Rare Neurological Diseases

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (15 October 2021) | Viewed by 16208

Special Issue Editors


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Guest Editor
1. Unit of Rare Neurodegenerative Diseases, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
2. CIPF-IIS La Fe Joint Unit Rare Diseases, 46012 Valencia, Spain
3. UPV-CIPF Joint Research Unit Disease Mechanisms and Nanomedicine, 46012 Valencia, Spain
Interests: rare diseases; movement disorders; genetics and genomics; biomarkers
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
1. Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politécnica de València, Universitat de València, 46012 Valencia, Spain
2. Unit of Developmental Biology and Disease Models, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
3. UPV-CIPF Joint Research Unit Disease Mechanisms and Nanomedicine, 46012 Valencia, Spain
Interests: cell biology; drosophila; genetics; neurodegeneration
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
1. CIPF-IIS La Fe Joint Unit Rare Diseases, 46012 Valencia, Spain
2. Unit of Pathophysiology and Therapies for Vision Disorders, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
3. Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
Interests: inflammation; oxidative stress; neuroprotection; retinal dystrophies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In Europe, a rare disease is one that affects fewer than 5 people per 10,000 in the population. This low prevalence results in a relatively low interest in investing in research into these diseases and the development of therapies. Nevertheless, they exist. More than 7000 rare diseases are supposed to exist, and a relevant group are neurological disorders: inherited retinal dystrophies, epilepsies, ataxias, choreas, dystonias, etc. Most of them are Mendelian disorders, affect children, are congenital, and may cause severe disability. They are often chronic and life-threatening. To make things worse, most of them lack an effective treatment. In this Special Issue, we invite you to submit original articles, reviews, or case reports focused on how neurodegeneration is commonly involved in the pathomechanisms of many rare diseases, and the most recent advances that may enable patients to receive an accurate diagnosis and achieve a rational treatment.

Dr. Carmen Espinós
Dr. Máximo Ibo Galindo
Dr. Regina Rodrigo
Guest Editors

Manuscript Submission Information

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Keywords

  • Rare diseases
  • Neurodegeneration
  • Genetics
  • Omics
  • Biomarkers
  • Drug discovery
  • Cell therapy
  • Pharmacological therapy
  • Genomic edition
  • Clinical trials

Published Papers (5 papers)

