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

Journal

Book Volume: 143

Pages Range: 2929-2944

Journal Issue: 10

DOI: 10.1093/brain/awz307

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.

Involved external institutions

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

How to cite

APA:

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

MLA:

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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