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Introduction/aims: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany., Methods: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS)., Results: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80)., Discussion: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1 D91A in Europe, exceeding 1% in Finno-Scandinavia., Methods: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1 D91A allele for up to 16 months with tofersen., Results: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1 D91A . We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1 D91A . The results indicate that both mono- and bi-allelic SOD1 D91A are causally relevant targets, with a possibly reduced effect size of SOD1 D91Ahet ., Conclusions: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1 D91A patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment., (© 2024. The Author(s).)

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1 -amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated., Methods: Between 03/2022 and 04/2023, 24 patients with SOD1 -ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events., Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n  = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n  = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n  = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n  = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported., Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction., Funding: No funding was received towards this study., Competing Interests: MW reports no competing interests. JD reports speaker honoraria from Biogen Inc. ZE, ÖP, KK, KM, UWei, CH, JS, KM, RS, FB, TS, KG, EF, AK, TK, PR, UWey, MV, MJ, THaa, IV, JH, JC, JHW, PS, PK, WPR and SW report no competing interests. DB reports stocks from Ionis Pharmaceuticals (100 stocks). ZU reports financial support from Biogen, Roche and Novartis for SMArtCARE data collection (site Ulm). He received grants, consulting fees for advisory boards, lectures, presentations, manuscript writing, educational events, and support for travel expenses from Biogen. He received payment for expert testimony (Case report, no guideline development) from Thieme and Biogen. AF reports grants or contracts from DFG (German Research Foundation, Project funding not related to this manuscript). MR received lecture honoraria from Zambon. AG reports grants from German Society of Cryobanks (GDK e.V.). SP reports grants or contracts from the German Israeli Foundation, the German Neuromuscular Society, and the Neurodegenerative Research Inc. SP reports consulting fees from Amylyx, Biogen, ITF Pharma, Roche, Zambon and Ferrer, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amylyx, Biogen, ITF Pharma, Roche, and Zambon. SP received support for travel and/or attend meetings from Amylyx, Zambon, and PTC Therapeutics. JG reports a startup grant from the University foundation of the University of Lübeck. He received consultation fees from Amylyx, Clene Nanomedicine for consultancy on drug development in ALS and payment for expert testimony on EU and national level from Amylyx. JG participated on Data Safety Monitoring Boards or Advisory Boards for UCB, ITF Pharma, and Ferrer. FS reports participation on Advisory Boards for Amylyx, Alnylam, and Alexion. THag reports grants and honoraria from Biogen, Roche, Novartis (all for SMA-Research), Sanofi Genzyme (Neuromuscular Diseases Research), and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Argenx (both for Myasthenia gravis), Biogen, Novartis, Sanofi Genzyme, Roche (SMA) and Amylyx (ALS). THag participated on Data Safety Monitoring Boards or Advisory Boards for Biogen, Novartis, Roche (all for SMA), Alexion, Argenx, UCB (all for Myasthenia gravis), Amylyx (for ALS), Sanofi Genzyme (for LOPD). RG reports honoraria for lectures from Biogen, Roche, and Zambon. He participated on Advisory Boards for Biogen, Roche, Zambon, and ITF Pharma. RG reports research support from Biogen and Zambon. PW served on Advisory Boards for Zambon, and ITF Pharma. PK reports consulting fees from Biogen. TM is on the Advisory Board of Biogen and received consulting fees from Biogen. MS reports consulting fees from Alexion, Bayer, Biogen, Bristol-Myers-Squibb/Celgene, Merck, Horizon, Roche, and Sanofi Genzyme. MS reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Horizon, Roche, and Sanofi Genzyme and support for attending meetings and/or travel from Alexion, Celgene, Horizon, Roche, and Sanofi Genzyme. MS participated on Data Safety Monitoring Board or Advisory Board for Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Horizon, Roche, and Sanofi Genzyme. HT reports grants or contracts from Sanofi Genzyme, German Multiple Sclerosis Society (DMSG), AMSEL Ursula-Späth-Stiftung, Bayern-DMSG, Deutsche MS-Stiftung, Ministry of Science, Research and Arts of the State Baden-Württemberg (MWK-BW), Chemische Fabrik Karl Bucher. HT received consulting fees from Merck, Novartis, Roche and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Bayer, Biogen, Celgene, GSK, Janssen, Merck, Novartis, Roche, Sanofi Genzyme, Siemens, TEVA, Viatris. HT reports support for attending meetings and/or travel from Janssen, Merck, Novartis, Roche, Sanofi Genzyme. He reports leadership or fiduciary role in DGLN, DMSG and AMSEL. ACL is a member of Advisory Boards of Roche Pharma AG, Biogen, Alector and Amylyx. He received compensation for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx and the company Streamed Up! GmbH. He is involved in trials which are sponsored by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, the European Union, BMBF, Biogen and Orphazyme, Ionis Pharmaceuticals, QurAlis and Alector., (© 2024 The Author(s).)

