Posted - December 2020 in Research Highlights
Covers SPG47, SPG50, SPG51 and SPG52
The Cure AP-4 Foundation sponsors this global research collaboration at Boston Children’s Hospital/Harvard Medical School into these rare forms of childhood-onset, complex HSP that are all related to abnormalities in the adaptor protein complex (AP-4). This publication describes what is now known about these related conditions, as a basis for developing therapies.
This image links to a video on another website of the main findings in this study (look for ‘Video Abstract’):
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.
SOURCE: Brain. 2020 Oct 1;143(10):2929-2944. doi: 10.1093/brain/awz307. PMID: 32979048 © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected]
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
Darius Ebrahimi-Fakhari 1 , Julian Teinert 1 2 , Robert Behne 1 3 , Miriam Wimmer 1 , Angelica D’Amore 1 4 , Kathrin Eberhardt 1 , Barbara Brechmann 1 , Marvin Ziegler 1 , Dana M Jensen 5 , Premsai Nagabhyrava 1 6 , Gregory Geisel 1 6 , Erin Carmody 1 6 , Uzma Shamshad 1 6 , Kira A Dies 1 6 , Christopher J Yuskaitis 1 , Catherine L Salussolia 1 , Daniel Ebrahimi-Fakhari 7 8 , Toni S Pearson 9 , Afshin Saffari 2 , Andreas Ziegler 2 , Stefan Kölker 2 , Jens Volkmann 3 , Antje Wiesener 10 , David R Bearden 11 , Shenela Lakhani 12 , Devorah Segal 12 13 , Anaita Udwadia-Hegde 14 , Andrea Martinuzzi 15 , Jennifer Hirst 16 , Seth Perlman 17 , Yoshihisa Takiyama 18 , Georgia Xiromerisiou 19 , Katharina Vill 20 , William O Walker 21 , Anju Shukla 22 , Rachana Dubey Gupta 23 , Niklas Dahl 24 , Ayse Aksoy 25 , Helene Verhelst 26 , Mauricio R Delgado 27 , Radka Kremlikova Pourova 28 , Abdelrahim A Sadek 29 , Nour M Elkhateeb 30 , Lubov Blumkin 31 , Alejandro J Brea-Fernández 32 , David Dacruz-Álvarez 33 , Thomas Smol 34 , Jamal Ghoumid 34 , Diego Miguel 35 , Constanze Heine 36 , Jan-Ulrich Schlump 37 , Hendrik Langen 38 , Jonathan Baets 39 , Saskia Bulk 40 , Hossein Darvish 41 , Somayeh Bakhtiari 42 , Michael C Kruer 42 , Elizabeth Lim-Melia 43 , Nur Aydinli 44 , Yasemin Alanay 45 , Omnia El-Rashidy 46 , Sheela Nampoothiri 47 , Chirag Patel 48 , Christian Beetz 49 , Peter Bauer 49 , Grace Yoon 50 , Mireille Guillot 51 , Steven P Miller 51 , Thomas Bourinaris 52 , Henry Houlden 52 , Laura Robelin 53 , Mathieu Anheim 53 , Abdullah S Alamri 54 , Adel A H Mahmoud 55 , Soroor Inaloo 56 , Parham Habibzadeh 57 , Mohammad Ali Faghihi 57 58 , Anna C Jansen 59 , Stefanie Brock 59 , Agathe Roubertie 60 , Basil T Darras 1 , Pankaj B Agrawal 61 , Filippo M Santorelli 4 , Joseph Gleeson 62 , Maha S Zaki 63 , Sarah I Sheikh 64 , James T Bennett 5 , Mustafa Sahin 1 6
1 Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
2 Division of Child Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
3 Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
4 Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.
5 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
6 Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
7 Pediatric Neurology, Saarland University Medical Center, Homburg/Saar, Germany.
8 Department of General Pediatrics, University Children’s Hospital Muenster, Muenster, Germany.
9 Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
10 Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
11 Child Neurology, University of Rochester School of Medicine, Rochester, NY, USA.
12 Center for Neurogenetics, Weill Cornell Medical College, New York, NY, USA.
13 Division of Child Neurology, Weill Cornell Medicine, New York City, NY, USA.
14 Department of Pediatric Neurology, Jaslok Hospital and Research Centre, Mumbai, India.
15 Scientific Institute, IRCCS E. Medea, Unità Operativa Conegliano, Treviso, Italy.
16 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
17 Division of Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
18 Department of Neurology, University of Yamanashi, Yamanashi, Japan.
19 Department of Neurology, Papageorgiou Hospital, Thessaloniki, Greece.
20 Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany.
