Article
Clinical Neurology
Shao-Lun Hsu, Hsueh-Wen Hsueh, Shih-Ying Chen, Yung-Yee Chang, Shennie Tan, Chien-Tai Hong, Yu-Shuen Tsai, Kai-Wei Yu, Hsiu-Mei Wu, Yi-Chu Liao, Bing-Wen Soong, Chaur-Jong Hu, Min-Yu Lan, Yi-Chung Lee
Summary: This study investigated the clinical and genetic features of SPG3A in Taiwan and identified that SPG3A accounts for 4% of HSP cases in Taiwan. The most common mutation found in SPG3A patients was ATL1 p.R416C, with 18 patients typically presenting with a pure form HSP phenotype. Haplotype analysis suggested a shared haplotype in patients carrying the p.R416C allele.
PARKINSONISM & RELATED DISORDERS
(2021)
Review
Neurosciences
Neha Mohan, Liang Qiang, Gerardo Morfini, Peter W. Baas
Summary: Mutations in the SPAST gene cause Hereditary Spastic Paraplegia by compromising the function of spastin and giving it toxic gain-of-function properties. Therapeutic strategies are discussed to alleviate symptoms in patients with SPAST-based Hereditary Spastic Paraplegia, also known as SPG4-HSP.
Article
Clinical Neurology
Parizad Varghaei, Mehrdad A. Estiar, Setareh Ashtiani, Simon Veyron, Kheireddin Mufti, Etienne Leveille, Eric Yu, Dan Spiegelman, Marie-France Rioux, Grace Yoon, Mark Tarnopolsky, Kym M. Boycott, Nicolas Dupre, Oksana Suchowersky, Jean-Francois Trempe, Guy A. Rouleau, Ziv Gan-Or
Summary: SPG4 is the most common type of hereditary spastic paraplegia, characterized by diverse genetic features and clinical manifestations. In rare cases, biallelic inheritance, de novo mutations, pathogenic synonymous mutations and CNVs should be considered.
PARKINSONISM & RELATED DISORDERS
(2022)
Article
Clinical Neurology
Francesca Sardina, Davide Valente, Gaia Fattorini, Ettore Cioffi, Gianmarco Dalla Zanna, Alessandra Tessa, Daniela Trisciuoglio, Silvia Soddu, Filippo M. Santorelli, Carlo Casali, Cinzia Rinaldo
Summary: The study developed an automated, simple, fast, and non-invasive cell imaging-based method to quantify microtubule cytoskeleton organization changes in lymphoblastoid cells and peripheral blood mononuclear cells. The results showed that individuals affected by SPG4-hereditary spastic paraplegia have a polarized microtubule cytoskeleton organization. The method was able to discriminate SPG4-hereditary spastic paraplegia from healthy donors and other subtypes, and detect the effects of spastin protein level changes.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
Seyyed-Saleh Hashemi, Reza Hajati, Atefeh Davarzani, Mohammad Rohani, Fardad DanaeeFard, Mohammad Masoud Rahimi Bidgoli, Farzad Fatehi, Ariana Kariminejad, Hossein Najmabadi, Shahriar Nafissi, Afagh Alavi
Summary: Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder with different inheritance patterns, and most autosomal-dominant HSPs (AD-HSPs) are associated with mutations in the SPAST gene. Anticipation may be a common finding in SPG4 families, with affected individuals showing earlier age-at-onset in successive generations. This study suggests that SPAST is a key gene in families with pure forms of AD-HSP and anticipation, indicating a strong genotype-phenotype correlation.
CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
(2022)
Article
Clinical Neurology
Haitian Nan, Min Chu, Li Liu, Kexin Xie, Liyong Wu
Summary: In this study, we identified a novel frameshift variant in the SPAST gene in a pure HSP family, suggesting haploinsufficiency as the pathogenic mechanism and expanding the known mutation spectrum of SPAST.
FRONTIERS IN NEUROLOGY
(2022)
Review
Clinical Neurology
Haitian Nan, Hiroshi Shiraku, Tomoko Mizuno, Yoshihisa Takiyama
Summary: Spastic paraplegia type 4 (SPG4) is a form of autosomal-dominant hereditary spastic paraplegia caused by mutations in the SPAST gene, which can manifest as a complex form with symptoms such as ataxia, epilepsy, and cognitive decline. A study found that the p.Arg499His mutation in SPAST may result in varying complex phenotypes, which can be primarily categorized into three subgroups. This study provides new insights into the genotype-phenotype correlation of SPG4 and suggests a potential association between infantile-onset complicated HSP and the p.Arg499His mutation in SPAST.
