Prevalence of SOD1 allele associated with degenerative myelopathy in canine population in Greece.

Canine degenerative myelopathy (CDM) is a late-onset fatal disorder associated with a point mutation of the superoxide dismutase 1 (SOD1) gene (c.118G > A). The purpose of this study was to determine the genotype and allele frequencies of this mutation in 108 dogs, mainly in Belgian Malinois and German Shepherd dogs with (CDM-affected group) and without CDM clinical symptoms (control group) in Greece. Genotyping of the c.118G > A mutation was possible by Sanger sequencing and PCR-RFLP. The observed genotype frequencies for the control group were 89.4% for the homozygous (G/G), 9.6% for the heterozygous (A/G), and 0.96% for the homozygous mutant (A/A) allele. The mutant allele was not common in the Belgian Malinois dogs (allele frequency = 0.029), but quite common in the German Shepherd dogs (allele frequency = 0.138). In the CDM affected group, all 4 dogs were homozygous for the mutant allele. These frequencies were close to those expected, indicating no significant departure from Hardy-Weinberg equilibrium. A strong but not statistically significant association between the mutant allele and CDM was observed. A previously identified deletion upstream of the mutation of interest was found at a high frequency (0.361) in the population.

Nano Zinc Supplementation Affects Immunity, Hormonal Profile, Hepatic Superoxide Dismutase 1 (SOD1) Gene Expression and Vital Organ Histology in Wister Albino Rats.

The study was conducted to assess nano zinc (ZnN) as a feed supplement with an aim to compare the supplemental dose of inorganic zinc (ZnI). ZnN was synthesized from 0.45 molar (M) zinc nitrate [Zn(NO3)2.6H2O] and 0.9 M sodium hydroxide (NaOH) and was confirmed to be of ZnN by TEM-EDAX measurements. Wister albino rats (rats; 84, 53.6 ± 0.65 g) were divided into seven groups (4 replicate with 3 rats each) and given feed supplemented with zinc for 60 days with either of the following diets: (1) normal control (NC): basal diet (BD) + no supplemental Zn; (2) ZnI-25: BD + 25 mg/kg Zn from inorganic ZnO; (3) ZnN-25: BD + 25 mg/kg of ZnN; (4) ZnN-12.5: BD + 12.5 mg/kg of ZnN; (5) ZnN-6.25: BD + 6.25 mg/kg of ZnN; (6) ZnN-3.125: BD + 3.125 mg/kg of ZnN; (7) ZnN-50: BD + 50 mg/kg of ZnN. T3 and insulin-like growth factor-1 (IGF-1) hormone levels were similar among groups (P > 0.05), whereas T4 and testosterone were significantly affected, based on supplemented dose. Zn supplementation improved both cell-mediated and humoral immunity. However, both cell-mediated immunity at 24 h and humoral immunity were statistically similar in ZnI-25 and ZnN-6.25 groups. Superoxide dismutase 1 gene expression was found to be similar in all experimental groups. The vascular degeneration were found in liver tissues moderately in NC, mildly in ZnN-6.25 and ZnN-3.125 groups, and no observable changes were noticed in kidney and spleen tissues. However, there was a mild damage in intestinal epithelium of ZnN-25 group rats, hyperplasia of goblet cells, and moderate damage in intestinal villi were observed in ZnN-50 group rats. From the study, it can be concluded that ZnN at half the dose of ZnI showed similar or better responses in terms of immunity, SOD-1 expression, hormonal profiles, and the tissue architecture of vital organs in rats, i.e., 25 mg/kg of Zn from ZnI and 12.5 mg/kg of ZnN impacted similar biological responses like immunity, SOD-1 expression, hormonal profiles, and the tissue architecture of vital organs in rats.