Background: ALS patients with a negative family history (sporadic ALS, SALS) represent more than 90% of all ALS cases. In light of the gene-specific therapies that are currently in development for ALS, knowledge about the genetic landscape of SALS in Germany is urgently needed. Objectives: We aimed to determine the frequency of C9orf72 hexanucleotide repeat expansion (HRE) and SOD1 mutations among patients in Germany with a diagnosis of sporadic or idiopathic ALS. Methods : We genotyped SALS patients from three German ALS centers. Sanger sequencing, fragment length analysis, and repeat-primed PCR technologies were used to detect mutations in SOD1 and C9orf72 HRE. Pathological C9orf72 HRE results were confirmed in an independent laboratory. Results : In 302 patients with SALS, 27 (8.9%) patients with a C9orf72 HRE mutation were detected. Moreover, we identified two patients with a pathogenic SOD1 mutation, one patient with a heterozygous p.D91A mutation in SOD1, and three additional patients with rare SOD1 variants not predicted to change the amino acid sequence. Conclusions : According to our data, the proportion of SALS patients with SOD1 mutations is in the expected range, whereas that with C9orf72 HRE is higher, suggesting a reduced penetrance. A considerable number of SALS patients can be amenable to gene-specific therapies.

Primary familial brain calcification (PFBC; formerly Fahr's disease) and early-onset Alzheimer's disease (EOAD) may share partially overlapping pathogenic principles. Although the heterozygous loss-of-function mutation c.1523 + 1G > T in the PFBC-linked gene SLC20A2 was detected in a patient with asymmetric tremor, early-onset dementia, and brain calcifications, CSF β-amyloid parameters and FBB-PET suggested cortical β-amyloid pathology. Genetic re-analysis of exome sequences revealed the probably pathogenic missense mutation c.235G > A/p.A79T in PSEN1. The SLC20A2 mutation segregated with mild calcifications in two children younger than 30 years. We thus describe the stochastically extremely unlikely co-morbidity of genetic PFBC and genetic EOAD. The clinical syndromes pointed to additive rather than synergistic effects of the two mutations. MRI data revealed the formation of PFBC calcifications decades before the probable onset of the disease. Our report furthermore exemplifies the value of neuropsychology and amyloid PET for differential diagnosis., (© 2023. The Author(s).)

Objectives: Due to upcoming gene-specific therapy approaches for ALS patients, understanding familial and sporadic ALS genetics is becoming increasingly important. In this study, we wanted to investigate underlying genetic causes for an SALS patient., Methods: We performed ALS gene panel sequencing and subsequent segregation analysis in the family., Results: Genetic studies suggest that a proportion of SALS cases has an oligogenic origin due to the combination of low-effect size mutations in several ALS genes. Maximally three mutations in different ALS disease genes have been described in isolated ALS patients. Here, we report for the first time the co-occurrence of rare nonsynonymous variants in four known ALS genes in a SALS patient (c.859G > A/p.Gly287Ser in TARDBP, c.304G > T/p.Glu102* in NEK1, c.3446C > A/p.Gly1149Val in ERBB4, and c.1015C > T/p.Arg339Trp in VEGFA). All four variants were unique for the patient, whereas up to three of these variants were detected in the unaffected family members, all older than the patient., Discussion: Our study suggests that SALS can be caused by the additive or synergistic action of low-effect size mutations. Broader use of gene panel analysis or whole exome/genome sequencing may reveal a potentially treatable oligogenic causation in a higher percentage of SALS than previously thought., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction Laryngomalacia (LM) is a condition that is clinically diagnosed in the pediatric period with inspiratory stridor and is caused by a congenital or acquired collapse of laryngeal suprastructures. Endoscopic supraglottoplasty is the modern gold standard surgical treatment for severe or complicated laryngomalacia. Various cold and powered surgical devices have been used to approach the aryepiglottic folds, and their advantages and drawbacks have been widely discussed. The applicability of Ultracision Harmonic shears (Ethicon Inc., NJ, US) for the sake of supraglottoplasty has not been previously advocated in the literature and is the subject of this study. Methods This was a review of the medical records of pediatric patients, with moderate to severe congenital laryngomalacia, who underwent supraglottoplasty with Harmonic at a single institution, from 2013 to 2019. Results A total of six patients underwent bilateral aryepiglottic fold division with the use of Ultracision in the study period (4 male, 2 female; mean age 7+/-9 months, age range 1m-24m). Postoperatively, all of the children were extubated and admitted to the pediatric intensive care unit (PICU) as a precaution measure. There were no early or late complications after the intervention. The postoperative endoscopic picture was evaluated in three patients (two of which for another reason). A stable laryngeal frame with no collapse or excessive scarring was observed. None of the patients required repeat surgery. Conclusion Based on the ease of surgical access, performance, surgical precision, and postoperative results, the use of Harmonic scissors appears to be a safe, practical, affordable, and easily applicable alternative for supraglottoplasty Type 2., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Sapundzhiev et al.)