Title Participants Abstract "Myelin protein zero mutation-related hereditary neuropathies" "Juliane Bremer, Axel Meinhardt, Istvan Katona, Jan Senderek, Elke K. Kaemmerer-Gassler, Andreas Roos, Andreas Ferbert, J. Michael Schroeder, Stefan Nikolin, Kay Nolte, Bernd Sellhaus, Klimentina Popzhelyazkova, Frank Tacke, Ulrike Schara-Schmidt, Eva Neuen-Jacob, Chantal De Groote, Peter De Jonghe, Vincent Timmerman, Jonathan Baets, Joachim Weis" "Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease-associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype-specific morphological features. Here, we aimed at enhancing the understanding of these subtype-specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot-Marie-Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non-myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle." "Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients" "Laura Krumm, Tatyana Pozner, Naime Zagha, Roland Coras, Philipp Arnold, Thanos Tsaktanis, Kathryn Scherpelz, Marie Y. Davis, Johanna Kaindl, Iris Stolzer, Patrick Suess, Mukhran Khundadze, Christian A. Huebner, Markus J. Riemenschneider, Jonathan Baets, Claudia Guenther, Suman Jayadev, Veit Rothhammer, Florian Krach, Juergen Winkler, Beate Winner, Martin Regensburger" "Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11-HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11-HSP, including examination of three human postmortem brain donations, immunophenotyping of patients' peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11-HSP. Neuropathological analysis of SPG11-HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11-HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFN gamma led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFN gamma-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11(-/- )mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11-HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11-HSP. IFN gamma/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression." "C-terminal frameshift variant of TDP-₄₃ with pronounced aggregation-propensity causes rimmed vacuole myopathy but not ALS/FTD" "Pedro Ervilha Pereira, Nika Schuermans, Antoon Meylemans, Pontus LeBlanc, Lauren Versluys, Katie E.E. Copley, Jack D.D. Rubien, Christopher Altheimer, Myra Peetermans, Elke Debackere, Olivier Vanakker, Sandra Janssens, Jonathan Baets, Kristof Verhoeven, Martin Lammens, Sofie Symoens, Boel De Paepe, Sami J.J. Barmada, James Shorter, Jan L.L. De Bleecker, Elke Bogaert, Bart Dermaut" "Neuronal TDP-43-positive inclusions are neuropathological hallmark lesions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathogenic missense variants in TARDBP, the gene encoding TDP-43, can cause ALS and cluster in the C-terminal prion-like domain (PrLD), where they modulate the liquid condensation and aggregation properties of the protein. TDP-43-positive inclusions are also found in rimmed vacuole myopathies, including sporadic inclusion body myositis, but myopathy-causing TDP-43 variants have not been reported. Using genome-wide linkage analysis and whole exome sequencing in an extended five-generation family with an autosomal dominant rimmed vacuole myopathy, we identified a conclusively linked frameshift mutation in TDP-43 producing a C-terminally altered PrLD (TDP-43(p.Trp385IlefsTer10)) (maximum multipoint LOD-score 3.61). Patient-derived muscle biopsies showed TDP-43-positive sarcoplasmic inclusions, accumulation of autophagosomes and transcriptomes with abnormally spliced sarcomeric genes (including TTN and NEB) and increased expression of muscle regeneration genes. In vitro phase separation assays demonstrated that TDP-43(Trp385IlefsTer10) does not form liquid-like condensates and readily forms solid-like fibrils indicating increased aggregation propensity compared to wild-type TDP-43. In Drosophila TDP-43(p.Trp385IlefsTer10) behaved as a partial loss-of-function allele as it was able to rescue the TBPH (fly ortholog of TARDBP) neurodevelopmental lethal null phenotype while showing strongly reduced toxic gain-of-function properties upon overexpression. Accordingly, TDP-43(p.Trp385IlefsTer10) showed reduced toxicity in a primary rat neuron disease model. Together, these genetic, pathological, in vitro and in vivo results demonstrate that TDP-43(p.Trp385IlefsTer10) is an aggregation-prone partial loss-of-function variant that causes autosomal dominant vacuolar myopathy but not ALS/FTD. Our study genetically links TDP-43 proteinopathy to myodegeneration, and reveals a tissue-specific role of the PrLD in directing pathology." "Autosomal recessive cerebellar ataxias in Europe" "Andreas Traschuetz, Astrid D. Adarmes-Gomez, Mathieu Anheim, Jonathan Baets, Bjoern H. Falkenburger, Janina Gburek-Augustat, Sarah Doss, Christoph Kamm, Peter Klivenyi, Marcus Grobe-Einsler, Thomas Klopstock, Martina