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Genetics of Motor Neuron Diseases
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Genetics of Motor Neuron Diseases

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

Deadline for manuscript submissions: closed (25 April 2022) | Viewed by 44163

Special Issue Editor

Dr. Christopher Grunseich

E-Mail Website
Guest Editor
Neurogenet Branch, National Institutes of Health (NIH), Bethesda, MD, USA
Interests: spinal and bulbar muscular atrophy; motor neuron disease; neurogenetics; amyotrophic lateral sclerosis type 4
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Motor neuron disease is a neurodegenerative condition that results in progressive atrophy and muscle loss as a consequence of motor neuron degeneration. Most cases of the disease are sporadic, and approximately 10% are familial. Progress has been made in identifying genes implicated in familial forms of the disease and identifying pathways and cellular processes that are altered by the mutations. Candidate genes with high penetrance have typically been identified through linkage analysis and next-generation sequencing, and other strategies including genome-wide association studies have been used to identify genes with low disease penetrance. The identification of genetic causes and risk factors is helpful to not only develop better models of disease and understand the pathogenesis, but also to guide the rationale and design of new avenues for therapeutic development. An example of success with this approach comes from the development of an antisense oligonucleotide (nusinersen) which can target exon 7 retention in the SMN2 gene and improve the amount of functional SMN protein in patients with spinal muscular atrophy and deletion in SMN1. Nusinersen was approved by the US Food and Drug Agency in December 2016 for the treatment of spinal muscular atrophy.

This Special Issue aims to provide a broad and updated overview of the genetics of motor neuron diseases and the resulting clinical and molecular observations which may lead to new therapeutic insights for the treatment of the disease.

Dr. Christopher Grunseich
Guest Editor

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 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

  • motor neuron disease
  • familial amyotrophic lateral sclerosis (fALS)
  • gene therapy
  • antisense oligonucleotides (ASOs)
  • precision medicine
  • novel therapeutic approaches

Published Papers (15 papers)