Riluzole and Edavarone: The Hope Against Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is one of the most frequent motor neuron illnesses. Motor neuron illnesses are various disorders that include upper and lower motor neuron abnormalities. Amyotrophic lateral sclerosis accounts for roughly 80% of motor neuron disorders. ALS is a fatal motor neuron disease that involves the loss of motor neurons in the spinal cord and brain, resulting in gliosis and muscle weakening and wasting in the upper, lower, and respiratory muscles, reducing life expectancy to 2-5 years from the onset of symptoms. Up until now, oral riluzole, a glutamatergic neurotransmitter inhibitor, has been used to manage ALS, the only drug for the management of ALS that has been approved by the United States (US) Food and Drug Administration (FDA). In recent studies, edaravone has been used through intravenous mode to halt the progression of ALS. We conducted a systematic search on PubMed; we selected Google Scholar, PubMed, websites regarding ALS, WebMD, Researchgate, als.org, consultant360, and the relevant articles for the review. It shows us riluzole and edaravone's efficacy for managing A.L.S. and how it can increase the life span of the patients.

Molecular Epidemiological Survey for Degenerative Myelopathy in German Shepherd Dogs in Japan: Allele Frequency and Clinical Progression Rate.

Canine degenerative myelopathy (DM) is an adult-onset, chronic, progressive neurodegenerative disease reported in multiple canine breeds, including the German Shepherd Dog (GSD). Clinical signs include progressive motor neuron paralysis, which begins in the pelvic limbs and eventually leads to respiratory distress, which may necessitate euthanasia. A common DM-associated mutation is a single nucleotide substitution that causes an amino acid substitution (c.118G>A, p.E40K) in the canine SOD1 gene. This SOD1 mutation and the clinical progression rate of A/A risk genotype in the Japanese GSD population have not been analyzed before. Therefore, the aim of this study was to determine the frequency of the mutated allele and analyze the clinical progression rate in the Japanese GSD population. We studied 541 GSDs registered with the Japanese German Shepherd Dog Registration Society between 2000 and 2019. Genotyping was performed using real-time PCR with DNA extracted from the hair roots of each dog. The study revealed 330 G/G dogs (61%), 184 G/A dogs (34%), and 27 A/A dogs (5%), indicating a frequency of the mutant allele of 0.220, which are in Hardy−Weinberg equilibrium. We analyzed the clinical signs in A/A dogs with an age limit of 10 years based on information obtained from the dogs' owners. Of the seven A/A dogs older than 10 years, owners reported DM-related clinical signs, indicating a clinical progression rate of 100%. These results, further genotyping, and thorough clinical examinations of SOD1 A/A risk genotype will help control and prevent DM in the Japanese GSD population.

Atypical Familial Amyotrophic Lateral Sclerosis Secondary to Superoxide Dismutase 1 Gene Mutation With Coexistent Axonal Polyneuropathy: A Challenging Diagnosis.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disease that involves both the upper and lower motor neurons. Familial ALS, including superoxide dismutase 1 (SOD1) mutation, accounts for 5-10% of all cases of ALS. Typically, the symptoms of ALS are purely motor, though coexistent sensory symptoms have been reported in rare cases. In this report, we describe the case of a 47-year-old man who presented with progressive bilateral lower limb weakness and numbness for the last four years. A nerve conduction study (NCS) showed evidence of coexistent axonal sensorimotor polyneuropathy in addition to the typical findings of ALS in needle electromyography. Genetic testing confirmed the diagnosis of familial ALS secondary to the SOD1 genetic mutation. This report highlights that the presence of sensory symptoms should not exclude the possibility of ALS in an appropriate clinical setting.

A Novel Variant in Superoxide Dismutase 1 Gene (p.V119M) in Als Patients with Pure Lower Motor Neuron Presentation.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder characterized by degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord. Most cases of ALS appear sporadically, but 5-10% of patients have a family history of disease. Mutations in the superoxide dismutase 1 gene (SOD1) have been found in 12-23% of familial cases and in 1-2% of sporadic cases. Currently, more than 180 different SOD1 gene variants have been identified in ALS patients. Here, we describe two apparently sporadic ALS patients carrying the same SOD1 c.355G>A variant, leading to the p.V119M substitution, not previously described. Both the patients showed pure lower motor neuron phenotype. The former presented with the flail leg syndrome, a rare ALS variant, characterized by progressive distal onset weakness and atrophy of lower limbs, slow progression and better survival than typical ALS. The latter exhibited rapidly progressive weakness of upper and lower limbs, neither upper motor neuron nor bulbar involvement, and shorter survival than typical ALS. We provide an accurate description of the phenotype, and a bioinformatics analysis of the p.V119M variant on protein structure. This study may increase the knowledge about genotype-phenotype correlations in ALS and improve the approach to ALS patients.

Frequency of canine degenerative myelopathy SOD1:c.118G>A mutation in 22 dog breeds in Guadalajara, Mexico / Frecuencia de la mutación SOD1:c.118G>A de mielopatía degenerativa canina en 22 razas de perros en Guadalajara, México / Frequência da mutação SOD1: c.118G>A de mielopatía degenerativa canina em 22 raças de cães no Guadalajara, México

Abstract Background: Canine degenerative myelopathy (DM) is a late-onset disease that primarily affects large-breed dogs. The disease involves the spinal cord and produces progressive paresia and, eventually, complete loss of mobility. DM has been related to missense mutation c.118G>A in the SOD1 gene. Objective: To determine the genotypic and genic frequencies of DM in Mexico. Methods: In total, 330 samples from 22 different dog breeds were genotyped using the polymerase chain reaction and restriction fragment length polymorphisms (PCR-RFLP) technique. Results: The mutation was identified in 71 animals from 11 different breeds. Observed genic frequencies were 0.78 for the G allele and 0.14 for the A allele. Genotypic frequencies were 0.79 for the G/G wild-type, 0.14 for the G/A heterozygote, and 0.7 for the A/A homozygote. Conclusion: The genic frequency of this allele is high among the studied populations. A molecular marker program that identifies the DM mutation in breeding dogs should be implemented in order to reduce this frequency.

Resumen Antecedentes: La mielopatía degenerativa canina (MD) es una enfermedad progresiva de presentación tardía que afecta a la médula espinal, generalmente en caninos de razas grandes, y que produce paresis progresiva y eventual pérdida completa de la movilidad. Se ha relacionado con una mutación puntual por sustitución de bases en el gen SOD1 recientemente identificado como c.118G>A. Objetivo: Determinar las frecuencias genotípicas y génicas para la presentación de DM en México. Métodos: Se genotipificaron 330 muestras de perros de 22 razas mediante la técnica de reacción en cadena de la polimerasa y polimorfismos de longitud de fragmentos de restricción (PCR- RFLPs). Resultados: Se identificó la mutación en 71 animales de 11 razas diferentes. Las frecuencias génicas encontradas fueron de 0,78 para el alelo G y de 0,14 para el alelo A. Las frecuencias genotípicas fueron de 0,79 para el tipo silvestre G/G, 0,14 para el heterocigoto G/A y 0,7 para el homocigoto A/A. Conclusión: La frecuencia encontrada para la mutación es alta en las poblaciones estudiadas. La aplicación de un programa de selección asistida por marcadores moleculares contra la mutación causante de MDC en perros reproductores resultaría útil para reducir su frecuencia.

Resumo Antecedentes: A mielopatía degenerativa canina (MD) é uma doença progressiva de apresentação tardia que afeta a medula espinal geralmente de caninos de raças grandes e que produz paresia progressiva e eventualmente a perda completa da mobilidade. Tem sido relacionada com uma mutação pontual por substituição de bases no gen SOD1, recentemente identificado como c.118G>A. Objetivo: Determinar as frequências genotípicas e genéticas para a apresentação de DM no México. Métodos: Genotipagem de 330 amostras de cães de 22 raças por meio da técnica de reação em cadeia da polimerase e polimorfismos no comprimento de fragmentos de restrição (PCR- RFLPs). Resultados: A mutação foi identificada em 71 animais de 11 raças diferentes. As frequências gênicas encontradas foram de 0,78 para o alelo G e de 0,14 para o alelo A. As frequências genotípicas foram de 0,79 para o tipo silvestre G/G, 0,14 para o heterozigoto G/A e 0,7 para o homozigoto A/A. Conclusão: A frequência encontrada para a mutação é alta nas populações estudadas. A implementação de um programa de seleção assistida por marcadores moleculares contra a mutação que causa MDC seria útil para reduzir a sua frequência.

Analysis of the SOD1 Gene in Keratoconus Patients from Saudi Arabia.

