Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Darius Ebrahimi-Fakhari; Julian Teinert; Robert Behne; Miriam Wimmer; Angelica D'Amore; Kathrin Eberhardt; Barbara Brechmann; Marvin Ziegler; Dana M Jensen; Premsai Nagabhyrava; Gregory Geisel; Erin Carmody; Uzma Shamshad; Kira A Dies; Christopher J Yuskaitis; Catherine L Salussolia; Daniel Ebrahimi-Fakhari; Toni S Pearson; Afshin Saffari; Andreas Ziegler; Stefan Kölker; Jens Volkmann; Antje Wiesener; David R Bearden; Shenela Lakhani; Devorah Segal; Anaita Udwadia-Hegde; Andrea Martinuzzi; Jennifer Hirst; Seth Perlman; Yoshihisa Takiyama; Georgia Xiromerisiou; Katharina Vill; William O Walker; Anju Shukla; Rachana Dubey Gupta; Niklas Dahl; Ayse Aksoy; Helene Verhelst; Mauricio R Delgado; Radka Kremlikova Pourova; Abdelrahim A Sadek; Nour M Elkhateeb; Lubov Blumkin; Alejandro J Brea-Fernández; David Dacruz-Álvarez; Thomas Smol; Jamal Ghoumid; Diego Miguel; Constanze Heine; Jan-Ulrich Schlump; Hendrik Langen; Jonathan Baets; Saskia Bulk; Hossein Darvish; Somayeh Bakhtiari; Michael C Kruer; Elizabeth Lim-Melia; Nur Aydinli; Yasemin Alanay; Omnia El-Rashidy; Sheela Nampoothiri; Chirag Patel; Christian Beetz; Peter Bauer; Grace Yoon; Mireille Guillot; Steven P Miller; Thomas Bourinaris; Henry Houlden; Laura Robelin; Mathieu Anheim; Abdullah S Alamri; Adel A H Mahmoud; Soroor Inaloo; Parham Habibzadeh; Mohammad Ali Faghihi; Anna C Jansen; Stefanie Brock; Agathe Roubertie; Basil T Darras; Pankaj B Agrawal; Filippo M Santorelli; Joseph Gleeson; Maha S Zaki; Sarah I Sheikh; James T Bennett; Mustafa Sahin

doi:10.1093/brain/awz307

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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Journal article

Peer reviewed

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Darius Ebrahimi-Fakhari, Julian Teinert, Robert Behne, Miriam Wimmer, Angelica D'Amore, Kathrin Eberhardt, Barbara Brechmann, Marvin Ziegler, Dana M Jensen, Premsai Nagabhyrava, …

Brain (London, England : 1878), Vol.143(10), pp.2929-2944

2020-10-01

DOI: https://doi.org/10.1093/brain/awz307

PMID: 32979048

Abstract

Spastic Paraplegia, Hereditary - genetics

Magnetic Resonance Imaging - trends

Cross-Sectional Studies

Humans

Middle Aged

Child, Preschool

Magnetic Resonance Imaging - methods

Infant

Male

Adaptor Protein Complex 4 - genetics

Spastic Paraplegia, Hereditary - diagnostic imaging

Young Adult

Corpus Callosum - diagnostic imaging

Adolescent

Adult

Female

Registries

Child

Cohort Studies

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.96 Cell Biology; 1.96.302 Exocytosis
Web Of Science research areas: Clinical Neurology; Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
Creators: Darius Ebrahimi-Fakhari - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Julian Teinert - Division of Child Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Robert Behne - Department of Neurology, University Hospital Würzburg, Würzburg, Germany
Miriam Wimmer - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Angelica D'Amore - Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy
Kathrin Eberhardt - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Barbara Brechmann - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Marvin Ziegler - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Dana M Jensen - Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
Premsai Nagabhyrava - Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Gregory Geisel - Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Erin Carmody - Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Uzma Shamshad - Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Kira A Dies - Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Christopher J Yuskaitis - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Catherine L Salussolia - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Daniel Ebrahimi-Fakhari - Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
Toni S Pearson - Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Afshin Saffari - Division of Child Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Andreas Ziegler - Division of Child Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Stefan Kölker - Division of Child Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Jens Volkmann - Department of Neurology, University Hospital Würzburg, Würzburg, Germany
Antje Wiesener - Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
David R Bearden - Child Neurology, University of Rochester School of Medicine, Rochester, NY, USA
Shenela Lakhani - Center for Neurogenetics, Weill Cornell Medical College, New York, NY, USA
Devorah Segal - Division of Child Neurology, Weill Cornell Medicine, New York City, NY, USA
Anaita Udwadia-Hegde - Department of Pediatric Neurology, Jaslok Hospital and Research Centre, Mumbai, India
Andrea Martinuzzi - Scientific Institute, IRCCS E. Medea, Unità Operativa Conegliano, Treviso, Italy
Jennifer Hirst - Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
Seth Perlman - Division of Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Yoshihisa Takiyama - Department of Neurology, University of Yamanashi, Yamanashi, Japan
Georgia Xiromerisiou - Department of Neurology, Papageorgiou Hospital, Thessaloniki, Greece
Katharina Vill - Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany
William O Walker - Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA
Anju Shukla - Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
Rachana Dubey Gupta - Pediatric Neurology, Medanta Hospital, Indore, India
Niklas Dahl - Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Ayse Aksoy - Pediatric Neurology, Dr. Sami Ulus Hospital, Ankara, Turkey
Helene Verhelst - Pediatric Neurology, Ghent University Hospital, Ghent, Belgium
Mauricio R Delgado - Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Radka Kremlikova Pourova - Department of Biology and Medical Genetics, Second Medical Faculty, Charles University and UH Motol, Prague, Czech Republic
Abdelrahim A Sadek - Pediatric Neurology, Faculty of Medicine, Sohag University, Sohag, Egypt
Nour M Elkhateeb - Pediatric Neurology, Cairo University, Cairo, Egypt
Lubov Blumkin - Movement Disorders Clinic, Pediatric Neurology Unit, Wolfson Medical Center, Holon, Sackler School of Medicine, Tel-Aviv University, Israel
Alejandro J Brea-Fernández - Grupo de Medicina Xenómica, CIBERER, Santiago de Compostela, Spain
David Dacruz-Álvarez - Neurología Pediátrica, Complexo Hospitalario Universitario, Santiago de Compostela, Spain
Thomas Smol - CHU Lille, Institut de Génétique Médicale, RADEME, Lille, France
Jamal Ghoumid - CHU Lille, Institut de Génétique Médicale, RADEME, Lille, France
Diego Miguel - Serviço de Genética Médica, Universidade Federal da Bahia, Salvador, Brazil
Constanze Heine - Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany
Jan-Ulrich Schlump - Pediatrics, Evangelisches Krankenhaus Oberhausen, Oberhausen, Germany
Hendrik Langen - Sozialpädiatrisches Zentrum Hannover, Hannover, Germany
Jonathan Baets - Neurogenetics Group and Neuromuscular Reference Center, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
Saskia Bulk - Medical Genetics, Centre Hospitalier Universitaire de Liège, Liège, Belgium
Hossein Darvish - Cancer Research Center and Department of Medical Genetics, Semnan University of Medical Sciences, Semnan, Iran
Somayeh Bakhtiari - Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA
Michael C Kruer - Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA
Elizabeth Lim-Melia - Pediatric Medical Genetics, Maria Fareri Children's Hospital, Valhalla, NY, USA
Nur Aydinli - Pediatric Genetics, Department of Pediatrics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
Yasemin Alanay - Pediatric Neurology, Istanbul Medical Faculty, Istanbul, Turkey
Omnia El-Rashidy - Pediatrics, Ain Shams University, Cairo, Egypt
Sheela Nampoothiri - Amrita Institute of Medical Sciences and Research Centre, Cochin, India
Chirag Patel - Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia
Christian Beetz - Centogene AG, Rostock, Germany
Peter Bauer - Centogene AG, Rostock, Germany
Grace Yoon - Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
Mireille Guillot - Department of Paediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, Canada
Steven P Miller - Department of Paediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, Canada
Thomas Bourinaris - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Henry Houlden - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
Laura Robelin - Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Mathieu Anheim - Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Abdullah S Alamri - Pediatric Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
Adel A H Mahmoud - Pediatrics, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
Soroor Inaloo - Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Parham Habibzadeh - Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Iran
Mohammad Ali Faghihi - Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
Anna C Jansen - Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium
Stefanie Brock - Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium
Agathe Roubertie - Pediatric Neurology, CHU Montpellier, Montpellier, France
Basil T Darras - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Pankaj B Agrawal - Divisions of Newborn Medicine and Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Filippo M Santorelli - Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy
Joseph Gleeson - Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA, USA
Maha S Zaki - Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
Sarah I Sheikh - Translational Neuroscience, Celgene, Cambridge, MA, USA
James T Bennett - Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA
Mustafa Sahin - Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Publication Details: Brain (London, England : 1878), Vol.143(10), pp.2929-2944
Publisher: England
Grant note: R01 NS106298 / NINDS NIH HHS Wellcome Trust U54 HD090255 / NICHD NIH HHS
Academic Unit: Miller School of Medicine; UMMG Dept of Psychiatry & Behavioral Sciences
Language: English
Resource Type: Journal article
PMID: 32979048
Record Identifier: 991031576739702976