دورية أكاديمية
Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis.
| العنوان: | Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis. |
|---|---|
| المؤلفون: | Guerrini, R., Mei, D., Kerti-Szigeti, K., Pepe, S., Koenig, M. K., Von Allmen, G., Cho, M. T., Mcdonald, K., Baker, J., Bhambhani, V., Powis, Z., Rodan, L., Nabbout, R., Barcia, G., Rosenfeld, J. A., Bacino, C. A., Mignot, C., Power, L. H., Harris, C. J., Marjanovic, D., Møller, R. S., Hammer, T. B., Keski Filppula, R., Vieira, P., Hildebrandt, C., Sacharow, S., Maragliano, L., Benfenati, F., Lachlan, K., Benneche, A., Petit, Florence, De Sainte Agathe, J. M., Hallinan, B., Si, Y., Wentzensen, I. M., Zou, F., Narayanan, V., Matsumoto, N., Boncristiano, A., La Marca, G., Kato, M., Anderson, K., Barba, C., Sturiale, L., Garozzo, D., Bei, R., Masuelli, L., Conti, V., Novarino, G., Fassio, A. |
| المساهمون: | Université de Lille, CHU Lille, Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364 |
| سنة النشر: | 2023 |
| المجموعة: | LillOA (Lille Open Archive - Université de Lille) |
| مصطلحات موضوعية: | epileptic encephalopathy, lysosomal disorder, progressive brain atrophy, developmental delay |
| الوصف: | Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/octet-stream |
| اللغة: | unknown |
| العلاقة: | Brain; http://hdl.handle.net/20.500.12210/84149Test |
| الإتاحة: | https://doi.org/20.500.12210/84149Test https://hdl.handle.net/20.500.12210/84149Test |
| رقم الانضمام: | edsbas.148498C1 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |