, cells harboring each of the mutant proteins did not. Taken together, these results indicate that an HLD10-associated PYCR2 mutation leads to the formation of large mitochondria with decreased activities, inhibiting oligodendroglial cell morphological differentiation. These results may reveal some of the pathological mechanisms in oligodendroglial cells underlying HLD10 at the molecular and cellular levels. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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Review

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30 pages, 3208 KiB  
Review
Molecular and Biochemical Therapeutic Strategies for Duchenne Muscular Dystrophy
by Lakshmi Krishna, Akila Prashant, Yogish H. Kumar, Shasthara Paneyala, Siddaramappa J. Patil, Shobha Chikkavaddaragudi Ramachandra and Prashant Vishwanath
Neurol. Int. 2024, 16(4), 731-760; https://doi.org/10.3390/neurolint16040055 - 5 Jul 2024
Viewed by 385
Abstract
Significant progress has been achieved in understanding Duchenne muscular dystrophy (DMD) mechanisms and developing treatments to slow disease progression. This review article thoroughly assesses primary and secondary DMD therapies, focusing on innovative modalities. The primary therapy addresses the genetic abnormality causing DMD, specifically [...] Read more.
Significant progress has been achieved in understanding Duchenne muscular dystrophy (DMD) mechanisms and developing treatments to slow disease progression. This review article thoroughly assesses primary and secondary DMD therapies, focusing on innovative modalities. The primary therapy addresses the genetic abnormality causing DMD, specifically the absence or reduced expression of dystrophin. Gene replacement therapies, such as exon skipping, readthrough, and gene editing technologies, show promise in restoring dystrophin expression. Adeno-associated viruses (AAVs), a recent advancement in viral vector-based gene therapies, have shown encouraging results in preclinical and clinical studies. Secondary therapies aim to maintain muscle function and improve quality of life by mitigating DMD symptoms and complications. Glucocorticoid drugs like prednisone and deflazacort have proven effective in slowing disease progression and delaying loss of ambulation. Supportive treatments targeting calcium dysregulation, histone deacetylase, and redox imbalance are also crucial for preserving overall health and function. Additionally, the review includes a detailed table of ongoing and approved clinical trials for DMD, exploring various therapeutic approaches such as gene therapies, exon skipping drugs, utrophin modulators, anti-inflammatory agents, and novel compounds. This highlights the dynamic research field and ongoing efforts to develop effective DMD treatments. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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16 pages, 1275 KiB  
Review
New Insights into Risk Genes and Their Candidates in Multiple Sclerosis
by Remina Shirai and Junji Yamauchi
Neurol. Int. 2023, 15(1), 24-39; https://doi.org/10.3390/neurolint15010003 - 29 Dec 2022
Cited by 1 | Viewed by 2462
Abstract
Oligodendrocytes are central nervous system glial cells that wrap neuronal axons with their differentiated myelin membranes as biological insulators. There has recently been an emerging concept that multiple sclerosis could be triggered and promoted by various risk genes that appear likely to contribute [...] Read more.
Oligodendrocytes are central nervous system glial cells that wrap neuronal axons with their differentiated myelin membranes as biological insulators. There has recently been an emerging concept that multiple sclerosis could be triggered and promoted by various risk genes that appear likely to contribute to the degeneration of oligodendrocytes. Despite the known involvement of vitamin D, immunity, and inflammatory cytokines in disease progression, the common causes and key genetic mechanisms remain unknown. Herein, we focus on recently identified risk factors and risk genes in the background of multiple sclerosis and discuss their relationships. Full article
(This article belongs to the Special Issue New Insights into Genetic Neurological Diseases)
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