The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Afshin Saffari - , Harvard University, Heidelberg University  (Author)
  • Tracy Lau - , University College London (Author)
  • Homa Tajsharghi - , University of Skövde (Author)
  • Ehsan Ghayoor Karimiani - , St. George's University of London, Next Generation Genetic Polyclinic (Author)
  • Ariana Kariminejad - , Kariminejad-Najmabadi Pathology & Genetics Center (Author)
  • Stephanie Efthymiou - , University College London (Author)
  • Giovanni Zifarelli - , Centogene AG (Author)
  • Tipu Sultan - , University College London (Author)
  • Mehran Beiraghi Toosi - , Mashhad University of Medical Sciences (Author)
  • Sahar Sedighzadeh - , Shahid Chamran University of Ahvaz, KaryoGen (Author)
  • Victoria Mok Siu - , Western University (Author)
  • Juan Darío Ortigoza-Escobar - , Hospital Sant Joan de Déu Barcelona (Author)
  • Aisha M. Alshamsi - , Tawam Hospital (Author)
  • Shahnaz Ibrahim - , Aga Khan University (Author)
  • Nouriya Abbas Al-Sannaa - , Saudi Aramco (Author)
  • Walla Al-Hertani - , Harvard University (Author)
  • Whalen Sandra - , Hopital Armand-Trousseau (Author)
  • Mark Tarnopolsky - , McMaster University (Author)
  • Shahryar Alavi - , University College London (Author)
  • Chumei Li - , McMaster University (Author)
  • Debra Lynn Day-Salvatore - , Rutgers - The State University of New Jersey, New Brunswick (Author)
  • Maria Jesús Martínez-González - , Hospital de Cruces (Author)
  • Kristin M. Levandoski - , Rutgers - The State University of New Jersey, New Brunswick (Author)
  • Emma Bedoukian - , University of Pennsylvania (Author)
  • Suneeta Madan-Khetarpal - , University of Pittsburgh (Author)
  • Michaela J. Idleburg - , University of Pittsburgh (Author)
  • Minal Juliet Menezes - , University of Sydney (Author)
  • Aishwarya Siddharth - , Harvard University (Author)
  • Konrad Platzer - , Leipzig University (Author)
  • Henry Oppermann - , Leipzig University (Author)
  • Martin Smitka - , Department of Paediatrics, Division of Neuropediatrics (Author)
  • Felicity Collins - , University of Sydney (Author)
  • Monkol Lek - , Yale University (Author)
  • Mohmmad Shahrooei - , Medical Laboratory of Dr. Shahrooei, KU Leuven (Author)
  • Maryam Ghavideldarestani - , Medical Laboratory of Dr. Shahrooei (Author)
  • Isabella Herman - , Baylor College of Medicine, Boys Town National Research Hospital (Author)
  • John Rendu - , Grenoble Institut Neurosciences (Author)
  • Julien Faure - , Grenoble Institut Neurosciences (Author)
  • Janice Baker - , University of Minnesota System (Author)
  • Vikas Bhambhani - , University of Minnesota System (Author)
  • Laurel Calderwood - , Lucille Packard Children's Hospital, Stanford University (Author)
  • Javad Akhondian - , Mashhad University of Medical Sciences (Author)
  • Shima Imannezhad - , Mashhad University of Medical Sciences (Author)
  • Hanieh Sadat Mirzadeh - , Mashhad University of Medical Sciences (Author)
  • Narges Hashemi - , Mashhad University of Medical Sciences (Author)
  • Mohammad Doosti - , Next Generation Genetic Polyclinic (Author)
  • Mojtaba Safi - , Next Generation Genetic Polyclinic (Author)
  • Najmeh Ahangari - , Islamic Azad University (Author)
  • Paria Najarzadeh Torbati - , Next Generation Genetic Polyclinic (Author)
  • Soheila Abedini - , Next Generation Genetic Polyclinic (Author)
  • Vincenzo Salpietro - , University College London (Author)
  • Elif Yilmaz Gulec - , Istanbul Medeniyet University (Author)
  • Safieh Eshaghian - , Isfahan Fertility and Infertility Center (Author)
  • Mohammadreza Ghazavi - , Isfahan University of Medical Sciences (Author)
  • Michael T. Pascher - , Ludwig Maximilian University of Munich (Author)