Minnerop, Alexander Muenchau, Chiara Pane, Mathilde Renaud, Filippo M. Santorelli, Ludger Schoels, Dagmar Timmann, Stefan Vielhaber, Tobias B. Haack, Bart P. van de Warrenburg, Ginevra Zanni, Matthis Synofzik" "A homozygous loss of function variant in POPDC3" "Willem De Ridder, Geert de Vries, Kristof Van Schil, Tine Deconinck, Vincent Mouly, Volker Straub, Jonathan Baets" "Recessive pathogenic variants in POPDC3 have recently been associated with the rare limb-girdle muscular dystrophy (LGMD) subtype LGMDR26. We studied three siblings and a distantly related individual with a skeletal muscle disorder, harboring the c.486–6T>A splice site variant in POPDC3 in homozygosity. Immunohistochemistry, western blot, and mRNA experiments on patients’ skeletal muscle tissue as well as on patients’ myoblasts were performed to study the pathogenicity of the predicted loss of function mechanism of the variant. Patients mainly presented with invalidating myalgia and exercise intolerance and limited to no segmentary muscle weakness. CK levels were markedly elevated in all patients. A loss of function mechanism at the RNA level was shown (r.485_486insauag, p.Ile163*). Muscle biopsies performed in three out of four patients showed non-specific myopathic features with a marked type 2 fiber predominance and the presence of a large number of severely atrophic fibers with pyknotic nuclear clumps. We show that skeletal muscle symptoms in LGMDR26 may range from an overt late juvenile to young adult-onset limb-girdle muscular dystrophy phenotype to severe exercise intolerance and myalgia, with consistently highly elevated CK levels. We further prove a clear LOF mechanism of POPDC3 in this rare disorder." "Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14" "Adam Jackson, Sheng-Jia Lin, Elizabeth A. Jones, Kate E. Chandler, David Orr, Celia Moss, Zahra Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon Lovell, Konstantina Drosou, Gaurav K. Varshney, Siddharth Banka, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.A. Brown, M.J. Caulfield, G.C. Chan, A. Giess, J.N. Griffin, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Olaf Riess, Tobias B. Haack, Holm Graessner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze-Hentrich, Rebecca Schüle, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Sablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldiz, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, Chiara Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Siddharth Banka, Elizabeth Alexander, Adam Jackson, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Emilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Carles Garcia, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Enzo Cohen, Antonio Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcova, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter De Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloes, Séverine Drunat, Caroline Rooryck, Aurelien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada De la Paz, Eva Bermejo Sánchez, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Maria Judit Molnar, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Hanns Lochmüller, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodriguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Evelin Schröck, Andreas Rump" "Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies" "Annette Lischka, Katja Eggermann, Christopher J. Record, Maike F. Dohrn, Petra Laššuthová, Florian Kraft, Matthias Begemann, Daniela Dey, Thomas Eggermann, Danique Beijer, Jana Šoukalová, Matilde Laura, Alexander M. Rossor, Radim Mazanec, Jonas Van lent, Pedro J. Tomaselli, Martin Ungelenk, Karlien Y. Debus, Shawna M.E. Feely, Dieter Gläser, Sujatha Jagadeesh, Madelena Martin, Geeta M. Govindaraj, Pratibha Singhi, Revanth Baineni, Niranjan Biswal, Marisol Ibarra-Ramírez, Maryse Bonduelle, Burkhard Gess, Juan Romero Sánchez, Renu Suthar, Vrajesh Udani, Atchayaram Nalini, Gopikrishnan Unnikrishnan, Wilson Marques Junior, Sandra Mercier, Vincent Procaccio, Céline Bris, Beena Suresh, Vaishnavi Reddy, Mariola Skorupinska, Nathalie Bonello-Palot, Fanny Mochel, Georg Dahl, Karthika Sasidharan, Fiji M. Devassikutty, Sheela Nampoothiri, Maria J Rodovalho Doriqui, Wolfgang Müller-Felber, Katharina Vill, Tobias B. Haack, Andreas Dufke, Michael Abele, Rolf Stucka, Saima Siddiqi, Noor Ullah, Stephanie Spranger, Deborah Chiabrando, Behiye S Bolgül, Yesim Parman, Pavel Seeman, Angelika Lampert, Jörg B. Schulz, John N. Wood, James J. Cox, Michaela Auer-Grumbach, Vincent Timmerman, Jonathan De Winter, Andreas C. Themistocleous, Michael Shy, David L. Bennett, Jonathan Baets, Christian A. Hübner, Enrico Leipold, Stephan Züchner, Miriam Elbracht, Arman Çakar, Jan Senderek, Thorsten Hornemann, C. Geoffrey Woods, Mary M. Reilly, Ingo Kurth" "Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited.Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign.The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies." "A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing" "Anne-Sophie Denomme-Pichon, Leslie Matalonga, Elke de Boer, Adam Jackson, Elisa Benetti, Siddharth Banka, Ange-Line Bruel, Andrea Ciolfi, Jill Clayton-Smith, Bruno Dallapiccola, Yannis Duffourd, Kornelia Ellwanger, Chiara Fallerini, Christian Gilissen, Holm Graessner, Tobias B. Haack, Marketa Havlovicova, Alexander Hoischen, Nolwenn Jean-Marcais, Tjitske Kleefstra, Estrella Lopez-Martin, Milan Macek, Maria Antonietta Mencarelli, Sebastien Moutton, Rolph Pfundt, Simone Pizzi, Manuel Posada, Francesca Clementina Radio, Alessandra Renieri, Caroline Rooryck, Lukas Ryba, Hana Safraou, Martin Schwarz, Marco Tartaglia, Christel Thauvin-Robinet, Julien Thevenon, Frederic Tran Mau-Them, Aurelien Trimouille, Pavel Votypka, Bert B.A. de Vries, Marjolein H. Willemsen, Birte Zurek, Alain Verloes, Christophe Philippe, Antonio Vitobello, Lisenka E.L.M. Vissers, Laurence Faivre, Vincent Timmerman, Jonathan Baets, Geert de Vries, Jonathan De Winter, Danique Beijer, Peter De Jonghe, Liedewei Van de Vondel, Willem De Ridder, Sarah Weckhuysen, Solve-RD DITF-ITHACA, Solve-RD SNV-indel Working Group, Solve-RD Consortia, Orphanomix Group" "Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the ""ClinVar low-hanging fruit"" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other ap-proaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The ""ClinVar low-hanging fruit"" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)." "Responsiveness of the scale for the assessment and rating of ataxia and natural history in 884 recessive and early onset ataxia patients" "Andreas D. Traschuetz, Astrid Adarmes-Gomez, Mathieu Anheim, Jonathan Baets, Bernard Brais, Cynthia Gagnon, Janina Gburek-Augustat, Sarah Doss, Hasmet A. Hanagasi, Christoph Kamm, Peter Klivenyi, Thomas Klockgether, Thomas Klopstock, Martina Minnerop, Alexander Muenchau, Mathilde M. Renaud, Filippo Santorelli, Ludger Schoels, Andreas Thieme, Stefan P. Vielhaber, Bart van de Warrenburg, Ginevra Zanni, Ralf-Dieter Hilgers, Matthis Synofzik" "Objective: The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.Methods: Subitem-level correlation and distribution-based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2-8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes.Results: Although SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions (""static periods""), and fluctuating decreases/increases. All subitems except nose-finger showed moderate-to-strong correlations to activities of daily living, indicating that metric properties-not content validity-limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes (eg, SYNE1-ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG-ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix-Saguenay, COQ8A-ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20 to 25%.Interpretation: This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023" "Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP-mediated disease reveals characteristic features useful for diagnosis" "Diana Esteller, Marianela Schiava, Rocio-Nur Villar-Quiles, Boris Dibowski, Nadia Venturelli, Pascal Laforet, Jorge Alonso-Perez, Montse Olive, Cristina Dominguez-Gonzalez, Carmen Paradas, Beatriz Velez, Anna Kostera-Pruszczyk, Biruta Kierdaszuk, Carmelo Rodolico, Kristl Claeys, Endre Pal, Edoardo Malfatti, Sarah Souvannanorath, Willem De Ridder, Eline De Smet, George Papadimas, Constantinos Papadopoulos, Sofia Xirou, Sushan Luo, Nuria Muelas, Juan J. Vilchez, Alba Ramos-Fransi, Mauro Monforte, Giorgio Tasca, Bjarne Udd, Johanna Palmio, Srtuhi Sri, Sabine Krause, Benedikt Schoeser, Roberto Fernandez-Torron, Adolfo Lopez de Munain, Elena Pegoraro, Maria Elena Farrugia, Mathias Vorgerd, Georgious Manousakis, Jean Baptiste Chanson, Aleksandra Nadaj-Pakleza, Hakan Cetin, Umesh Badrising, Jodi Warman-Chardon, Jorge Bevilacqua, Nicholas Earle, Mario Campero, Jorge Diaz, Chiseko Ikenaga, Thomas E. Lloyd, Ichizo Nishino, Yukako Nishimori, Yoshihiko Saito, Yasushi Oya, Yoshiaki Takahashi, Atsuko Nishikawa, Ryo Sasaki, Chiara Marini-Bettolo, Michela Guglieri, Volker Straub, Tanya Stojkovic, Robert Y. Carlier, Jordi Diaz-Manera" "BackgroundThe diagnosis of patients with mutations in the VCP gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for VCP patients have not been reported so far.MethodsWe collected muscle MRIs of 80 of the 255 patients who participated in the ""VCP International Study"" and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of VCP disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs.ResultsFat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy.ConclusionsPatients with mutations in the VCP gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles."