دورية أكاديمية
Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course.
| العنوان: | Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course. |
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| المؤلفون: | Esposito, A., Falace, A., Wagner, M., Gal, M., Mei, D., Conti, V., Pisano, T., Aprile, D., Cerullo, M.S., De Fusco, A., Giovedì, S., Seibt, A., Magen, D., Polster, T., Eran, A., Stenton, S., Fiorillo, C., Ravid, S., Mayatepek, E., Hafner, H., Wortmann, S.B., Levanon, E.Y., Marini, C., Mandel, H., Benfenati, F., Distelmaier, F., Fassio, A., Guerrini, R. |
| المصدر: | Brain 142, 3876-3891 (2019) |
| بيانات النشر: | Oxford Univ Press |
| سنة النشر: | 2019 |
| المجموعة: | PuSH - Publikationsserver des Helmholtz Zentrums München |
| مصطلحات موضوعية: | Autophagy, Developmental And Epileptic Encephalopathy, Neuropathy, Ohtahara Syndrome, Progressive Disorder |
| الوصف: | Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C4T (p.Ala1712Val) missense substitution and the c.4478C4G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C4A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G4A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients’ fibroblasts also exhibited an increased LysoTrackerÕ signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0006-8950 1460-2156 |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/31688942; info:eu-repo/semantics/altIdentifier/wos/WOS:000504324300026; info:eu-repo/semantics/altIdentifier/isbn/0006-8950; info:eu-repo/semantics/altId; https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=57270Test; urn:isbn:0006-8950; urn:issn:0006-8950; urn:issn:1460-2156 |
| DOI: | 10.1093/brain/awz326 |
| الإتاحة: | https://doi.org/10.1093/brain/awz326Test https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=57270Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.E25FC353 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00068950 14602156 |
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| DOI: | 10.1093/brain/awz326 |