Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration最新文献

{"title":"Verbal expressive language minimally affected in non-demented people living with amyotrophic lateral sclerosis","authors":"Elisabeth Kasper, Anna G. M. Temp, Verena Köckritz, Lisa Meier, Judith Machts, Stefan Vielhaber, Andreas Hermann, Johannes Prudlo","doi":"10.1080/21678421.2024.2307512","DOIUrl":"https://doi.org/10.1080/21678421.2024.2307512","url":null,"abstract":"Objective: Language dysfunction is one of the most common cognitive impairments in amyotrophic lateral sclerosis (ALS). Although discourse capacities are essential for daily functioning, verbal exp...","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"60 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139664738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time from amyotrophic lateral sclerosis symptom onset to key disease milestones: analysis of data from a multinational cross-sectional survey","authors":"Paulos Gebrehiwet, Johan Brekke, Stacy A. Rudnicki, Jennifer Mellor, Jack Wright, Lucy Earl, Nathan Ball, Halima Iqbal, Owen Thomas, Giorgio Castellano","doi":"10.1080/21678421.2023.2297795","DOIUrl":"https://doi.org/10.1080/21678421.2023.2297795","url":null,"abstract":"To determine the average time from Amyotrophic Lateral Sclerosis (ALS) symptom onset to 11 pre-defined milestones, overall and according to ALS progression rate and geographic location.Data were dr...","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"131 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139067100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALS Health care provider wellness","authors":"Gregory Hansen, Sarah Burton-MacLeod, Kerri Lynn Schellenberg","doi":"10.1080/21678421.2023.2291710","DOIUrl":"https://doi.org/10.1080/21678421.2023.2291710","url":null,"abstract":"Interest in health care provider (HCP) wellness and burnout is increasing; however, minimal literature explores HCP wellness in the context of Amyotrophic Lateral Sclerosis (ALS) care.We sought to ...","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"11 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138567548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What, how and when do families communicate about ALS? A qualitative exploration of parents’ and children’s perceptions","authors":"Marion Sommers-Spijkerman, Anna Stukker, Melinda S. Kavanaugh, Marjolijn Ketelaar, Johanna M. A. Visser-Meily, Anita Beelen","doi":"10.1080/21678421.2023.2290738","DOIUrl":"https://doi.org/10.1080/21678421.2023.2290738","url":null,"abstract":"Objectives: In families with a parent diagnosed with amyotrophic lateral sclerosis (ALS), children’s adaptation depends among others on how their parents communicate with them about the disease and...","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"57 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138567394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of normal <i>C9orf72</i> repeat length as possible disease modifier in amyotrophic lateral sclerosis","authors":"Silvia Peverelli, Alberto Brusati, Valeria Casiraghi, Marta Nice Sorce, Sabrina Invernizzi, Serena Santangelo, Claudia Morelli, Federico Verde, Vincenzo Silani, Nicola Ticozzi, Antonia Ratti","doi":"10.1080/21678421.2023.2273965","DOIUrl":"https://doi.org/10.1080/21678421.2023.2273965","url":null,"abstract":"AbstractThe C9orf72 hexanucleotide repeat (HR) expansion is the main genetic cause of amyotrophic lateral sclerosis (ALS), with expansion size from 30 to >4000 units. Normal C9orf72 HR length is polymorphic (2–23 repeats) with alleles >8 units showing a low frequency in the general population. This study aimed to investigate if the normal C9orf72 HR length influences C9orf72 gene expression and acts as disease modifier in ALS patients negative for C9orf72 mutation (ALS-C9Neg). We found that the distribution of HR alleles was similar in 325 ALS-C9Neg and 303 healthy controls. Gene expression analysis in blood revealed a significant increase of total C9orf72 and V3 mRNA levels in ALS-C9Neg carrying two long alleles (L/L; ≥8 units) compared to patients homozygous for the 2-unit short allele (S/S). However, HR allele genotypes (L/L, S/L, S/S) correlated with no clinical parameters. Our data suggest that normal C9orf72 HR length does not act as disease modifier in ALS-C9Neg despite increasing gene expression.Keywords: amyotrophic lateral sclerosisC9orf72gene expressiondisease modifier AcknowledgementsThe Authors acknowledge the ERN Euro-NMD. AR acknowledges “Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics”, Università degli Studi di Milano. VC and SS were recipients of a fellowship from the PhD program in “Experimental Medicine”, Università degli Studi di Milano.Declaration of interestsV.S. is in the Editorial Advisory Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. All the other Authors report no conflicts of interest.Additional informationFundingThis work was supported by Italian Ministry of Health—Ricerca Corrente.