Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
| العنوان: | Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia |
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| المؤلفون: | Yoshihisa Takiyama, Stefanie Brock, Jennifer Hirst, Niklas Dahl, Radka Kremlikova Pourova, Andrea Martinuzzi, Seth Perlman, Helene Verhelst, Omnia Fathy El-Rashidy, Nour Elkhateeb, Sarah I. Sheikh, Jamal Ghoumid, Erin Carmody, Georgia Xiromerisiou, Diego Miguel, James T. Bennett, Barbara Brechmann, William O. Walker, David Dacruz-Álvarez, Mathieu Anheim, Dana M. Jensen, Stefan Kölker, Uzma Shamshad, Darius Ebrahimi-Fakhari, Grace Yoon, Katharina Vill, David Bearden, Adel A. Mahmoud, Sheela Nampoothiri, Devorah Segal, Antje Wiesener, Shenela Lakhani, Joseph G. Gleeson, Chirag Patel, Angelica D'Amore, Abdelrahim Abdrabou Sadek, Marvin Ziegler, Mustafa Sahin, Toni S. Pearson, Julian Teinert, Kira A. Dies, Christopher J. Yuskaitis, Catherine L. Salussolia, Lubov Blumkin, Jonathan Baets, Laura Robelin, Daniel Ebrahimi-Fakhari, Parham Habibzadeh, Anju Shukla, Peter O. Bauer, Saskia Bulk, Afshin Saffari, Elizabeth Lim-Melia, Michael C. Kruer, Christian Beetz, Andreas Ziegler, Pankaj B. Agrawal, Thomas Bourinaris, Filippo M. Santorelli, Mireille Guillot, Abdullah Alamri, Mohammad Ali Faghihi, Kathrin Eberhardt, Thomas Smol, Henry Houlden, Nur Aydinli, Constanze Heine, Soroor Inaloo, Anaita Udwadia-Hegde, Alejandro Brea-Fernández, Yasemin Alanay, Rachana Dubey Gupta, Ayse Aksoy, Agathe Roubertie, Jens Volkmann, Basil T. Darras, Hendrik Langen, Mauricio R. Delgado, Jan Ulrich Schlump, Gregory Geisel, Anna Jansen, Somayeh Bakhtiari, Steven P. Miller, Miriam Wimmer, Maha S. Zaki, Premsai Nagabhyrava, Robert Behne, Hossein Darvish |
| المساهمون: | Acibadem University Dspace |
| المصدر: | Brain |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Adult, Male, SPG47, Microcephaly, Pediatrics, medicine.medical_specialty, Adolescent, Hereditary spastic paraplegia, Adaptor Protein Complex 4, Cerebral palsy, Corpus Callosum, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Spastic diplegia, medicine, SPG51, Humans, SPG50, Registries, SPG52, Child, Tetraplegia, business.industry, Spastic Paraplegia, Hereditary, neurodegeneration, Infant, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Corrigenda, Hypotonia, 030104 developmental biology, Cross-Sectional Studies, Child, Preschool, Speech delay, Female, Neurology (clinical), Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery, Ventriculomegaly |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1460-2156 0006-8950 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e16bcaf88226cde8fedce925b8e3ea36Test https://pubmed.ncbi.nlm.nih.gov/33294911Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e16bcaf88226cde8fedce925b8e3ea36 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602156 00068950 |
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