We investigated Saudi patients with familial and sporadic Keratoconus for mutations in the Superoxide dismutase 1, soluble (SOD1) gene. We sequenced the entire coding region, exon-intron boundaries and intron 2 encompassing a 7-bp deletion in clinically confirmed Keratoconus patients (n = 55) and 100 ethnically matched healthy controls. All cases and controls were unrelated. Sequencing the SOD1 gene revealed the presence of four nucleotide changes and all were non-coding. Those were g.12035 C > A; g.13978 T > A; g.12037 G > A and g.11931 A > C with similar frequencies in patients and controls. All four sequence changes were benign polymorphisms with no apparent clinical significance. Additionally, the 7-bp deletion in intro2 reported previously, were not detected in any of our Keratocnus cohort. In our Keratoconus cohort, no pathogenic SOD1 mutation(s) was identified.

Exploring SOD1 Gene for the Detection of Fetal Down Syndrome.

OBJECTIVE: Fetal cells and circulating cellfree fetal DNA increases in the maternal circulation in women carrying trisomy 21 fetus. METHODS: We attempted the use of superoxide dismutase (SOD-1) gene, which is located at the Down Syndrome Critical Region, to overcome this situation for the prenatal screening of Down syndrome. The prospective of the gene using real-time quantitative polymerase chain reaction was explored. RESULTS: The level of SOD-1 sequences is significantly elevated in the third trimester normal pregnancies (mean = 11728 copies/µl) when compared to the second trimester (mean = 5705.6 copies/µl), (p<0.005) and non pregnant normal women (mean = 3580.2 copies/µl), (p<0.0001). Down syndrome pregnancies have the greatest elevation compared to all the three trimesters of normal singleton pregnancies and twin pregnancies, p<0.05. CONCLUSIONS: These data indicate that a quantitative analysis using a gene associated with a disorder could be used in screening for the prenatal diagnosis of fetal aneuploidies regardless of the sex of the fetus.

Anticipation and phenotypic heterogeneity in korean familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutation.

BACKGROUND AND PURPOSE: Different mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have been reported in approximately 10% of cases of familial amyotrophic lateral sclerosis (ALS). The aim of this study was to analyze for mutations in the SOD1 gene and clinical characteristics in Korean family of ALS. METHODS: A subpopulation of the family reported here has been described previously. In the present study, we analyzed the SOD1 gene in the proband and his immediate family members, who were not reported on previously. Genomic DNA was isolated from the leukocytes of whole blood samples and the coding region of the SOD1 gene was analyzed by PCR and direct sequencing. RESULTS: The genetic alterations were a GGC-to-GTT transition at codon 10 in exon 1 and [IVS4+15_16insA; IVS4+42delG; IVS4+59_60insT] in intron 4. Patients with these mutations exhibit diverse clinical onset symptoms and acceleration of the age at onset in successive generations, which is called anticipation. CONCLUSIONS: We have described a family with familial ALS that showed autosomal-dominant inheritance and two distinct genetic alterations in Cu/Zn-SOD1. The affected family members had different phenotypes and anticipation.

Anticipation and Phenotypic Heterogeneity in Korean Familial Amyotrophic Lateral Sclerosis with Superoxide Dismutase 1 Gene Mutation

BACKGROUND AND PURPOSE: Different mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have been reported in approximately 10% of cases of familial amyotrophic lateral sclerosis (ALS). The aim of this study was to analyze for mutations in the SOD1 gene and clinical characteristics in Korean family of ALS. METHODS: A subpopulation of the family reported here has been described previously. In the present study, we analyzed the SOD1 gene in the proband and his immediate family members, who were not reported on previously. Genomic DNA was isolated from the leukocytes of whole blood samples and the coding region of the SOD1 gene was analyzed by PCR and direct sequencing. RESULTS: The genetic alterations were a GGC-to-GTT transition at codon 10 in exon 1 and [IVS4+15_16insA; IVS4+42delG; IVS4+59_60insT] in intron 4. Patients with these mutations exhibit diverse clinical onset symptoms and acceleration of the age at onset in successive generations, which is called anticipation. CONCLUSIONS: We have described a family with familial ALS that showed autosomal-dominant inheritance and two distinct genetic alterations in Cu/Zn-SOD1. The affected family members had different phenotypes and anticipation.