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"119 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135371698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theme 03 - In Vitro Experimental Models","authors":"S. Baver, V. Smith, A. Robertson, L. Lenkiu, H. Cannon, D. Martinez, J. Hickman, D. Eyerman, G. Edozie, S. Pigeyre, A. Gosselin, M. Brenes, C. Sephton, S. Pozzi","doi":"10.1080/21678421.2022.2120679","DOIUrl":"https://doi.org/10.1080/21678421.2022.2120679","url":null,"abstract":"The aggregation of amyloidogenic proteins/peptides is asso- ciated with the onset and progression of several amyloidoses, including neurodegenerative disorders, such as Alzheimer ‘ s or Parkinson ‘ s diseases. In recent years, it has been observed that the cross-interaction between these protein molecules may be one of the main influences for amyloid aggregate formation. This was first suggested by the presence of different proteins in amyloid plaques found in the nervous tissue of patients. While the cross-interaction between Alzheimer ‘ s disease-related amyloid-beta and tau protein is documented in numerous cases (1,2), there is a lack of information on other protein coaggregation. One such paring, which was examined in this work, was superoxide dismutase-1 (SOD1, related to amyotrophic lateral sclerosis) and prion protein (PrP, relation to prionopathies). Both of them share a localisation in vivo and there was only a single report regarding the influence that SOD1 had on the aggregation of PrP (3), which prompted this investigation. In order to investigate the influence of non-aggregated SOD1 on prion protein fibril formation, conditions were chosen which did not facilitate the aggregation SOD1, while actively promoting the fibrilization of PrP. A large number of samples was analyzed using different SOD1 concentrations to determine if there was a notable effect induced by the pro- tein cross-interaction. The resulting fibrils were examined using Fourier-transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). Parameters obtained from each assay were compared between each condition to determine the significance of SOD1 influence on PrP aggregation. It was discovered that the presence of SOD1 increased the lag time of PrP fibril formation and reduced their apparent rate of replication. There was also Background: The complement cascade is a critical compo-nent of the immune system, and its activation has been implicated in ALS (1). Furthermore, complement cascade components (e.g. C3 breakdown products) are reported to be deposited on the neuromuscular junction (NMJ) in people living with restored NMJ numbers to 76.1% of the ND control and fatigue index by 30.1% from hCS. In TDP-43 NMJs, hCS reduced NMJ numbers by 82.9% of the ND control and increased fatigue index by 22.8% (stimulation frequency of 2Hz), while the addition of pegcetacoplan restored NMJ numbers to 60.5% of the ND control and fatigue index by 9% from hCS. Furthermore, fidelity was increased in SOD-1 NMJs following treatment of pegcetacoplan and remained stable in TDP-43 NMJs. Conclusions: These data demonstrate that inhibiting C3 with pegcetacoplan in an inflammatory environment may improve overall NMJ survival and function. Background: Neuroinflammation plays a significant role in the onset and progression of amyotrophic lateral sclerosis (ALS), which presently has no effective treatment. Peptidylprolyl cis-/trans-isomerase A (PPIA), also as Background: RNA-bindi","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"23 1","pages":"57 - 68"},"PeriodicalIF":2.8,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42473753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theme 10 - Disease Stratification and Phenotyping of Patients","authors":"E. Young, D. Wang, J. Meyer, B. Narapureddy, D. Manta, B. Sah, U. Desai, B. Brooks","doi":"10.1080/21678421.2022.2120686","DOIUrl":"https://doi.org/10.1080/21678421.2022.2120686","url":null,"abstract":"Background: COVID-19 pandemic presents new opportunities to augment respiratory monitoring complementary to remote telehealth services. Stratification of vital capacity may allow for characterization of FVC and disease trajectory clusters (1). Objective(s): In this implementation science study, we assessed the feasibility of measuring FVC in seated upright and supine positions obtained with in-clinic-conventional (Viaire and Vyasis, USA), in-clinic-portable and at-home-portable (MIR Spirobank Smart, Italy) spirometers with respiratory therapist coaching. Method(s): Electronic health records of 22/95 ALS clinic patients (23%) from single-center in Central New York that launched AHT between July 2020 and June 2021 was reviewed in this IRB-approved retrospective study. Mean age of patients was 65 years old and 9 were males. Patients were stratified according to baseline seated FVC % predicted by conventional method: Group A, FVC >80%, Group B, 60-80%, Group C <60% predicted. Patients unable to come to clinic received spirometers by mail followed with remote training with respiratory therapists without conventional spirometry. Result(s): Pearson correlation coefficient was used to evaluate the correlation between FVC measurement using conventional and portable spirometry by position. Bland-Altman analysis was performed to evaluate the mean difference (conventional - portable) with 95% limits of agreement. Measurement of seated FVC acquired during the same clinic visit (N=13) were highly correlated in liters (R2=0.95, p<0.0001) and % predicted (R2=0.952, p<0.0001). Bland- Altman analysis showed good agreement with a mean difference of 0.147L, 0.345 to 0.639L);4.154% predicted, (8.004 to 16.311%). In-clinic supine FVC (N=4) were highly correlated in liters (R2=0.987, p=0.007) and % predicted (R2=0.987, p=0.007) with a mean difference of =0.33L, (0.101 to 0.761L);8.5% predicted, (0.043-17.043%). Supine vital capacity measurements were more frequently obtained with AHT 35/52 (67.31%) vs. 9/21(42.86%) with Conventional spirometry. Safety concerns associated with patient transfers were the most frequently encountered barrier in performing supine testing in clinic. Reason for drop out for 2/22 patients with no remote AHT was attributed to perceived aggravation of anxiety from readily viewing FVC results on smartphone and low baseline FVC (<50% predicted). AHT led to prompt initiation of NIV in 5/22 patients, of which 3 were homebound, had low FVC at initial AHT (12-48% predicted), low ALS FRSR (14-28 out of 48) and received remote AHT training without conventional spirometry. An ongoing slow vital capacity (NCT05106569) prospective clinical study in ALS will determine if frequent respiratory surveillance from home using AHT leads to better outcomes in relation to use of NIV.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"32 1","pages":"150 - 166"},"PeriodicalIF":2.8,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75615872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theme 09 - Clinical Trials and Trial Design","authors":"S. Badri, J. Mason, S. Paganoni, J. Timmons, P. Yeramian, M. Cudkowicz, S. Appel, S. Ladha, N. Maragakis, M. Rivner, J. Katz, A. Genge, N. Olney, D. Lange, D. Heitzman, C. Bodkin, O., Jawdat, N. Goyal, J. Bornstein, C. Mak, S. Perrin","doi":"10.1080/21678421.2022.2120685","DOIUrl":"https://doi.org/10.1080/21678421.2022.2120685","url":null,"abstract":"Background: The safety and efficacy of sodium phenylbutyrate (PB) and taurursodiol (TURSO, also known as ursodoxicol- taurine) coformulation in ALS were evaluated in a phase 2 US multicenter trial (CENTAUR) encompassing both randomized (NCT03127514) and open-label extension (OLE; NCT03488524) phases. While overall treatment-emergent adverse event (TEAE) incidence was similar in the PB&TURSO versus placebo groups in the randomized phase and between those continuing versus switching to PB&TURSO in the OLE phase, treatment-emergent cardiac adverse events (TECAEs) and centrally read electrocardiographic abnormalities were reported more frequently among those receiving PB&TURSO in both phases. Objective: Describe the findings of independent expert reviews of reported TECAEs and electrocardiographic abnor- malities and of recorded electrocardiographic parameters in CENTAUR. Methods: Occurrence of TEAEs was assessed at each visit during both phases. Standard 12-lead electrocardiograms were performed at baseline in both phases and at a total of 2 visits in the randomized phase and up to 10 visits in the OLE phase, blinded and centrally read. Unblinded independent expert reviews assessed