Article
Neurosciences
Gautam Wali, Sue-Faye Siow, Erandhi Liyanage, Kishore R. R. Kumar, Alan Mackay-Sim, Carolyn M. M. Sue
Summary: HSP-SPAST is the most common form of hereditary spastic paraplegia (HSP), causing lower limb spasticity. Both patient-derived cortical neurons and peripheral blood mononuclear cells (PBMCs) show reduced levels of acetylated alpha-tubulin, which can be restored by noscapine treatment. Noscapine treatment can potentially benefit HSP-SPAST patients by increasing acetylated alpha-tubulin levels.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Cell Biology
Stojan Peric, Vladana Markovic, Ayse Candayan, Els De Vriendt, Nikola Momcilovic, Andrija Savic, Natasa Dragasevic-Miskovic, Marina Svetel, Zorica Stevic, Ivo Bozovic, Sarlota Mesaros, Jelena Drulovic, Ivana Basta, Igor Petrovic, Olivera Tamas, Milija Mijajlovic, Ivana Novakovic, Dragoslav Sokic, Albena Jordanova
Summary: The study analyzed the genetic causes of HSP in adult Serbian patients and found a high genetic diversity in this population. The findings have important implications for molecular diagnostics and broaden the knowledge on the genetic epidemiology of HSP.
Article
Clinical Neurology
Manuela Wiessner, Reza Maroofian, Meng-Yuan Ni, Andrea Pedroni, Juliane S. Muller, Rolf Stucka, Christian Beetz, Stephanie Efthymiou, Filippo M. Santorelli, Ahmed A. Alfares, Changlian Zhu, Anna Uhrova Meszarosova, Elham Alehabib, Somayeh Bakhtiari, Andreas R. Janecke, Maria Gabriela Otero, Jin Yun Helen Chen, James T. Peterson, Tim M. Strom, Peter De Jonghe, Tine Deconinck, Willem De Ridder, Jonathan De Winter, Rossella Pasquariello, Ivana Ricca, Majid Alfadhel, Bart P. van de Warrenburg, Ruben Portier, Carsten Bergmann, Saghar Ghasemi Firouzabadi, Sheng Chih Jin, Kaya Bilguvar, Sherifa Hamed, Mohammed Abdelhameed, Nourelhoda A. Haridy, Shazia Maqbool, Fatima Rahman, Najwa Anwar, Jenny Carmichael, Alistair Pagnamenta, Nick W. Wood, Frederic Tran Mau-Them, Tobias Haack, Maja Di Rocco, Isabella Ceccherini, Michele Iacomino, Federico Zara, Vincenzo Salpietro, Marcello Scala, Marta Rusmini, Yiran Xu, Yinghong Wang, Yasuhiro Suzuki, Kishin Koh, Haitian Nan, Hiroyuki Ishiura, Shoji Tsuji, Laetitia Lambert, Emmanuelle Schmitt, Elodie Lacaze, Hanna Kuepper, David Dredge, Cara Skraban, Amy Goldstein, Mary J. H. Willis, Katheryn Grand, John M. Graham, Richard A. Lewis, Francisca Millan, Ozgur Duman, Nihal Dundar, Gokhan Uyanik, Ludger Schols, Peter Nuernberg, Gudrun Nuernberg, Andrea Catala Bordes, Pavel Seeman, Martin Kuchar, Hossein Darvish, Adriana Rebelo, Filipa Boucanova, Jean-Jacques Medard, Roman Chrast, Michaela Auer-Grumbach, Fowzan S. Alkuraya, Hanan Shamseldin, Saeed Al Tala, Jamileh Rezazadeh Varaghchi, Maryam Najafi, Selina Deschner, Dieter Glaeser, Wolfgang Huettel, Michael C. Kruer, Erik-Jan Kamsteeg, Yoshihisa Takiyama, Stephan Zuchner, Jonathan Baets, Matthis Synofzik, Rebecca Schuele, Rita Horvath, Henry Houlden, Luca Bartesaghi, Hwei-Jen Lee, Konstantinos Ampatzis, Tyler Mark Pierson, Jan Senderek
Summary: This study identified families with neurological diseases caused by HPDL variants, showing various phenotypes ranging from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia. Experimental evidence suggested a role of HPDL in the nervous system and supported its link to neurological disease.