21 Department of Pediatrics, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA, USA.
22 Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.
23 Pediatric Neurology, Medanta Hospital, Indore, India.
24 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
25 Pediatric Neurology, Dr. Sami Ulus Hospital, Ankara, Turkey.
26 Pediatric Neurology, Ghent University Hospital, Ghent, Belgium.
27 Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
28 Department of Biology and Medical Genetics, Second Medical Faculty, Charles University and UH Motol, Prague, Czech Republic.
29 Pediatric Neurology, Faculty of Medicine, Sohag University, Sohag, Egypt.
30 Pediatric Neurology, Cairo University, Cairo, Egypt.
31 Movement Disorders Clinic, Pediatric Neurology Unit, Wolfson Medical Center, Holon, Sackler School of Medicine, Tel-Aviv University, Israel.
32 Grupo de Medicina Xenómica, CIBERER, Santiago de Compostela, Spain.
33 Neurología Pediátrica, Complexo Hospitalario Universitario, Santiago de Compostela, Spain.
34 CHU Lille, Institut de Génétique Médicale, RADEME, Lille, France.
35 Serviço de Genética Médica, Universidade Federal da Bahia, Salvador, Brazil.
36 Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
37 Pediatrics, Evangelisches Krankenhaus Oberhausen, Oberhausen, Germany.
38 Sozialpädiatrisches Zentrum Hannover, Hannover, Germany.
39 Neurogenetics Group and Neuromuscular Reference Center, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
40 Medical Genetics, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
41 Cancer Research Center and Department of Medical Genetics, Semnan University of Medical Sciences, Semnan, Iran.
42 Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, USA.
43 Pediatric Medical Genetics, Maria Fareri Children’s Hospital, Valhalla, NY, USA.
44 Pediatric Genetics, Department of Pediatrics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
45 Pediatric Neurology, Istanbul Medical Faculty, Istanbul, Turkey.
46 Pediatrics, Ain Shams University, Cairo, Egypt.
47 Amrita Institute of Medical Sciences and Research Centre, Cochin, India.
48 Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia.
49 Centogene AG, Rostock, Germany.
50 Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
51 Department of Paediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, Canada.
52 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
53 Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
54 Pediatric Neurology, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
55 Pediatrics, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
56 Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
57 Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Iran.
58 Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA.
59 Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium.
60 Pediatric Neurology, CHU Montpellier, Montpellier, France.
61 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.
62 Rady Children’s Institute for Genomic Medicine, Rady Children’s Hospital, San Diego, CA, USA.
63 Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
64 Translational Neuroscience, Celgene, Cambridge, MA, USA.
Here is another study, also accompanied by video, discussing the AP-4 complex and how deficiency might explain the clinical features seen in AP-4 related HSPs.
Heterotetrameric adaptor protein (AP) complexes play key roles in protein sorting and transport vesicle formation in the endomembrane system of eukaryotic cells. One of these complexes, AP-4, was identified over 20 years ago but, up until recently, its function remained unclear. AP-4 associates with the trans-Golgi network (TGN) through interaction with small GTPases of the ARF family and recognizes transmembrane proteins (i.e. cargos) having specific sorting signals in their cytosolic domains. Recent studies identified accessory proteins (tepsin, RUSC2 and the FHF complex) that co-operate with AP-4, and cargos (amyloid precursor protein, ATG9A and SERINC3/5) that are exported from the TGN in an AP-4-dependent manner. Defective export of ATG9A from the TGN in AP-4-deficient cells was shown to reduce ATG9A delivery to pre-autophagosomal structures, impairing autophagosome formation and/or maturation. In addition, mutations in AP-4-subunit genes were found to cause neurological dysfunction in mice and a form of complicated hereditary spastic paraplegia referred to as ‘AP-4-deficiency syndrome’ in humans.
These findings demonstrated that mammalian AP-4 is required for the development and function of the central nervous system, possibly through its role in the sorting of ATG9A for the maintenance of autophagic homeostasis. In this article, we review the properties and functions of AP-4, and discuss how they might explain the clinical features of AP-4 deficiency.
SOURCE: Biochem Soc Trans. 2020 Oct 30;48(5):1877-1888. doi: 10.1042/BST20190664. PMID: 33084855 © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia
- Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, U.S.A.
# Contributed equally.