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

Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernández AJ, Dacruz-Álvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AA, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M (2020)

Publication Type: Journal article

Publication year: 2020


Book Volume: 143

Pages Range: 2929-2944

Journal Issue: 10

DOI: 10.1093/brain/awz307


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.

Involved external institutions

Veterans Affairs Healthcare System Boston and Harvard Medical School US United States (USA) (US) University of Washington US United States (USA) (US) Universitätsklinikum Heidelberg DE Germany (DE) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) University Hospital Ghent BE Belgium (BE) Phoenix Children's Hospital US United States (USA) (US) Maria Fareri Children's Hospital US United States (USA) (US) Hôpitaux universitaires de Strasbourg (HUS) / University Hospital Strasbourg FR France (FR) Centogene GmbH DE Germany (DE) Universitair Ziekenhuis Brussel BE Belgium (BE) Royal Brisbane and Women's Hospital AU Australia (AU) Université de Lille (ULille) / University of Lille Nord de France / Université Lille Nord de France / Université Lille II FR France (FR) The Hospital for Sick Children (SickKids) CA Canada (CA) Weill Cornell Medicine US United States (USA) (US) Tel Aviv University IL Israel (IL) Acıbadem Mehmet Ali Aydınlar University / Acıbadem Mehmet Ali Aydınlar Üniversitesi TR Turkey (TR) Shiraz University of Medical Sciences / دانشگاه علوم پزشکی شیراز IR Iran, Islamic Republic of (IR) Ain Shams University EG Egypt (EG) Centre Hospitalier Universitaire de Liège (CHU Liège) BE Belgium (BE) Klinikum der Universität München DE Germany (DE) Amrita University / Amrita Vishwa Vidyapeetham IN India (IN) Rady Children's Hospital San Diego US United States (USA) (US) Uppsala University SE Sweden (SE) National Research Centre (NRC) / المركز القومي للبحوث EG Egypt (EG) University College London (UCL) GB United Kingdom (GB) Yamanashi Gakuin University (YGU) / 山梨学院大学 JP Japan (JP) University of Rochester Medical Center Rochester, NY US United States (USA) (US) Jaslok Hospital and Research Centre IN India (IN) Papageorgiou General Hospital / ΓΕΝΙΚΟ ΝΟΣΟΚΟΜΕΙΟ ΘΕΣΣΑΛΟΝΙΚΗΣ ΠΑΠΑΓΕΩΡΓΙΟΥ GR Greece (GR) Ciber de Enfermedades Raras (CIBERER) ES Spain (ES) King Fahad Medical City SA Saudi Arabia (SA) Centre Hospitalier Universitaire de Montpellier (CHU/CHRU MTP) FR France (FR) University of Cambridge GB United Kingdom (GB) Washington University in St. Louis US United States (USA) (US) Universidade Federal da Bahia BR Brazil (BR) IRCCS Fondazione Stella Maris IT Italy (IT) Sohag-University EG Egypt (EG) Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ) Medanta IN India (IN) University of Texas Southwestern Medical Center (UT Southwestern) US United States (USA) (US) Hospital Network Antwerp / Ziekenhuis Netwerk Antwerpen (ZNA) BE Belgium (BE) Semnan University of Medical Sciences / دانشگاه علوم پزشکی و خدمات بهداشتی درمانی سمنان‎ IR Iran, Islamic Republic of (IR) University of Iowa US United States (USA) (US) Universitätsklinikum Leipzig DE Germany (DE) Universitätsklinikum Würzburg DE Germany (DE) Evangelisches Krankenhaus Oberhausen DE Germany (DE) Imam Abdulrahman Bin Faisal University SA Saudi Arabia (SA) Complejo Hospitalario Universitario de Santiago de Compostela ES Spain (ES) Dr. Sami Ulus Children's Hospital / Dr. Sami Ulus Kadın Doğum, Çocuk Sağlığı ve Hastalıkları Eğitim ve Araştırma Hastanesi TR Turkey (TR) Kasturba Medical College (KMC) IN India (IN) Scientific Institute for Rehabilitation Medicine Eugenio Medea (IRCCS) IT Italy (IT) Cairo University EG Egypt (EG) Istanbul University / İstanbul Üniversitesi TR Turkey (TR)

How to cite


Ebrahimi-Fakhari, D., Teinert, J., Behne, R., Wimmer, M., D'Amore, A., Eberhardt, K.,... Sahin, M. (2020). Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain, 143(10), 2929-2944.


Ebrahimi-Fakhari, Darius, et al. "Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia." Brain 143.10 (2020): 2929-2944.

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