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1. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author

Eugenio Mercuri, Nicolas Deconinck, Elena S Mazzone, Andres Nascimento, Maryam Oskoui, Kayoko Saito, Carole Vuillerot, Giovanni Baranello, Odile Boespflug-Tanguy, Nathalie Goemans, Janbernd Kirschner, Anna Kostera-Pruszczyk, Laurent Servais, Marianne Gerber, Ksenija Gorni, Omar Khwaja, Heidemarie Kletzl, Renata S Scalco, Hannah Staunton, Wai Yin Yeung, Carmen Martin, Paulo Fontoura, John W Day, Joseph J. Volpe, John Posner, Ulrich Kellner, Rosaline Quinlivan, Aurore Daron, Stéphanie Delstanche, Romain Bruninx, Fabian Dal Farra, Olivier Schneider, Irina Balikova, Patricia Delbeke, Inge Joniau, Valentine Tahon, Sylvia Wittevrongel, Elke De Vos, Ingele Casteels, Liesbeth De Waele, Catherine Cassiman, Lies Prové, David Kinoo, Lisa Vancampenhout, Marleen Van Den Hauwe, Annelies Van Impe, Alexandra Prufer de Queiroz Campos Araujo, Aline Chacon Pereira, Flávia Nardes, Lorena Haefeli, Julia Rossetto, Marcos Ferreira Rebel, Jaqueline Almeida Pereira, Craig Campbell, Sapna Sharan, Wendy McDonald, Cheryl Scholtes, Jean Mah, Maria Sframeli, Angela Chiu, Jane Hagel, Raquel Beneish, Gaela Cariou-Palmer, Connie Pham, Daniela Toffoli, Stephanie Arpin, Sarah Turgeon Desilets, Yi Wang, Chaoping Hu, Jianfeng Huan, Chen Qian, Li Shen, Ying Xiao, Zhenxuan Zhou, Hui Li, Sujuan Wang, Hui Xiong, Xingzhi Chang, Hui Dong, Ying Liu, Tian Sang, Cuijie Wei, Jing Wen, Yiwen Cao, Xingyao Ly, Jingjing Zhao, Wenzhu Li, Lun Qin, Nina Barisic, Martina Galiot Delic, Petra Kristina Ivkic, Nenad Vukojevic, Ivana Kern, Boris Najdanovic, Marin Skugor, Teresa Gidaro, Andreea Seferian, Silvana De Lucia, Emmanuel Barreau, Nabila Mnafek, Marta Milkova Momtchilova, Helene Peche, Carole Valherie, Allison Grange, Charlotte Lilien, Darko Milascevic, Shotaro Tachibana, Claudia Ravelli, Ruxandra Cardas, Jessica Taytard, Guillaume Aubertin, Laure Vanden Brande, Jean-Baptiste Davion, Stephanie Coopman, Ikram Bouacha, Philippe Debruyne, Sabine Defoort, Gilles Derlyn, Florian Leroy, Loïc Danjoux, Julie Guilbaud, Isabelle Desguerre, Christine Barnérias, Michaela Semeraro, Dominique Bremond-Gignac, Lenaic Bruere, Maxence Rateaux, Élodie Deladrière, Virginie Germa, Yann Pereon, Sandra Mercie, Fanny Billaud, Lucie Le Goff, Guy Letellier, Aurélie Portefaix, Camille De-Montferrand, Laure Le-Goff, Stephanie Fontaine, Manel Saidi, Nabil Bouzid, Aurélie Barriere, Marie Tinat, Michelle Dreesbach, Wolf Lagréze, Bettina Michaelis, Fanni Molnar, Dorina Seger, Sibylle Vogt, Enrico Bertini, Adele D'Amico, Sergio Petroni, Anna Maria Bonetti, Adelina Carlesi, Irene Mizzoni, Claudio Bruno, Enrico Priolo, Giuseppe Rao, Simone Morando, Paola Tacchetti, Ambra Zuffi, Giacomo Pietro Comi, Roberta Brusa, Stefania Corti, Velardo Daniele, Alessandra Govoni, Francesca Magri, Valeria Minorini, Silvia Gabriella Osnaghi, Francesca Abbati, Federica Fassini, Michaela Foa, Amaqlia Lopopolo, Megi Meneri, Francesca Zoppas, Valeria Parente, Riccardo Masson, Stefania Bianchi Marzoli, Diletta Santarsiero, Myriam Garcia Sierra, Gemma Tremolada, Maria Teresa Arnoldi, Marta Vigano, Riccardo Zanin, Laura Antonaci, Roberto de Sanctis, Marika Pane, Maria Carmela Pera, Giulia Maria Amorelli, Costanza Barresi, Gugliemo D'Amico, Lorenzo Orazi, Giorgia Coratti, Kazuhiro Haginoya, Atsuko Kato, Yuko Morishita, Ryutaro Kira, Kiyomu Akiyama, Miwako Goto, Yujiro Mori, Misato Okamoto, Saki Tsutsui, Yuta Takatsuji, Aya Tanaka, Hirofumi Komaki, Miina Omori, Ippei Suzuki, Mizuki Takeuchi, Daisuke Todoroki, Seji Watanabe, Tomoko Matsubayashi, Emi Inakazu, Hiroe Nagura, Akira Suzuki, Manami Usui, Nobutsune Ishikawa, Yousuke Harada, Kenishi Fudeyasu, Kazuhiko Hirata, Kana Michiue, Kazuyuki Ueda, Junko Fujitani, Reiko Arakawa, Kozue Takano, Shigeko Yashiro, Maiko Seki, Nozomi Sano, Koji Fukuyama, Yuki Matsumoto, Hirofumi Miyazaki, Minoru Shibata, Kyoko Kobayashi, Yukie Nakamura, Yasuhiro Takeshima, Moe Kuma, Anna Fraczek, Maria Jedrzejowska, Anna Lusakowska, Agnieszka Czeszyk-Piotrowicz, Wojciech Hautz, Klaudia Rakusiewicz, Malgorzata Burlewicz, Zuzanna Gierlak-Wojcicka, Malwina Kepa, Adam Sikorski, Marcin Sobieraj, Maria Mazurkiewicz-Beldzinska, Anna Lemska, Sandra Modrzejewska, Mateusz Koberda, Urszula Stodolska-Koberda, Agnieszka Waskowska, Jagoda Kolendo, Agnieszka Sobierajska-Rek, Barbara Steinborn, Magdalena Dalz, Julia Grabowska, Wojciech Hajduk, Justyna Janasiewicz-Karachitos, Monika Klimas, Marcin Stopa, Ewa Gajewska, Beata Pusz, Dmitry Vlodavets, Evgenia Melnik, Natalya Leppenen, Nataliya Yupatova, Anastasya Monakhova, Yulia Papina, Olga Shidlovsckaia, Vedrana Milic Rasic, Vesna Brankovic, Ana Kosac, Olivera Djokic, Vesna Jakšic, Ana Pepic, Jelena Martinovic, Francina Munell Casadesus, Eduardo Tizzano, Nieves Martín Begué, Charlotte Wolley Dod, Olaia Subira, Bernat Planas Pascual, Esther Toro Tamargo, Marcos Madruga Garrido, José David Medina Romero, Marta Peña Salinas, Andrés Nascimento Osorio, Ana Díaz Cortés, Enrique Jiménez Gañan, Simone Dowon Suh, Julita Medina Cantillo, Obdulia Moya, Nuria Padros, Sandra Roca Urraca, Hugo Gonzalez Valdivia, Samuel Pascual Pascual, Sofía de Manuel, Susana Noval Martin, Paul Burnham, Sandra Espinosa, Mercedes Martinez Moreno, Haluk Topaloglu, Ibrahim Oncel, Nesibe Eroglu Ertugru, Bahadir Konuskan, Bora Eldem, Sibel Kadayifçilar, Ipek Alemdaroglu, Aynur Ayse Karaduman, Oznur Tunca Yilmaz, Neslihan Bilgin, Seher Sari, Claudia Chiriboga, John J. Lee, Donnielle Rome-Martin, John W. Day, Shannon Beres, Tina Duong, Richard Gee, Sally Dunaway Young, Sabine Fuerst-Recktenwald, Anne Marquet, Nicoletta Muelhardt, and Dylan Trundell

Subjects
Adult, Risdiplam, spinal muscular atrophy, Adolescent, Spinal Muscular Atrophies of Childhood, Settore MED/26 - NEUROLOGIA, Young Adult, Pyrimidines, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Double-Blind Method, Child, Preschool, Humans, Neurology (clinical), Child, Preschool, Azo Compounds, Aged
Abstract

BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Published
2022
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2. Clinical Variability in Spinal Muscular Atrophy Type <scp>III</scp>

Author

Claudio Bruno, Gian Luca Vita, Jacqueline Montes, Maria Sframeli, Tina Duong, Valeria Sansone, Annalia Frongia, Mariacristina Scoto, John W. Day, Francesco Muntoni, Giorgia Coratti, Enrico Bertini, Jessica Exposito Escudero, Simona Lucibello, Marika Pane, Sonia Messina, Allan M. Glanzman, Eugenio Mercuri, Roberto De Sanctis, Elena S. Mazzone, Anna Mayhew, Laura Antonaci, Francesca Bovis, Andrés Nascimento Osorio, Matthew Civitello, Sara Carnicella, Rachel Salazar, Richard S. Finkel, Chiara Marini Bettolo, Adele D'Amico, Nathalie Goemans, Robert Muni Lofra, Darryl C. De Vivo, Marleen Van den Hauwe, Maria Carmela Pera, Evelin Milev, Amy Pasternak, Sally Dunaway Young, Emilio Albamonte, and Basil T. Darras

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Longitudinal study, Adolescent, Models, Neurological, Gene Dosage, Spinal Muscular Atrophies of Childhood, Young Adult, 03 medical and health sciences, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, 0302 clinical medicine, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Humans, Survival of Motor Neuron 2 Protein, Models, Internal medicine, medicine, Preschool, business.industry, Repeated measures design, Retrospective cohort study, Spinal muscular atrophy, medicine.disease, SMA, 030104 developmental biology, Neurology, Neurological, Cohort, Neurology (clinical), sma, Age of onset, business, 030217 neurology & neurosurgery, Cohort study
Abstract

OBJECTIVE: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments. RESULTS: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (ß = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (ß = -1.15, p < 0.0001) and IIIB (ß = -0.69, p = 0.002). INTERPRETATION: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117.

Published
2020
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3. Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease

Author

Pouria Mashouri, Krish Ohri, Andrés Nascimento Osorio, Ronald D. Cohn, Peiqui Wang, Steven A. Moore, Arun K. Ramani, Katherine D. Mathews, Hernan Gonorazky, James J. Dowling, Michael Brudno, Dwi U. Kemaladewi, Mark A. Tarnopolsky, Senthuri Viththiyapaskaran, David Villanova, Sergey Naumenko, Dennis Kao, and Viswateja Nelakuditi

Subjects
Adult, Genetic Markers, Male, muscular dystrophy, 0301 basic medicine, Adolescent, transdifferentiation, Muscle Fibers, Skeletal, RNA-Seq, Disease, Computational biology, Biology, Article, Cohort Studies, Transcriptome, Young Adult, Exon, transcriptomics, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Muscular Diseases, diagnostics, Genetics, Humans, Child, Exome, Cells, Cultured, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Intron, Genetic Variation, High-Throughput Nucleotide Sequencing, Correction, RNA, Exon skipping, 3. Good health, 030104 developmental biology, myotubes, Mutation, Female, RNA-seq, Mendelian disease, 030217 neurology & neurosurgery
Abstract

Gene-panel and whole-exome analyses are now standard methodologies for mutation detection in Mendelian disease. However, the diagnostic yield achieved is at best 50%, leaving the genetic basis for disease unsolved in many individuals. New approaches are thus needed to narrow the diagnostic gap. Whole-genome sequencing is one potential strategy, but it currently has variant-interpretation challenges, particularly for non-coding changes. In this study we focus on transcriptome analysis, specifically total RNA sequencing (RNA-seq), by using monogenetic neuromuscular disorders as proof of principle. We examined a cohort of 25 exome and/or panel "negative" cases and provided genetic resolution in 36% (9/25). Causative mutations were identified in coding and non-coding exons, as well as in intronic regions, and the mutational pathomechanisms included transcriptional repression, exon skipping, and intron inclusion. We address a key barrier of transcriptome-based diagnostics: the need for source material with disease-representative expression patterns. We establish that blood-based RNA-seq is not adequate for neuromuscular diagnostics, whereas myotubes generated by transdifferentiation from an individual's fibroblasts accurately reflect the muscle transcriptome and faithfully reveal disease-causing mutations. Our work confirms that RNA-seq can greatly improve diagnostic yield in genetically unresolved cases of Mendelian disease, defines strengths and challenges of the technology, and demonstrates the suitability of cell models for RNA-based diagnostics. Our data set the stage for development of RNA-seq as a powerful clinical diagnostic tool that can be applied to the large population of individuals with undiagnosed, rare diseases and provide a framework for establishing minimally invasive strategies for doing so.

Published
2019
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4. Ataluren use in patients with nonsense mutation Duchenne muscular dystrophy: patient demographics and characteristics from the STRIDE Registry

Author

Traci Schilling, Eugenio Mercuri, Janbernd Kirschner, Abdallah Delage, Mar Tulinius, Filippo Buccella, Panayiota Trifillis, Francesco Muntoni, C. Werner, Olivia Zhang, Michela Guglieri, Andrés Nascimento Osorio, Claudio Santos, Gary Elfring, and Isabelle Desguerre

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Patient demographics, Duchenne muscular dystrophy, Population, Nonsense mutation, Guinea Pigs, STRIDE, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, International database, medicine, Animals, Humans, In patient, Registries, education, Child, STRIDE Registry, ataluren, demographics, dystrophin, nonsense mutation Duchenne muscular dystrophy, Aged, education.field_of_study, Oxadiazoles, business.industry, Health Policy, Infant, medicine.disease, Ataluren, Muscular Dystrophy, Duchenne, chemistry, 030220 oncology & carcinogenesis, Child, Preschool, Rabbits, business, 030217 neurology & neurosurgery
Abstract

Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (DMD) in clinical practice (NCT02369731). Here, we describe the initial demographic characteristics of the registry population. Patients & methods: Patients will be followed up from enrollment for ≥5 years or until study withdrawal. Results & conclusion: As of 9 July 2018, 213 DMD boys were enrolled from 11 countries. Mean (standard deviation) ages at first symptoms and at study treatment start were 2.7 (1.7) years and 9.8 (3.7) years, respectively. Corticosteroids were used by 190 patients (89.2%) before data cut-off. Mean (standard deviation) ataluren exposure was 639.0 (362.9) days. Six patients withdrew. STRIDE is the first drug registry for patients with DMD and represents the largest real-world registry of patients with nmDMD to date.

Published
2019

5. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

Nathalie Goemans, Perry B. Shieh, Eugenio Mercuri, M. James, Maria Bernadete Dutra de Resende, Kathryn Selby, Jean K. Mah, Brigitte Chabrol, Juan J. Vílchez, Andrés Nascimento Osorio, Yann Péréon, Linda Lowes, Gihan Tennekoon, Leslie Nelson, Jahannaz Dastgir, Janbernd Kirschner, Thomas Voit, Haluk Topaloglu, Joseph McIntosh, Marcio Souza, Francesco Muntoni, Susan D. Apkon, Richard S. Finkel, Enrico Bertini, R. Spiegel, Kristi J. Jones, Timothy Lotze, Julie A. Parsons, Peter Riebling, Kristy Rose, Giuseppe Vita, H. Kroger, Tuyen Ong, H. Lee Sweeney, Susan T. Iannaccone, Michela Guglieri, Craig Campbell, Kevin M. Flanigan, Clemens Bloetzer, Xiaohui Luo, Peter Heydemann, Michelle Eagle, Anna Kamińska, Stuart W. Peltz, Peter I. Karachunski, Martin Kudr, Giacomi Pietro Comi, Hoda Abdel-Hamid, Lausanne Canton de Vaud, Craig M. McDonald, Basil T. Darras, Yoram Nevo, Ulrike Schara, Alexandra Prufer de Queiroz Campos Araujo, Lindsay N. Alfano, Russell J. Butterfield, J. Ben Renfroe, Thomas Sejersen, Erika Finanger, Gary Elfring, Katherine D. Mathews, Jong-Hee Chae, Isabelle Desguerre, Daehak-ro Jongno-gu, Raul G Escobar, Elena S. Mazzone, Anna Mayhew, Brenda Wong, Richard J. Barohn, Monique M. Ryan, Imelda Hughes, Ricardo Erazo Torricelli, and Mar Tulinius

Subjects
0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Patients, Adolescent, Population, Nonsense mutation, Medizin, Subgroup analysis, Walking, Placebo, Global Health, Muscular Dystrophies, Dystrophin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Double-Blind Method, Clinical endpoint, Medicine, Humans, Muscular Dystrophy, education, Child, Muscular Dystrophy, Duchenne, Muscular Dystrophies, Patients, education.field_of_study, Oxadiazoles, Intention-to-treat analysis, business.industry, duchenne, General Medicine, Ataluren, Muscular Dystrophy, Duchenne, 030104 developmental biology, Treatment Outcome, chemistry, Codon, Nonsense, Ambulatory, business, 030217 neurology & neurosurgery
Abstract

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. METHODS: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (

Published
2016

6. Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients

Author

Elisabeth Holme, Rosalba Carrozzo, Andrés Nascimento Osorio, Robert W. Taylor, Carlo Dionisi-Vici, Kirstine Ravn, Hernan Amartino, Duccio Maria Cordelli, Alberto Burlina, Karin Naess, Filippo M. Santorelli, René de Coo, Niklas Darin, Berit Woldseth, Alfred Peter Born, Päivi Vieira, Morten Duno, Flemming Wibrand, Fróði Joensen, Enrico Bertini, Magnhild Rasmussen, Robert McFarland, Daniela Buhas, Gabriela Stangoni, Elsebet Ostergaard, Samir Mesli, Johanna Uusimaa, Marzia Bianchi, Paolo Prontera, Mustafa Batbayli, Isabelle Redonnet-Vernhet, Mar Tulinius, Daniela Verrigni, Philippe Jouvencel, Neurology, Carrozzo, Rosalba, Verrigni, Daniela, Rasmussen, Magnhild, de Coo, Rene, Amartino, Hernan, Bianchi, Marzia, Buhas, Daniela, Mesli, Samir, Naess, Karin, Born, Alfred Peter, Woldseth, Berit, Prontera, Paolo, Batbayli, Mustafa, Ravn, Kirstine, Joensen, Fróði, Cordelli, Duccio M., Santorelli, Filippo Maria, Tulinius, Mar, Darin, Nikla, Duno, Morten, Jouvencel, Philippe, Burlina, Alberto, Stangoni, Gabriela, Bertini, Enrico, Redonnet-Vernhet, Isabelle, Wibrand, Flemming, Dionisi-Vici, Carlo, Uusimaa, Johanna, Vieira, Paivi, Osorio, Andrés Nascimento, McFarland, Robert, Taylor, Robert W., Holme, Elisabeth, and Ostergaard, Elsebet

Subjects
Male, 0301 basic medicine, Mitochondrial Diseases, SUCLA2, DNA Mutational Analysis, Methylmalonic acid, Bioinformatics, Gastroenterology, Mitochondrial Encephalomyopathie, chemistry.chemical_compound, Succinate-CoA Ligases, Gene duplication, Genotype, Mitochondrial Disease, Missense mutation, Child, Genetics (clinical), education.field_of_study, Amino Acid Metabolism, Inborn Error, Phenotype, Codon, Nonsense, Child, Preschool, Female, Human, Adult, medicine.medical_specialty, Adolescent, Nonsense mutation, Population, Mutation, Missense, DNA, Mitochondrial, DNA Mutational Analysi, Young Adult, 03 medical and health sciences, Genetic, Mitochondrial Encephalomyopathies, Internal medicine, Genetics, medicine, Humans, Amino Acid Sequence, education, Amino Acid Metabolism, Inborn Errors, Succinate-CoA Ligase, business.industry, Infant, Newborn, Infant, 030104 developmental biology, Methylmalonic aciduria, chemistry, business, Methylmalonic Acid
Abstract

Background: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Patients and results: Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38 % of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14 % of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12 % of SUCLA2 and in 10 % of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of SUCLA2 and 80 % of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found. Conclusions: To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.

Published
2016

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