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9 pages, 505 KiB  
Article
Genetic Workup for Charcot–Marie–Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years
by Chiara Gemelli, Alessandro Geroldi, Sara Massucco, Lucia Trevisan, Ilaria Callegari, Lucio Marinelli, Giulia Ursino, Mehrnaz Hamedani, Giulia Mennella, Silvia Stara, Giovanni Maggi, Laura Mori, Cristina Schenone, Fabio Gotta, Serena Patrone, Alessia Mammi, Paola Origone, Valeria Prada, Lucilla Nobbio, Paola Mandich, Angelo Schenone, Emilia Bellone and Marina Grandisadd Show full author list remove Hide full author list
Life 2022, 12(3), 402; https://doi.org/10.3390/life12030402 - 10 Mar 2022
Cited by 7 | Viewed by 2797
Abstract
Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution [...] Read more.
Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation. Full article
(This article belongs to the Special Issue Rare Neurological Diseases)
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18 pages, 8855 KiB  
Article
Generation and Characterization of the Drosophila melanogaster paralytic Gene Knock-Out as a Model for Dravet Syndrome
by Andrea Tapia, Carlo N. Giachello, Martina Palomino-Schätzlein, Richard A. Baines and Máximo Ibo Galindo
Life 2021, 11(11), 1261; https://doi.org/10.3390/life11111261 - 18 Nov 2021
Cited by 5 | Viewed by 3027
Abstract
Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the paralytic gene, the single Drosophila melanogaster gene encoding this type [...] Read more.
Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the paralytic gene, the single Drosophila melanogaster gene encoding this type of protein, by homologous recombination. These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight, and walking tests. Moreover, they also manifested some cognitive alterations, such as anxiety and problems in learning. Electrophysiological analyses from larval motor neurons showed a decrease in cell capacitance and membrane excitability, while persistent sodium current increased. To detect alterations in metabolism, we performed an NMR metabolomic profiling of heads, which revealed higher levels in some amino acids, succinate, and lactate; and also an increase in the abundance of GABA, which is the main neurotransmitter implicated in Dravet syndrome. All these changes in the paralytic knock-out flies indicate that this is a good model for epilepsy and specifically for Dravet syndrome. This model could be a new tool to understand the pathophysiology of the disease and to find biomarkers, genetic modifiers and new treatments. Full article
(This article belongs to the Special Issue Rare Neurological Diseases)
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9 pages, 861 KiB  
Communication
Exploitation of Thermal Sensitivity and Hyperalgesia in a Mouse Model of Dystonia
by Damiana Scuteri, Laura Rombolà, Silvia Natoli, Antonio Pisani, Paola Bonsi, Kengo Hamamura, Giacinto Bagetta, Paolo Tonin and Maria Tiziana Corasaniti
Life 2021, 11(9), 985; https://doi.org/10.3390/life11090985 - 19 Sep 2021
Cited by 2 | Viewed by 2186
Abstract
Neuropathic pain is characterized by mechanical allodynia and thermal hyperalgesia to heat, and it affects some 20% of European population. Patients suffering from several neurologic diseases experience neuropathic pain, often finding no relief in therapy. Transgenic mice expressing the gene encoding the human [...] Read more.
Neuropathic pain is characterized by mechanical allodynia and thermal hyperalgesia to heat, and it affects some 20% of European population. Patients suffering from several neurologic diseases experience neuropathic pain, often finding no relief in therapy. Transgenic mice expressing the gene encoding the human mutant (hMT) or the human wild-type (hWT) torsin A represent a preclinical model of DYT1 dystonia which is the most common form of early-onset inherited dystonia. Baseline thermal sensitivity and hyperalgesia to heat have never been studied in models of dystonia. Therefore, the aim of this research has been to characterize thermal sensitivity in baseline conditions and hyperalgesia to heat after the induction of neuropathic pain through the spinal nerve ligation (SNL) model in mice overexpressing human wild-type and mutated torsin A in comparison to non-transgenic C57BL/6 mice. According to our results, the paw withdrawal latency time to heat in the Hargreaves’ test is significantly lower in the hMT mice (Kruskal–Wallis test = 6.933; p = 0.0312*; hMT vs. hWT p = 0.0317*). On the other hand, no significant differences in SNL-induced thermal hyperalgesia was found among the three strains (Friedman test = 4.933; p = 0.1019). Future studies are needed to better understand the role of torsin A in sensory processing of heat stimuli. Full article
(This article belongs to the Special Issue Rare Neurological Diseases)
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11 pages, 1927 KiB  
Article
Clinical and Neuroimaging Features in Charcot–Marie–Tooth Patients with GNB4 Mutations
by Hye Mi Kwon, Hyun Su Kim, Sang Beom Kim, Jae Hong Park, Da Eun Nam, Ah Jin Lee, Soo Hyun Nam, Soohyun Hwang, Ki Wha Chung and Byung-Ok Choi
Life 2021, 11(6), 494; https://doi.org/10.3390/life11060494 - 28 May 2021
Cited by 3 | Viewed by 3507
Abstract
Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 [...] Read more.
Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 Korean CMT families and excluded 344 families with a PMP22 duplication. We further analyzed the 799 remaining families to find their GNB4 mutations using whole-exome sequencing (WES). We identified two mutations (p.Gly77Arg and p.Lys89Glu) in three families, among which a heterozygous p.Gly77Arg mutation was novel. In addition, a significant uncertain variant (p.Thr177Asn) was observed in one family. The frequency of the GNB4 mutation in the Korean population is 0.38% in PMP22 duplication-negative families. All three families showed de novo mutation. Electrophysiological findings regarding the p.Lys89Glu mutation showed that the motor nerve conduction velocity (MNCV) of the median nerve was markedly reduced, indicating demyelinating neuropathy, and sural nerve biopsy revealed severe loss of myelinated axons with onion bulb formation. Lower extremity Magnetic Resonance Imaging (MRI) demonstrated relatively more severe intramuscular fat infiltrations in demyelinating type (p.Lys89Glu mutation) patients compared to intermediate type (p.Gly77Arg mutation) patients. The anterolateral and superficial posterior compartment muscles of the distal calf were preferentially affected in demyelinating type patients. Therefore, it seems that the investigated GNB4 mutations do cause not only the known intermediate type but also demyelinating-type neuropathy. We first presented three Korean families with GNB4 mutations and found phenotypic heterogeneities of both intermediate and demyelinating neuropathy. We suggest that those findings are useful for the differential diagnosis of CMT patients with unknown GNB4 variants. Full article
(This article belongs to the Special Issue Rare Neurological Diseases)
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8 pages, 977 KiB  
Case Report
NGLY1 Deficiency: A Rare Newly Described Condition with a Typical Presentation
by Ivana Dabaj, Bénédicte Sudrié-Arnaud, François Lecoquierre, Kimiyo Raymond, Franklin Ducatez, Anne-Marie Guerrot, Sarah Snanoudj, Sophie Coutant, Pascale Saugier-Veber, Stéphane Marret, Gaël Nicolas, Abdellah Tebani and Soumeya Bekri
Life 2021, 11(3), 187; https://doi.org/10.3390/life11030187 - 27 Feb 2021
Cited by 10 | Viewed by 3049
Abstract
NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide [...] Read more.
NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide the clinical, biochemical and molecular description of the first NGLY1-CDDG patient from France along with a literature review. The index case presented with developmental delay, acquired microcephaly, hypotonia, alacrimia, feeding difficulty, and dysmorphic features. Given the complex clinical picture and the multisystemic involvement, a trio-based exome sequencing was conducted and urine oligosaccharides were assessed using mass spectrometry. The exome sequencing revealed a novel variant in the NGLY1 gene in a homozygous state. NGLY1 deficiency was confirmed by the identification of the Neu5Ac1Hex1GlcNAc1-Asn oligosaccharide in the urine of the patient. Literature review revealed the association of some key clinical and biological features such as global developmental delay—hypertransaminasemia, movement disorders, feeding difficulties and alacrima/hypolacrima. Full article
(This article belongs to the Special Issue Rare Neurological Diseases)
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