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Research

Jump to: Review, Other

10 pages, 273 KiB  
Article
Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study
by Veria Vacchiano, Anna Bartoletti-Stella, Giovanni Rizzo, Patrizia Avoni, Piero Parchi, Fabrizio Salvi, Rocco Liguori and Sabina Capellari
Genes 2022, 13(8), 1306; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13081306 - 22 Jul 2022
Cited by 3 | Viewed by 2064
Abstract
Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) patients show a higher prevalence of Lewy body disease than the general population. Additionally, parkinsonian features were found in about 30% of ALS patients. We aimed to explore the frequency of Parkinson’s disease (PD)-causative genes [...] Read more.
Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) patients show a higher prevalence of Lewy body disease than the general population. Additionally, parkinsonian features were found in about 30% of ALS patients. We aimed to explore the frequency of Parkinson’s disease (PD)-causative genes in ALS patients, compared to AD and healthy controls (HCs). We used next-generation sequencing multigene panels by analyzing SNCA, LRRK2, PINK1, PARK2, PARK7, SYNJ1, CHCHD2, PLA2G6, GCH1, ATP13A2, DNAJC6 and FBXO genes. GBA gene, a risk factor for PD, was also analyzed. In total, 130 ALS and 100 AD patients were investigated. PD-related genes were found to be altered in 26.2% of ALS, 20% of AD patients and 19.2% of HCs. Autosomal recessive genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not significantly. However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were found to be decreased in ALS animal models and patients. Our results confirm the possible role of PD-related genes as risk modifier in ALS pathogenesis. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
6 pages, 811 KiB  
Communication
Nonalcoholic Fatty Liver Disease in Patients with Inherited and Sporadic Motor Neuron Degeneration
by Brian Johnson, Angela Kokkinis, Neville Gai, Ejaz A. Shamim, Craig Blackstone, Kenneth H. Fischbeck and Christopher Grunseich
Genes 2022, 13(6), 936; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13060936 - 24 May 2022
Cited by 2 | Viewed by 4603
Abstract
We describe evidence of fatty liver disease in patients with forms of motor neuron degeneration with both genetic and sporadic etiology compared to controls. A group of 13 patients with motor neuron disease underwent liver imaging and laboratory analysis. The cohort included five [...] Read more.
We describe evidence of fatty liver disease in patients with forms of motor neuron degeneration with both genetic and sporadic etiology compared to controls. A group of 13 patients with motor neuron disease underwent liver imaging and laboratory analysis. The cohort included five patients with hereditary spastic paraplegia, four with sporadic amyotrophic lateral sclerosis (ALS), three with familial ALS, and one with primary lateral sclerosis. A genetic mutation was reported in nine of the thirteen motor neuron disease (MND) patients. Fatty liver disease was detected in 10 of 13 (77%) MND patients via magnetic resonance spectroscopy, with an average dome intrahepatic triacylglycerol content of 17% (range 2–63%, reference ≤5.5%). Liver ultrasound demonstrated evidence of fatty liver disease in 6 of the 13 (46%) patients, and serum liver function testing revealed significantly elevated alanine aminotransferase levels in MND patients compared to age-matched controls. Fatty liver disease may represent a non-neuronal clinical component of various forms of MND. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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19 pages, 2951 KiB  
Article
New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
by Heike Kölbel, Florian Kraft, Andreas Hentschel, Artur Czech, Andrea Gangfuss, Payam Mohassel, Chi Nguyen, Werner Stenzel, Ulrike Schara-Schmidt, Corinna Preuße and Andreas Roos
Genes 2022, 13(5), 893; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13050893 - 17 May 2022
Cited by 2 | Viewed by 2177
Abstract
Serine palmitoyltransferase long chain base subunit 1 (SPTLC1) encodes a serine palmitoyltransferase (SPT) resident in the endoplasmic reticulum (ER). Pathological SPTLC1 variants cause a form of hereditary sensory and autonomic neuropathy (HSAN1A), and have recently been linked to unrestrained sphingoid base [...] Read more.
Serine palmitoyltransferase long chain base subunit 1 (SPTLC1) encodes a serine palmitoyltransferase (SPT) resident in the endoplasmic reticulum (ER). Pathological SPTLC1 variants cause a form of hereditary sensory and autonomic neuropathy (HSAN1A), and have recently been linked to unrestrained sphingoid base synthesis, causing a monogenic form of amyotrophic lateral sclerosis (ALS). It was postulated that the phenotypes associated with dominant variants in SPTLC1 may represent a continuum between neuropathy and ALS in some cases, complicated by additional symptoms such as cognitive impairment. A biochemical explanation for this clinical observation does not exist. By performing proteomic profiling on immortalized lymphoblastoid cells derived from one patient harbouring an alanine to serine amino acid substitution at position 20, we identified a subset of dysregulated proteins playing significant roles in neuronal homeostasis and might have a potential impact on the manifestation of symptoms. Notably, the identified p.(A20S)-SPTLC1 variant is associated with decrease of transcript and protein level. Moreover, we describe associated muscle pathology findings, including signs of mild inflammation accompanied by dysregulation of respective markers on both the protein and transcript levels. By performing coherent anti-Stokes Raman scattering microscopy, presence of protein and lipid aggregates could be excluded. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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16 pages, 612 KiB  
Article
Genetic Variability of Inflammation and Oxidative Stress Genes Affects Onset, Progression of the Disease and Survival of Patients with Amyotrophic Lateral Sclerosis
by Metka Ravnik-Glavač, Katja Goričar, David Vogrinc, Blaž Koritnik, Jakob Gašper Lavrenčič, Damjan Glavač and Vita Dolžan
Genes 2022, 13(5), 757; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13050757 - 25 Apr 2022
Cited by 8 | Viewed by 1853
Abstract
Inflammation and oxidative stress are recognized as important contributors to amyotrophic lateral sclerosis (ALS) disease pathogenesis. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in genes involved in inflammation and oxidative stress on ALS susceptibility and modification. One-hundred-and-eighty-five ALS patients [...] Read more.
Inflammation and oxidative stress are recognized as important contributors to amyotrophic lateral sclerosis (ALS) disease pathogenesis. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in genes involved in inflammation and oxidative stress on ALS susceptibility and modification. One-hundred-and-eighty-five ALS patients and 324 healthy controls were genotyped for nine polymorphisms in seven antioxidant and inflammatory genes using competitive allele-specific PCR. Logistic regression; nonparametric tests and survival analysis were used in the statistical analysis. Investigated polymorphisms were not associated with ALS susceptibility. Carriers of at least one polymorphic SOD2 rs4880 T or IL1B rs1071676 C allele more often had bulbar ALS onset (p = 0.036 and p = 0.039; respectively). IL1B rs1071676 was also associated with a higher rate of disease progression (p = 0.015). After adjustment for clinical parameters; carriers of two polymorphic IL1B rs1071676 C alleles had shorter survival (HR = 5.02; 95% CI = 1.92–13.16; p = 0.001); while carriers of at least one polymorphic CAT rs1001179 T allele had longer survival (HR = 0.68; 95% CI = 0.47–0.99; p = 0.046). Our data suggest that common genetic variants in the antioxidant and inflammatory pathways may modify ALS disease. Such genetic information could support the identification of patients that may be responsive to the immune or antioxidant system—based therapies. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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13 pages, 4388 KiB  
Article
High Concentration or Combined Treatment of Antisense Oligonucleotides for Spinal Muscular Atrophy Perturbed SMN2 Splicing in Patient Fibroblasts
by Yogik Onky Silvana Wijaya, Emma Tabe Eko Niba, Hisahide Nishio, Kentaro Okamoto, Hiroyuki Awano, Toshio Saito, Yasuhiro Takeshima and Masakazu Shinohara
Genes 2022, 13(4), 685; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040685 - 13 Apr 2022
Cited by 1 | Viewed by 2412
Abstract
Spinal muscular atrophy (SMA) is caused by survival motor neuron 1 SMN1 deletion. The survival motor neuron 2 (SMN2) encodes the same protein as SMN1 does, but it has a splicing defect of exon 7. Some antisense oligonucleotides (ASOs) have been proven to [...] Read more.
Spinal muscular atrophy (SMA) is caused by survival motor neuron 1 SMN1 deletion. The survival motor neuron 2 (SMN2) encodes the same protein as SMN1 does, but it has a splicing defect of exon 7. Some antisense oligonucleotides (ASOs) have been proven to correct this defect. One of these, nusinersen, is effective in SMA-affected infants, but not as much so in advanced-stage patients. Furthermore, the current regimen may exhibit a ceiling effect. To overcome these problems, high-dose ASOs or combined ASOs have been explored. Here, using SMA fibroblasts, we examined the effects of high-concentration ASOs and of combining two ASOs. Three ASOs were examined: one targeting intronic splicing suppressor site N1 (ISS-N1) in intron 7, and two others targeting the 3′ splice site and 5′ region of exon 8. In our experiments on all ASO types, a low or intermediate concentration (50 or 100 nM) showed better splicing efficiency than a high concentration (200 nM). In addition, a high concentration of each ASO created a cryptic exon in exon 6. When a mixture of two different ASOs (100 nM each) was added to the cells, the cryptic exon was included in the mRNA. In conclusion, ASOs at a high concentration or used in combination may show less splicing correction and cryptic exon creation. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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15 pages, 2647 KiB  
Article
Microglia Influence Neurofilament Deposition in ALS iPSC-Derived Motor Neurons
by Reilly L. Allison, Jacob W. Adelman, Jenica Abrudan, Raul A. Urrutia, Michael T. Zimmermann, Angela J. Mathison and Allison D. Ebert
Genes 2022, 13(2), 241; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13020241 - 27 Jan 2022
Cited by 5 | Viewed by 3204