Article
Clinical Neurology
Christian Lassmann, Winfried Ilg, Marc Schneider, Maximilian Voelker, Daniel F. B. Haeufle, Rebecca Schuele, Martin Giese, Matthis Synofzik, Ludger Schoels, Tim W. Rattay
Summary: This study found specific movement abnormalities in potential SPG4 patients before the manifestation of gait impairment, which were correlated with neurodegenerative biomarkers and could help in early interventions.
MOVEMENT DISORDERS
(2022)
Article
Clinical Neurology
Yi-Jun Chen, Meng-Wen Wang, Yu-Sen Qiu, Ru-Ying Yuan, Ning Wang, Xiang Lin, Wan-Jin Chen
Summary: The molecular cause of hereditary spastic paraplegia (HSP) in a four-generation family with autosomal dominant inheritance was diagnosed using MLPA, WES, and RNA-seq. An intronic AluYb9 insertion in the edge of intron 16 in SPAST was identified, which segregated with the disease phenotype. Our findings suggest that RNA-seq is a recommended first-line diagnostic approach for undiagnosed cases.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Lotte van de Venis, Vivian Weerdesteyn, Aletta Konijnenburg, Bart P. C. van de Warrenburg, Alexander C. H. Geurts, Jorik Nonnekes
Summary: This study found an association between increased trunk movements and reduced balance capacity in patients with HSP. The increased trunk movements may partly reflect balance correcting strategies, as ankle strategies and foot placement strategies become impaired and insufficient to restore balance after intrinsic perturbations.
JOURNAL OF NEUROLOGY
(2022)
Article
Clinical Neurology
Tim W. Rattay, Maximilian Voelker, Maren Rautenberg, Christoph Kessler, Isabel Wurster, Natalie Winter, Tobias B. Haack, Tobias Lindig, Holger Hengel, Matthis Synofzik, Rebecca Schule, Peter Martus, Ludger Schoels
Summary: This study explores early changes in the most common subtype of hereditary spastic paraplegia, SPG4, and identifies subclinical markers of disease activity in the prodromal stage. The findings suggest that certain clinical signs, such as increased reflexes and muscle weakness, may be more frequent in individuals who carry the genetic mutation associated with SPG4.
Letter
Genetics & Heredity
Rosangela Ferese, Simona Scala, Antonio Suppa, Rosa Campopiano, Francesco Asci, Maria Antonietta Chiaravalloti, Alessandro Zampogna, Carmelo D'Alessio, Filomena Fittipaldi, Fabio Buttari, Alba Di Pardo, Emiliano Giardina, Stefania Zampatti, Francesco Fornai, Giuseppe Novelli, Mirco Fanelli, Chiara Zecca, Giancarlo Logroscino, Diego Centonze, Stefano Gambardella
Summary: The flowchart presents the molecular approach employed for decoding non-canonical splicing mutations.
Article
Neurosciences
William Kristian Karlsson, Joan Lilja Sunnleyg Hojgaard, Anna Vilhelmsen, Clarissa Crone, Birgit Andersen, Ian Law, Lisbeth Birk Moller, Troels Tolstrup Nielsen, Emilie Neerup Nielsen, Thomas Krag, Kirsten Svenstrup, Jorgen Erik Nielsen
Summary: Pathogenic variants in the SYNE1 gene can lead to a range of symptoms from pure ataxia to multisystemic disease. This case study presents a novel homozygous truncating variant in the SYNE1 gene in a 20-year-old female patient with early-onset cerebellar deficits, motor neuron involvement, and cognitive deficits, expanding the understanding of the phenotypic spectrum associated with SYNE1 mutations. The findings also reveal unique neuroimaging and electrophysiological abnormalities that further characterize the disease presentation.
Article
Genetics & Heredity
Kristoffer Bjorkman, John Vissing, Elsebet ostergaard, Laurence A. Bindoff, Irenaeus F. M. de Coo, Martin Engvall, Omar Hikmat, Pirjo Isohanni, Gittan Kollberg, Christopher Lindberg, Kari Majamaa, Karin Naess, Johanna Uusimaa, Mar Tulinius, Niklas Darin
Summary: This study describes the clinical spectrum of pediatric-onset syndromes associated with large-scale mitochondrial DNA deletions (LMD). The study found a wider range of multisystem involvement compared to previous studies, likely due to longer follow-up.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Genetics & Heredity
Monica Villarreal-Salazar, Astrid Brull, Gisela Nogales-Gadea, Antoni L. Andreu, Miguel A. Martin, Joaquin Arenas, Alfredo Santalla, Alejandro Lucia, John Vissing, Thomas O. Krag, Tomas Pinos
Summary: In this study, the existing in vitro and in vivo preclinical models for McArdle disease are described, and the insights provided by these models are reviewed. Despite some differences from the typical patient phenotype, these models allow for a thorough study of the different features of the disease and serve as a necessary preclinical step to evaluate treatment efficacy and safety.
Article
Biochemistry & Molecular Biology
Tue L. Nielsen, Tessa M. Hornsyld, Tomas Pinos, Camilla Brolin, John Vissing, Thomas O. Krag
Summary: This study found that the growth factor cocktail did not significantly improve the functional level of mdx model during treatment, despite positive effects on some muscle types at a molecular level. Additionally, histopathology at the end of the treatment revealed signs of inflammation.
Meeting Abstract
Clinical Neurology
M. Naume, C. Hoi-Hansen, A. Born, M. Horby, L. Borgwardt, J. Vissing, D. Staerk, M. Orngreen
NEUROMUSCULAR DISORDERS
(2022)
Meeting Abstract
Clinical Neurology
K. Axelsen, R. Andersen, J. Vissing, N. Witting
NEUROMUSCULAR DISORDERS
(2022)
Article
Pediatrics
Marie Mostue Naume, Marianne Horby Jorgensen, Christina Engel Hoi-Hansen, Alfred Peter Born, John Vissing, Lise Borgwardt, Dorte Marianne Rohde Staerk, Mette Cathrine Orngreen
Summary: The aim of this study was to assess the metabolic and nutritional status of children with neuromuscular disorders, particularly focusing on the liver and bone mineral density. The study included 44 children, and assessments were conducted using various methods including ultrasound, blood samples, and diet registration. The findings showed that liver involvement was present in 31.0% of patients, while low bone mineral density was found in 44.0%. Vitamin D insufficiency or deficiency was also detected in 22.6% of patients. This study highlights the importance of monitoring liver function and nutrition in children with neuromuscular disorders.
Article
Biology
Gabriel Sturm, Kalpita R. Karan, Anna S. Monzel, Balaji Santhanam, Tanja Taivassalo, Celine Bris, Sarah A. Ware, Marissa Cross, Atif Towheed, Albert Higgins-Chen, Meagan J. McManus, Andres Cardenas, Jue Lin, Elissa S. Epel, Shamima Rahman, John Vissing, Bruno Grassi, Morgan Levine, Steve Horvath, Ronald G. Haller, Guy Lenaers, Douglas C. Wallace, Marie-Pierre St-Onge, Saeed Tavazoie, Vincent Procaccio, Brett A. Kaufman, Erin L. Seifert, Michio Hirano, Martin Picard
Summary: A meta-analysis of mitochondrial disease patients demonstrates that OxPhos defects contribute to hypermetabolism. Patient-derived fibroblast experiments confirm that mitochondrial OxPhos defects induce cell-autonomous hypermetabolism, which is associated with accelerated telomere shortening and epigenetic aging.
COMMUNICATIONS BIOLOGY
(2023)
Article
Neurosciences
Aurelie P. Bussy, Jake P. Levy, Tristin Best, Raihaan Patel, Lani Cupo, Tim Van Langenhove, Jorgen E. Nielsen, Yolande Pijnenburg, Maria Landqvist M. Waldo, Anne M. L. Remes, Matthias L. Schroeter, Isabel Santana, Florence Pasquier, Markus Otto, Adrian Danek, Johannes Levin, Isabelle Le Ber, Rik Vandenberghe, Matthis Synofzik, Fermin Moreno, Alexandre de Mendonca, Raquel Sanchez-Valle, Robert Laforce, Tobias Langheinrich, Alexander Gerhard, Caroline R. Graff, Chris R. Butler, Sandro Sorbi, Lize Jiskoot, Harro C. Seelaar, John C. van Swieten, Elizabeth Finger, Maria Carmela Tartaglia, Mario Masellis, Pietro Tiraboschi, Daniela Galimberti, Barbara B. Borroni, James B. Rowe, Martina D. Bocchetta, Jonathan D. A. Rohrer, Gabriel A. Devenyi, M. Mallar Chakravarty, Simon Ducharme
Summary: Recent studies have shown that early cerebellar and subcortical changes are seen in the progression of genetic frontotemporal dementia due to specific gene mutations. This study aimed to investigate the relationship between cerebellar and subcortical atrophy and neuropsychiatric symptoms across different genetic mutations in FTD.
HUMAN BRAIN MAPPING
(2023)
Article
Clinical Neurology
Salman F. Bhai, John Vissing
Summary: Metabolic myopathies are rare inherited disorders that disrupt energy production, leading to symptoms such as exercise intolerance, rhabdomyolysis, and weakness in skeletal muscles. Diagnosis can be challenging due to non-specific and dynamic symptoms, as well as conditions that mimic metabolic myopathies. Next generation sequencing can help clinicians recognize typical clinical phenotypes and shorten diagnosis time. With improved molecular testing accessibility, clinicians should be knowledgeable in interpreting variants of uncertain significance relevant to metabolic myopathies. Once diagnosed, patients can improve their quality of life, engage in exercise safely, and reduce episodes of rhabdomyolysis through diet and lifestyle modifications.
Correction
Multidisciplinary Sciences
Grigoris Effraimidis, Ase Krogh Rasmussen, Morten Dunoe, Lis F. Hasholt, Flemming Wibrand, Soren S. Sorensen, Allan M. Lund, Lars Kober, Henning Bundgaard, Puriya D. W. Yazdanfard, Peter Oturai, Vibeke A. Larsen, Victor Hugo Fraga de Abreu, Lotte Hahn Enevoldsen, Tatiana Kristensen, Kirsten Svenstrup, Margrethe Bastholm Bille, Farah Arif, Mette Mogensen, Mads Klokker, Vibeke Backer, Caroline Kistorp, Ulla Feldt-Rasmussen
Article
Nutrition & Dietetics
Nicoline Lokken, Nicol C. C. Voermans, Linda K. Andersen, Walaa Karazi, Stacey L. L. Reason, Heidi Zweers, Gustav Wilms, Alfredo Santalla, Edward Susanibar, Alejandro Lucia, John Vissing
Summary: The low-carbohydrate ketogenic diet (LCKD) has been increasingly used as a potential treatment option for individuals with McArdle disease. This study aimed to collect patient-reported experiences with a LCKD and found that one-third of the McArdle disease cohort had tried a LCKD. The majority of individuals reported positive effects on core symptoms, while adverse effects were rare and mild to moderate.
Correction
Clinical Neurology
Jorge Alonso-Perez, Lidia Gonzalez-Quereda, Luca Bello, Michela Guglieri, Volker Straub, Pia Gallano, Claudio Semplicini, Elena Pegoraro, Vittoria Zangaro, Andres Nascimento, Carlos Ortez, Giacomo Pietro Comi, Leroy ten Dam, Marianne De Visser, A. J. van der Kooi, Cristina Garrido, Manuela Santos, Ulrike Schara, Andrea Gangfuss, Nicoline Lokken, Jesper Helbo Storgaard, John Vissing, Benedikt Schoser, Gabriele Dekomien, Bjarne Udd, Johanna Palmio, Adele D'Amico, Luisa Politano, Vincenzo Nigro, Claudio Bruno, Chiara Panicucci, Anna Sarkozy, Omar Abdel-Mannan, Alicia Alonso-Jimenez, Kristl G. Claeys, David Gomez-Andres, Francina Munell, Laura Costa-Comellas, Jana Haberlova, Marie Rohlenova, De Vos Elke, Jan L. De Bleecker, Cristina Dominguez-Gonzalez, Giorgio Tasca, Claudia Weiss, Nicolas Deconinck, Roberto Fernandez-Torron, Adolfo Lopez de Munain, Ana Camacho-Salas, Bela Melegh, Kinga Hadzsiev, Lea Leonardis, Blaz Koritnik, Matteo Garibaldi, Juan Carlos de Leon-Hernandez, Edoardo Malfatti, Arturo Fraga-Bau, Isabelle Richard, Isabel Illa, Jordi Diaz-Manera
Meeting Abstract
Clinical Neurology
Vera Bril, Artur Druzdz, Julian Grosskreutz, Ali Habib, Renato Mantegazza, Sabrina Sacconi, Kimiaki Utsugisawa, John Vissing, Tuan Vu, Marion Boehnlein, Ali Bozorg, Maryam Gayfieva, Franz Woltering, Henry Kaminski
Meeting Abstract
Clinical Neurology
Ali Habib, Henry Kaminski, Artur Druzdz, Julian Grosskreutz, Renato Mantegazza, Sabrina Sacconi, Kimiaki Utsugisawa, John Vissing, Tuan Vu, Marion Boehnlein, Bernhard Greve, Franz Woltering, Vera Bril