  • Marina Vogel - , Ludwig Maximilian University of Munich, German Cancer Research Center (DKFZ) (Author)
  • Angela Abicht - , Ludwig Maximilian University of Munich, MGZ - Medical Genetics Center Munich (Author)
  • Sébastien Moutton - , Pôle mère enfant (Author)
  • Ange Line Bruel - , Université de Bourgogne (Author)
  • Claudine Rieubland - , University of Bern (Author)
  • Sabina Gallati - , University of Bern (Author)
  • Tim M. Strom - , Technical University of Munich (Author)
  • Hanns Lochmüller - , University of Ottawa (Author)
  • Mohammad Hasan Mohammadi - , Zabol University of Medical Sciences (Author)
  • Javeria Raza Alvi - , Children's Hospital Lahore (Author)
  • Elaine H. Zackai - , University of Pennsylvania (Author)
  • Beth A. Keena - , University of Pennsylvania (Author)
  • Cara M. Skraban - , University of Pennsylvania (Author)
  • Seth I. Berger - , Children's National Medical Center (Author)
  • Erin H. Andrew - , Children's National Medical Center (Author)
  • Elham Rahimian - , Haghighat Medical Imaging Center-Tehran (Author)
  • Michelle M. Morrow - , OPKO Health, Inc. (Author)
  • Ingrid M. Wentzensen - , OPKO Health, Inc. (Author)
  • Francisca Millan - , OPKO Health, Inc. (Author)
  • Lindsay B. Henderson - , OPKO Health, Inc. (Author)
  • Hormos Salimi Dafsari - , University of Cologne, Max Planck Institute for Biology of Ageing, Guy's and St Thomas' NHS Foundation Trust (Author)
  • Heinz Jungbluth - , Guy's and St Thomas' NHS Foundation Trust, King's College London (KCL) (Author)
  • Natalia Gomez-Ospina - , Stanford University (Author)
  • Anne McRae - , Ann and Robert H. Lurie Children's Hospital of Chicago (Author)
  • Merlene Peter - , Ann and Robert H. Lurie Children's Hospital of Chicago (Author)
  • Danai Veltra - , National and Kapodistrian University of Athens (Author)
  • Nikolaos M. Marinakis - , National and Kapodistrian University of Athens (Author)
  • Christalena Sofocleous - , National and Kapodistrian University of Athens (Author)
  • Farah Ashrafzadeh - , Mashhad University of Medical Sciences (Author)
  • Davut Pehlivan - , Baylor College of Medicine (Author)
  • Johannes R. Lemke - , Leipzig University (Author)
  • Judith Melki - , Université Paris-Saclay (Author)
  • Audrey Benezit - , Hôpital Raymond Poincaré (Author)
  • Peter Bauer - , Centogene AG (Author)
  • Denisa Weis - , Kepler University Hospital (Author)
  • James R. Lupski - , Baylor College of Medicine (Author)
  • Jan Senderek - , Ludwig Maximilian University of Munich (Author)
  • John Christodoulou - , University of Sydney, University of Melbourne (Author)
  • Wendy K. Chung - , Columbia University (Author)
  • Rose Goodchild - , KU Leuven (Author)
  • Amaka C. Offiah - , University of Sheffield (Author)
  • Andres Moreno-De-Luca - , Geisinger Medical Center (Author)
  • Mohnish Suri - , Nottingham University Hospitals NHS Trust (Author)
  • Darius Ebrahimi-Fakhari - , Harvard University (Author)
  • Henry Houlden - , University College London (Author)
  • Reza Maroofian - , University College London (Author)

Abstract

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.

Details

Original languageEnglish
Pages (from-to)3273-3288
Number of pages16
JournalBrain
Volume146
Issue number8
Publication statusPublished - 1 Aug 2023
Peer-reviewedYes

External IDs

PubMed 36757831

Keywords

ASJC Scopus subject areas

Keywords

  • AMC5, NDD, Torsin-1A, arthrogryposis multiplex congenita 5, biallelic variation, Cross-Sectional Studies, Mutation/genetics, Humans, Male, Nervous System Malformations, Dystonic Disorders/genetics, Molecular Chaperones/genetics, Phenotype, Dystonia/genetics

Library keywords