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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders
Brain, Volume 146, No. 12, Year 2023
Notification
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Description
MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'. © 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.
Authors & Co-Authors
Maroofian, Reza
United Kingdom, London
University College London
Kaiyrzhanov, Rauan
United Kingdom, London
University College London
Calì, Elisa
United Kingdom, London
University College London
Zamani, Mina
Iran, Ahvaz
Shahid Chamran University of Ahvaz
Iran, Ahvaz
Narges Medical Genetics and Prenatal Diagnosis Laboratory
Zaki, Maha S.
Egypt, Giza
National Research Centre
Ferla, Matteo Paolo
United Kingdom, Oxford
Nihr Oxford Biomedical Research Centre
Abdullah, Uzma
Pakistan, Rawalpindi
Pmas-arid Agriculture University Rawalpindi
Karimiani, Ehsan Ghayoor
Iran, Mashhad
Next Generation Genetic Polyclinic
United Kingdom, London
St George’s, University of London
Iran, Mashhad
Islamic Azad University, Mashhad Branch
Efthymiou, Stephanie
United Kingdom, London
University College London
Yesil, G.
Turkey, Istanbul
Istanbul Üniversitesi
Alavi, Shahryar
United Kingdom, London
University College London
Al-Shamsi, Aisha Mohamed
United Arab Emirates, Al Ain
Tawam Hospital
Tajsharghi, Homa
Sweden, Skovde
Högskolan I Skövde
Abdel-Hamid, M. S.
Egypt, Giza
National Research Centre
Saadi, Nebal Waill
Iraq, Baghdad
University of Baghdad
Iraq, Baghdad
Baghdad Teaching Hospital
Al-Mutairi, Fuad
Saudi Arabia, Riyadh
King Saud Bin Abdulaziz University for Health Sciences
AlAbdi, Lama
Saudi Arabia, Riyadh
King Saud University
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Beetz, Christian
Germany, Rostock
Centogene ag
Ali, Zafar
Denmark, Copenhagen
Københavns Universitet
Pakistan, Charbagh
University of Swat
Toosi, Mehran Beiraghi
Iran, Mashhad
Mashhad University of Medical Sciences
Rudnik-Schöneborn, Sabine S.
Austria, Innsbruck
Medizinische Universitat Innsbruck
Babaei, Meisam
Iran, Bojnord
North Khorasan University of Medical Sciences
Isohanni, Pirjo
Finland, Helsinki
Helsingin Yliopisto
Finland, Helsinki
Helsinki University Hospital
Khan, Sheraz
Pakistan, Faisalabad
National Institute for Biotechnology and Genetic Engineering Pakistan
Hickey, Scott E.
United States, Columbus
Nationwide Children’s Hospital
United States, Columbus
The Ohio State University College of Medicine
Marom, Daphna R.
Israel, Tel Aviv-yafo
Tel Aviv Sourasky Medical Center
Kurian, Manju A.
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Marafi, Dana
United States, Houston
Baylor College of Medicine
Kuwait, Kuwait City
Kuwait University
Spaull, Robert V.V.
Israel, Tel Aviv-yafo
Tel Aviv Sourasky Medical Center
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Meng, Linyan
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Lalani, Seema R.
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Maqbool, Shazia
Pakistan, Lahore
Children's Hospital Lahore
Rahman, Fatima
Pakistan, Lahore
Children's Hospital Lahore
Seeger, Jürgen
Unknown Affiliation
Palculict, Timothy Blake
United States, Gaithersburg
Genedx, Inc.
Lau, Tracy
United Kingdom, London
University College London
Murphy, David P.
United Kingdom, London
University College London
Mencacci, Niccolò Emanuele
United States, Evanston
Northwestern University
Steindl, Katharina L.
Switzerland, Zurich
Universität Zürich
Begemann, Anaïs
Switzerland, Zurich
Universität Zürich
Rauch, Anita M.
Switzerland, Zurich
Universität Zürich
Aslanger, Ayça Dilruba
Turkey, Istanbul
Istanbul Üniversitesi
Salpietro, Vincenzo Damiano
United Kingdom, London
University College London
Italy, L'aquila
Università Degli Studi Dell'aquila
Ben-Shachar, Shay
Israel, Tel Aviv-yafo
Clalit Health Services
Israel, Tel Aviv-yafo
Tel Aviv University
Ejeskär, Katarina
Sweden, Skovde
Högskolan I Skövde
Al-Aqeel, Aida Imbrahim
Saudi Arabia, Riyadh
Prince Sultan Military Medical City
Lebanon, Beirut
American University of Beirut
Saudi Arabia, Riyadh
Alfaisal University
High, Frances A.
United States, Boston
Massachusetts General Hospital
United States, Boston
Harvard Medical School
Armstrong-Javors, Amy
United States, Boston
Harvard Medical School
United States, Boston
Massachusetts General Hospital
Seifi, Tahereh
Iran, Ahvaz
Shahid Chamran University of Ahvaz
Iran, Ahvaz
Narges Medical Genetics and Prenatal Diagnosis Laboratory
Zeighami, Jawaher
Iran, Ahvaz
Narges Medical Genetics and Prenatal Diagnosis Laboratory
Shariati, Gholamreza H.
Iran, Ahvaz
Narges Medical Genetics and Prenatal Diagnosis Laboratory
Iran, Ahvaz
Ahvaz Jundishapur University of Medical Sciences
Sedaghat, Alireza
Iran, Ahvaz
Narges Medical Genetics and Prenatal Diagnosis Laboratory
Iran, Ahvaz
Ahvaz Jundishapur University of Medical Sciences
Zifarelli, Giovanni
Germany, Rostock
Centogene ag
Bürglen, Lydie
France, Paris
Sorbonne Université
France, Paris
Inserm
Ravelli, Claudia
France, Paris
Sorbonne Université
Zschocke, Johannes
Austria, Innsbruck
Medizinische Universitat Innsbruck
Schatz, Ulrich A.
Austria, Innsbruck
Medizinische Universitat Innsbruck
Germany, Munich
Technische Universität München
Ghavideldarestani, Maryam
United Kingdom, Hull
Hull York Medical School
Kamel, Walaa Ahmed
United States, Evanston
Northwestern University
Egypt, Beni Suef
Beni-suef University
Van Esch, Hilde
Belgium, Leuven
Ku Leuven– University Hospital Leuven
Belgium, Leuven
Ku Leuven
Hackenberg, Annette
Switzerland, Zurich
Universität Zürich
Taylor, Jenny C.
United Kingdom, Oxford
Nihr Oxford Biomedical Research Centre
Al-Gazali, Lihadh I.
United Arab Emirates, Al Ain
United Arab Emirates University
Bauer, Peter
Germany, Rostock
Centogene ag
Alkuraya., Fowzan S.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Galehdari, Hamid
Iran, Ahvaz
Shahid Chamran University of Ahvaz
Chung, Wendy Kay
United States, Boston
Boston Children's Hospital
Baig, Shahid Mahmood
Pakistan, Faisalabad
National Institute for Biotechnology and Genetic Engineering Pakistan
Pakistan, Karachi
The Aga Khan University
Houlden, Henry H.
United Kingdom, London
University College London
Severino, Mariasavina
Italy, Genoa
Istituto Giannina Gaslini
Statistics
Authors: 70
Affiliations: 62
Identifiers
Doi:
10.1093/brain/awad257
ISSN:
00068950
Research Areas
Disability
Genetics And Genomics
Study Design
Cohort Study
Participants Gender
Female