reported TECAEs and electrocar- diographic abnormalities for diagnostic accuracy and treatment emergence based on absence at baseline or lack Background: CD40L/CD40 costimulatory pathway mediates both humoral and adaptive immune responses in the pathophysiology of autoimmunity and transplant rejection. Studies have implicated CD40L (CD154) signaling and adaptive and innate immune cell activation in induction of neuroinflammation in neurodegenerative diseases. Methods: In this multicenter dose escalating phase 2 study 54 participants with a definite or probable diagnosis of ALS by El Escorial Criteria-revised received an anti CD154 antibody, tegoprubart, via intravenous infusion every two weeks for twelve weeks. Enrollment consisted of 9 participants in cohorts 1 and 2 (1 and 2mg/kg) and 18 participants in cohorts 3 and 4 (4 and 8mg/kg). The primary endpoint of the study was safety and tolerability. Secondary endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody responses. Exploratory endpoints evaluated changes in disease progression utilizing the ALS Functional Rating Scale-Revised (ALSFRS-R), assessment of CD154 target engagement specifically looking at change in circulating CD40L and CXCL13, and changes in the levels of pro-inflam-matory biomarkers in circulation, by looking at change from baseline in circulating levels of a panel of inflammatory che-mokines and cytokines. Results: Seventy participants were screened, and fifty-four were enrolled in the study. Forty-nine completed the study (90.7%) receiving all six infusions of tegoprubart and com- pleting their final follow up visit. The most common TEAEs overall ( 10%) were fatigue (25.9%), falls (22.2%), headaches and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increa","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"23 1","pages":"133 - 149"},"PeriodicalIF":2.8,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48272049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theme 04 - In Vivo Experimetal Models","authors":"C. Germeys, T. Vandoorne, K. Davie, S. Poovathingal, M. Moisse, A. Quaegebeur, A. Sierksma, P. Carmeliet, P. Van, Damme, K. Bock, L. Bosch, A. Mazzaro, I. Casola, V. Vita, A. Klein, G. Gobbo, G. Dobrowolny, G. Sorar, A. Musar, M. Mongillo, T. Zaglia","doi":"10.1080/21678421.2022.2120680","DOIUrl":"https://doi.org/10.1080/21678421.2022.2120680","url":null,"abstract":"Background: A growing body of evidence shows disturbances in energy metabolism in amyotrophic lateral sclerosis (ALS) (1). The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism and play a role in oxidative stress response. Interestingly, selective inhibition of the PHD isoen- zyme 1 (PHD1) protects cortical neurons via metabolic rewiring in a model for stroke (2). As the major source of oxidative stress, which is known to be elevated in ALS, energy metabol- ism forms a promising target for ALS research. Objectives: This project aims to investigate the effect of target- ing cellular metabolism, via selective PHD1 ablation, in ALS. Methods: To investigate the role and therapeutic potential of PHD1 in ALS, we intercrossed PHD1 knock-out mice with SOD1- G93A mice and monitored disease progression, evaluating weight, neuromuscular junction innervation and total motor neuron count. Single-nuclei RNA-sequencing (snRNAseq) was performed on the lumbar spinal cord of early symptomatic mice to investigate the molecular mechanisms underlying the observed beneficial effect of PHD1 deletion in SOD1-G93A mice. Results and discussion: We demonstrated that genetic dele- tion of PHD1 improves muscle innervation and motor neuron integrity and extends the lifespan of SOD1-G93A mice, increasing the disease duration with 40%. Using snRNAseq, we were able to identify the different cell types present in the spinal cord of SOD1-G93A mice with and without PHD1. Gene ontology analysis of the differentially expressed genes showed that pathways related to oxidative metabolism are downregulated upon PHD1 deletion in motor neurons. Moreover, we also found a downregulation of interferon-stimulated genes in astrocytes. Strikingly some of these genes have recently been shown to be upregulated in ALS patients and models. A downregulation of these genes in astrocytes, which may be dependent or independent from the downregulation of reactive oxygen species (ROS) produc- ing metabolic pathways in motor neurons, could contribute to the PHD1-mediated neuroprotection. In conclusion, our data identify PHD1 inhibition as a novel ALS therapeutic strategy