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motor neuron loss is the primary phenotype, leading to muscle weakness and wasting, respiratory failure, and death. Although a portion of ALS cases are linked to one of over [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motor neuron loss is the primary phenotype, leading to muscle weakness and wasting, respiratory failure, and death. Although a portion of ALS cases are linked to one of over 50 unique genes, the vast majority of cases are sporadic in nature. However, the mechanisms underlying the motor neuron loss in either familial or sporadic ALS are not entirely clear. Here, we used induced pluripotent stem cells derived from a set of identical twin brothers discordant for ALS to assess the role of astrocytes and microglia on the expression and accumulation of neurofilament proteins in motor neurons. We found that motor neurons derived from the affected twin which exhibited increased transcript levels of all three neurofilament isoforms and increased expression of phosphorylated neurofilament puncta. We further found that treatment of the motor neurons with astrocyte-conditioned medium and microglial-conditioned medium significantly impacted neurofilament deposition. Together, these data suggest that glial-secreted factors can alter neurofilament pathology in ALS iPSC-derived motor neurons. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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15 pages, 3339 KiB  
Article
Stability and Oligomerization of Mutated SMN Protein Determine Clinical Severity of Spinal Muscular Atrophy
by Emma Tabe Eko Niba, Hisahide Nishio, Yogik Onky Silvana Wijaya, Mawaddah Ar Rochmah, Toru Takarada, Atsuko Takeuchi, Tomokazu Kimizu, Kentaro Okamoto, Toshio Saito, Hiroyuki Awano, Yasuhiro Takeshima and Masakazu Shinohara
Genes 2022, 13(2), 205; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13020205 - 24 Jan 2022
Cited by 3 | Viewed by 3092
Abstract
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disease characterized by defects of lower motor neurons. Approximately 95% of SMA patients are homozygous for survival motor neuron 1 (SMN1) gene deletion, while ~5% carry an intragenic SMN1 mutation. Here, [...] Read more.
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disease characterized by defects of lower motor neurons. Approximately 95% of SMA patients are homozygous for survival motor neuron 1 (SMN1) gene deletion, while ~5% carry an intragenic SMN1 mutation. Here, we investigated the stability and oligomerization ability of mutated SMN1 proteins. Plasmids containing wild- and mutant-type SMN1 cDNA were constructed and transfected into HeLa cells. Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated similar abundances of transcripts from the plasmids containing SMN cDNA, but Western blotting showed different expression levels of mutated SMN1 proteins, reflecting the degree of their instability. A mutated SMN1 protein with T274YfsX32 exhibited a much lower expression level than other mutated SMN1 proteins with E134K, Y276H, or Y277C. In immunoprecipitation analysis, the mutated SMN1 protein with T274YfsX32 did not bind to endogenous SMN1 protein in HeLa cells, suggesting that this mutation completely blocks the oligomerization with full-length SMN2 protein in the patient. The patient with T274YfsX32 showed a much more severe phenotype than the other patients with different mutations. In conclusion, the stability and oligomerization ability of mutated SMN1 protein may determine the protein stability and may be associated with the clinical severity of SMA caused by intragenic SMN1 mutation. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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15 pages, 1519 KiB  
Article
Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients
by Alma Osmanovic, Isabel Gogol, Helge Martens, Maylin Widjaja, Kathrin Müller, Olivia Schreiber-Katz, Friedrich Feuerhake, Claus-Dieter Langhans, Gunnar Schmidt, Peter M. Andersen, Albert C. Ludolph, Jochen H. Weishaupt, Frank Brand, Susanne Petri and Ruthild G. Weber
Genes 2022, 13(1), 84; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010084 - 29 Dec 2021
Cited by 6 | Viewed by 2476
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in neurodegeneration. Thus, variants in the DHTKD1 gene encoding dehydrogenase E1 and transketolase domain containing 1 previously linked to 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth (CMT) disease type 2, and spinal muscular atrophy (SMA) were identified. In two independent European ALS cohorts (n = 643 cases), 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants predicted to be deleterious. Four DHTKD1 variants were previously described pathogenic variants, seven were recurrent, and eight were located in the E1_dh dehydrogenase domain. Nonsense variants located in the E1_dh domain were significantly more prevalent in ALS patients versus controls. The phenotype of ALS patients carrying DHTKD1 variants partially overlapped with CMT and SMA by presence of sensory impairment and a higher frequency of LMN-predominant cases. Our results argue towards rare heterozygous DHTKD1 variants as potential contributors to ALS phenotype and, possibly, pathogenesis. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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12 pages, 983 KiB  
Article
Investigating the Genetic Profile of the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS-FTD) Continuum in Patients of Diverse Race, Ethnicity and Ancestry
by Maysen Mesaros, Steven Lenz, Woobeen Lim, Jordan Brown, Luke Drury and Jennifer Roggenbuck
Genes 2022, 13(1), 76; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010076 - 28 Dec 2021
Cited by 5 | Viewed by 2607
Abstract
Preliminary evidence suggests that commonly used genetic tests may be less likely to identify a genetic etiology for ALS-FTD in patients of underrepresented race, ethnicity, and ancestry (REA), as compared to European REA. Patients of underrepresented REA may therefore be less likely to [...] Read more.
Preliminary evidence suggests that commonly used genetic tests may be less likely to identify a genetic etiology for ALS-FTD in patients of underrepresented race, ethnicity, and ancestry (REA), as compared to European REA. Patients of underrepresented REA may therefore be less likely to receive accurate and specific genetic counseling information and less likely to have access to gene-targeted therapies currently in clinical trials. We compiled outcome data from 1911 ALS-FTD patients tested at a commercial laboratory over a seven-year period for C9orf72 hexanucleotide repeat expansion (HRE) alone or C9orf72 and multigene sequencing panel testing. We compared the incidence of pathogenic (P), likely pathogenic (LP), and uncertain variants in C9orf72 and other ALS-FTD genes, as well as age at testing, in patients of different REA. The diagnostic rate in patients of European REA (377/1595, 23.64%) was significantly higher than in patients of underrepresented REA (44/316, 13.92%) (p < 0.001). Patients of European REA were more likely to have the C9orf72 HRE (21.3%) than patients of underrepresented REA (10.4%) (p < 0.001). The overall distribution of positive test outcomes in all tested genes was significantly different between the two groups, with relatively more P and LP variants in genes other than C9orf72 identified in patients of underrepresented REA. The incidence of uncertain test outcomes was not significantly different between patients of European and underrepresented REA. Patients with positive test outcomes were more likely to be younger than those with negative or uncertain outcomes. Although C9orf72 HRE assay has been advocated as the first, and in some cases, only genetic test offered to patients with ALS-FTD in the clinical setting, this practice may result in the reduced ascertainment of genetic ALS-FTD in patients of diverse REA. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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12 pages, 632 KiB  
Article
Individual Oligogenic Background in p.D91A-SOD1 Amyotrophic Lateral Sclerosis Patients
by Giulia Gentile, Benedetta Perrone, Giovanna Morello, Isabella Laura Simone, Sebastiano Andò, Sebastiano Cavallaro and Francesca Luisa Conforti
Genes 2021, 12(12), 1843; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12121843 - 23 Nov 2021
Cited by 3 | Viewed by 2149
Abstract
The p.D91A is one of the most common ALS-causing SOD1 mutations and is known to be either recessive or dominant. The homozygous phenotype is characterized by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary. To date, no [...] Read more.
The p.D91A is one of the most common ALS-causing SOD1 mutations and is known to be either recessive or dominant. The homozygous phenotype is characterized by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary. To date, no genetic protective factors located close to SOD1 have been associated with the mild progressive homozygous phenotype. Using Next Generation Sequencing (NGS), we characterized a small cohort of sporadic and familial p.D91A-SOD1 heterozygous (n = 2) or homozygous (n = 5) ALS patients, to reveal any additional contributing variant in 39 ALS-related genes. We detected unique sets of non-synonymous variants, four of which were of uncertain significance and several in untranslated regions of ALS-related genes. Our results supported an individual oligogenic background underlying both sporadic and familial p.D91A cases irrespective of their p.D91A mutant alleles. We suggest that a comprehensive genomic view of p.D91A-SOD1 ALS patients may be useful in identifying emerging variants and improving disease diagnosis as well as guiding precision medicine. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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10 pages, 3485 KiB  
Article
Detection of Spinal Muscular Atrophy Patients Using Dried Saliva Spots
by Yogik Onky Silvana Wijaya, Hisahide Nishio, Emma Tabe Eko Niba, Kentaro Okamoto, Haruo Shintaku, Yasuhiro Takeshima, Toshio Saito, Masakazu Shinohara and Hiroyuki Awano
Genes 2021, 12(10), 1621; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101621 - 14 Oct 2021
Cited by 3 | Viewed by 2337
Abstract
Spinal muscular atrophy (SMA) is a lower motor neuron disease, once considered incurable. The main symptoms are muscle weakness and muscular atrophy. More than 90% of cases of SMA are caused by homozygous deletion of survival motor neuron 1 (SMN1). Emerging [...] Read more.
Spinal muscular atrophy (SMA) is a lower motor neuron disease, once considered incurable. The main symptoms are muscle weakness and muscular atrophy. More than 90% of cases of SMA are caused by homozygous deletion of survival motor neuron 1 (SMN1). Emerging treatments, such as splicing modulation of SMN2 and SMN gene replacement therapy, have improved the prognoses and motor functions of patients. However, confirmed diagnosis by SMN1 testing is often delayed, suggesting the presence of diagnosis-delayed or undiagnosed cases. To enable patients to access the right treatments, a screening system for SMA is essential. Even so, the current newborn screening system using dried blood spots is still invasive and cumbersome. Here, we developed a completely non-invasive screening system using dried saliva spots (DSS) as an alternative DNA source to detect SMN1 deletion. In this study, 60 DSS (40 SMA patients and 20 controls) were tested. The combination of modified competitive oligonucleotide priming-polymerase chain reaction and melting peak analysis clearly distinguished DSS samples with and without SMN1. In conclusion, these results suggest that our system with DSS is applicable to SMA patient detection in the real world. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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Review

