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.

Amrita Institute of Medical Sciences and Research Centre Cochin India

Barrow Neurological Institute Phoenix Children's Hospital Phoenix AZ USA

Cambridge Institute for Medical Research University of Cambridge Cambridge UK

Cancer Research Center and Department of Medical Genetics Semnan University of Medical Sciences Semnan Iran

Center for Neurogenetics Weill Cornell Medical College New York NY USA

Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences University of Miami Miami FL USA

Centogene AG Rostock Germany

Child Neurology University of Rochester School of Medicine Rochester NY USA

CHU Lille Institut de Génétique Médicale RADEME Lille France

Clinical Genetics Human Genetics and Genome Research Division National Research Centre Cairo Egypt

Department of Biology and Medical Genetics 2nd Medical Faculty Charles University and UH Motol Prague Czech Republic

Department of General Pediatrics University Children's Hospital Muenster Muenster Germany

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Medical Genetics Kasturba Medical College Manipal Academy of Higher Education Manipal India

Department of Molecular Neuroscience UCL Institute of Neurology London UK

Department of Neurology Boston Children's Hospital Harvard Medical School Boston MA USA

Department of Neurology Papageorgiou Hospital Thessaloniki Greece

Department of Neurology University Hospital Würzburg Würzburg Germany

Department of Neurology University of Texas Southwestern Medical Center Dallas TX USA

Department of Neurology University of Yamanashi Yamanashi Japan

Department of Neurology Washington University School of Medicine St Louis MO USA

Department of Paediatrics The Hospital for Sick Children and The University of Toronto Toronto Canada

Department of Pediatric Neurology Jaslok Hospital and Research Centre Mumbai India

Department of Pediatrics Seattle Children's Hospital University of Washington School of Medicine Seattle WA USA

Division of Child Neurology and Metabolic Medicine Centre for Paediatric and Adolescent Medicine University Hospital Heidelberg Heidelberg Germany

Division of Child Neurology Weill Cornell Medicine New York City NY USA

Division of Clinical and Metabolic Genetics Department of Paediatrics The Hospital for Sick Children University of Toronto Toronto Canada

Division of Genetic Medicine Department of Pediatrics University of Washington Seattle WA USA

Division of Neurology Department of Pediatrics University of Iowa Carver College of Medicine Iowa City IA USA

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

Genetic Health Queensland Royal Brisbane and Women's Hospital Brisbane Australia

Grupo de Medicina Xenómica CIBERER Santiago de Compostela Spain

Institute of Human Genetics Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Institute of Human Genetics University Hospital Leipzig Leipzig Germany

Medical Genetics Centre Hospitalier Universitaire de Liège Liège Belgium

Molecular Medicine IRCCS Fondazione Stella Maris Pisa Italy

Movement Disorders Clinic Pediatric Neurology Unit Wolfson Medical Center Holon Sackler School of Medicine Tel Aviv University Israel

Neonatal Research Center Shiraz University of Medical Sciences Shiraz Iran

Neurogenetics Group and Neuromuscular Reference Center University of Antwerp and Antwerp University Hospital Antwerp Belgium

Neurología Pediátrica Complexo Hospitalario Universitario Santiago de Compostela Spain

Pediatric Genetics Department of Pediatrics Acibadem Mehmet Ali Aydinlar University Istanbul Turkey

Pediatric Medical Genetics Maria Fareri Children's Hospital Valhalla NY USA

Pediatric Neurology and Developmental Medicine Dr v Hauner Children's Hospital Ludwig Maximilians University Munich Germany

Pediatric Neurology Cairo University Cairo Egypt

Pediatric Neurology CHU Montpellier Montpellier France

Pediatric Neurology Dr Sami Ulus Hospital Ankara Turkey

Pediatric Neurology Faculty of Medicine Sohag University Sohag Egypt

Pediatric Neurology Ghent University Hospital Ghent Belgium

Pediatric Neurology Istanbul Medical Faculty Istanbul Turkey

Pediatric Neurology Medanta Hospital Indore India

Pediatric Neurology National Neuroscience Institute King Fahad Medical City Riyadh Saudi Arabia

Pediatric Neurology Saarland University Medical Center Homburg Saar Germany

Pediatric Neurology Unit Department of Pediatrics UZ Brussel Brussels Belgium

Pediatrics Ain Shams University Cairo Egypt

Pediatrics Evangelisches Krankenhaus Oberhausen Oberhausen Germany

Pediatrics Imam Abdulrahman Bin Faisal University Dammam Saudi Arabia

Persian BayanGene Research and Training Center Shiraz University of Medical Sciences Shiraz Iran

Rady Children's Institute for Genomic Medicine Rady Children's Hospital San Diego CA USA

Scientific Institute IRCCS E Medea Unità Operativa Conegliano Treviso Italy

Service de Neurologie Hôpitaux Universitaires de Strasbourg Strasbourg France

Serviço de Genética Médica Universidade Federal da Bahia Salvador Brazil

Sozialpädiatrisches Zentrum Hannover Hannover Germany

Translational Neuroscience Celgene Cambridge MA USA

Translational Neuroscience Center Boston Children's Hospital Harvard Medical School Boston MA USA

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Brain. 2020 Oct 1;143(10):2864-2866. doi: 10.1093/brain/awaa278. PubMed

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