that targets both the metabolic dysregulation and interferon-driven hyperinflammatory response linked to ALS pathology. Rationale: Amyotrophic Lateral Sclerosis (ALS) is a fatal neuromuscular disorder characterized by motor neuron (MN) degeneration, muscle weakness, paralysis and respiratory fail- ure, leading to death within 2 – 5 years after diagnosis. ALS sprouting, process fragmentation and irregular distribution of varicosities. Notably, similar alterations in neuronal morphology and topology have been observed in muscle biopsies from ALS patients, indicating that the alteration of sympathetic innervation is a common aspect in ALS muscles. Consistently, alterations of Heart Rate Variability and a greater incidence of arrhythmic events were observed in ALS patients, indicating that SN morphological a","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"23 1","pages":"69 - 82"},"PeriodicalIF":2.8,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46494551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theme 02 - Genetics and Genomics","authors":"L. Becattini, F. Bianchi, L. Fontanelli, A. Fogli, G. Siciliano, A. Bombaci, U. Manera, A. Canosa, M. Grassano, F. Palumbo, G. Marco, F. Casale, P. Salamone, G. Fuda, G. Marchese, C. Moglia, A. Chi, S. Gallone, A. Calvo","doi":"10.1080/21678421.2022.2120678","DOIUrl":"https://doi.org/10.1080/21678421.2022.2120678","url":null,"abstract":"Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder involving upper and lower motor neurons. It is mostly sporadic, tough pathogenic mutations are sometime detectable, mainly in those patients with a positive familiar track record for neurodegenerative disorders. More than 50 genes have been put in relation with ALS so far, among which SOD1, C9Orf72, FUS, ATXN2 and TARDBP are the most frequent. SOD1, encoding for the antioxidant enzyme Cu/ Zn superoxide dismutase and described for the first time in 1993, is the first gene that had been put in rela- tion with ALS. To date, over 180 different SOD1 mutations have been described throughout the five exons of the SOD1 gene. However, the exact pathogenic effect of this gene mutations are still unclear. Recently, a gene therapy targeting SOD1 has been approved for ALS patients carrying any SOD1 mutation. This new therapeutic approach has boosted the number of genetic tests performed, sometimes revealing unexpected positivity and sometimes underlying new genes ’ mutations. Here we describe a case of a woman with a new SOD1 mutation, not described in literature before and con- sidered as pathogenetic in VarSome. Case report: diseases, gait complete neurological dis-closing severe bulbar with anarthria, tongue hyposthenia and oral apraxia. presented mild upper hyposthenia, limbs Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders characterized by progressive weakness and spasticity of lower limbs. SPG15 is a rare form of autosomal recessive HSP due to mutations in ZFYVE26 gene, which encodes for spastizin, involved in autophagy and endocytosis (1). Here we describe the case of a 56 years old man who presented to our clinic in November 2020 referring a progressive motor clumsiness of both legs and walking instability during the last five years. No motor impairment at upper limb, no bulbar nor respiratory symptoms. These symptoms had a progressive evolution. In anamnesis only high blood pressure. No familiar history of neurodegenerative diseases. Neurological examination showed a spastic gait, a light hypo-trophy and hyposthenia of the left leg, brisk reflexes at lower limb, no Hoffmann nor Babinski signs, no urinary nor intes- tinal problems. He underwent: blood examination (resulted normal, no HIV, HTLV infections), electroneurography/electro- myography study (signs of chronic neurogenic muscle with apparently sporadic disease have a lower than expected testing yield. Increasing availability of wider genetic panels may confound our results and yield of testing with contemporary approaches may increase. Our data supports testing of individuals with early-onset disease but does not provide strong evidence for testing those without a family history. Interval re-evaluation of this cohort may be of benefit to appreciate the utility of an extended panel (26 genes plus C9orf72 established in 2021). Systematic questioning regarding fa","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"23 1","pages":"40 - 56"},"PeriodicalIF":2.8,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41698901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}