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10 pages, 509 KiB  
Review
Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders
by Tomoki Hirunagi, Kentaro Sahashi, Katherine G. Meilleur and Masahisa Katsuno
Genes 2022, 13(1), 109; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010109 - 05 Jan 2022
Cited by 6 | Viewed by 3308
Abstract
The recent advances in nucleic acid therapeutics demonstrate the potential to treat hereditary neurological disorders by targeting their causative genes. Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset neurodegenerative disorder caused by the expansion of trinucleotide cytosine-adenine-guanine repeats, which encodes [...] Read more.
The recent advances in nucleic acid therapeutics demonstrate the potential to treat hereditary neurological disorders by targeting their causative genes. Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset neurodegenerative disorder caused by the expansion of trinucleotide cytosine-adenine-guanine repeats, which encodes a polyglutamine tract in the androgen receptor gene. SBMA belongs to the family of polyglutamine diseases, in which the use of nucleic acids for silencing a disease-causing gene, such as antisense oligonucleotides and small interfering RNAs, has been intensively studied in animal models and clinical trials. A unique feature of SBMA is that both motor neuron and skeletal muscle pathology contribute to disease manifestations, including progressive muscle weakness and atrophy. As both motor neurons and skeletal muscles can be therapeutic targets in SBMA, nucleic acid-based approaches for other motor neuron diseases and myopathies may further lead to the development of a treatment for SBMA. Here, we review studies of nucleic acid-based therapeutic approaches in SBMA and related neurological disorders and discuss current limitations and perspectives to apply these approaches to patients with SBMA. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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16 pages, 804 KiB  
Review
Juvenile Amyotrophic Lateral Sclerosis: A Review
by Tanya Lehky and Christopher Grunseich
Genes 2021, 12(12), 1935; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12121935 - 30 Nov 2021
Cited by 18 | Viewed by 3765
Abstract
Juvenile amyotrophic lateral sclerosis (JALS) is a rare group of motor neuron disorders with gene association in 40% of cases. JALS is defined as onset before age 25. We conducted a literature review of JALS and gene mutations associated with JALS. Results of [...] Read more.
Juvenile amyotrophic lateral sclerosis (JALS) is a rare group of motor neuron disorders with gene association in 40% of cases. JALS is defined as onset before age 25. We conducted a literature review of JALS and gene mutations associated with JALS. Results of the literature review show that the most common gene mutations associated with JALS are FUS, SETX, and ALS2. In familial cases, the gene mutations are mostly inherited in an autosomal recessive pattern and mutations in SETX are inherited in an autosomal dominant fashion. Disease prognosis varies from rapidly progressive to an indolent course. Distinct clinical features may emerge with specific gene mutations in addition to the clinical finding of combined upper and lower motor neuron degeneration. In conclusion, patients presenting with combined upper and lower motor neuron disorders before age 25 should be carefully examined for genetic mutations. Hereditary patterns and coexisting features may be useful in determining prognosis. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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21 pages, 661 KiB  
Review
NAD+ Metabolism and Diseases with Motor Dysfunction
by Samuel Lundt and Shinghua Ding
Genes 2021, 12(11), 1776; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111776 - 09 Nov 2021
Cited by 9 | Viewed by 4613
Abstract
Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral [...] Read more.
Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot–Marie–Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson’s disease and Huntington’s disease. Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. NAD+ can be reversibly oxidized-reduced or directly consumed by NAD+-dependent proteins. NAD+ is synthesized in cells via three different paths: the de novo, Preiss–Handler, or NAD+ salvage pathways, with the salvage pathway being the primary producer of NAD+ in mammalian cells. NAD+ metabolism is being investigated for a role in the development of neurodegenerative diseases. In this review, we discuss cellular NAD+ homeostasis, looking at NAD+ biosynthesis and consumption, with a focus on the NAD+ salvage pathway. Then, we examine the research, including human clinical trials, focused on the involvement of NAD+ in MNDs and other neurodegenerative diseases with motor dysfunction. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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Other

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5 pages, 391 KiB  
Case Report
Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations
by Julian Theuriet, Antoine Pegat, Pascal Leblanc, Sandra Vukusic, Cécile Cazeneuve, Stéphanie Millecamps, Guillaume Banneau, Marine Guillaud-Bataille and Emilien Bernard
Genes 2021, 12(12), 1876; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12121876 - 25 Nov 2021
Cited by 1 | Viewed by 1804
Abstract
Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of [...] Read more.
Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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