FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4226371602> ?p ?o ?g. }

• W4226371602 endingPage "2703" @default.
• W4226371602 startingPage "2687" @default.
• W4226371602 abstract "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 increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants." @default.
• W4226371602 created "2022-05-05" @default.
• W4226371602 creator A5003237564 @default.
• W4226371602 creator A5005057454 @default.
• W4226371602 creator A5005400962 @default.
• W4226371602 creator A5007398000 @default.
• W4226371602 creator A5007583634 @default.
• W4226371602 creator A5008350546 @default.
• W4226371602 creator A5009870571 @default.
• W4226371602 creator A5011382435 @default.
• W4226371602 creator A5014090979 @default.
• W4226371602 creator A5017114009 @default.
• W4226371602 creator A5019361906 @default.
• W4226371602 creator A5021202240 @default.
• W4226371602 creator A5022527850 @default.
• W4226371602 creator A5023335987 @default.
• W4226371602 creator A5023701512 @default.
• W4226371602 creator A5026409719 @default.
• W4226371602 creator A5031935784 @default.
• W4226371602 creator A5032546809 @default.
• W4226371602 creator A5033672223 @default.
• W4226371602 creator A5033934218 @default.
• W4226371602 creator A5037005560 @default.
• W4226371602 creator A5044881711 @default.
• W4226371602 creator A5044976567 @default.
• W4226371602 creator A5045799604 @default.
• W4226371602 creator A5046953046 @default.
• W4226371602 creator A5048859419 @default.
• W4226371602 creator A5049497512 @default.
• W4226371602 creator A5049827690 @default.
• W4226371602 creator A5050073634 @default.
• W4226371602 creator A5053528322 @default.
• W4226371602 creator A5053773798 @default.
• W4226371602 creator A5055830314 @default.
• W4226371602 creator A5058934950 @default.
• W4226371602 creator A5062653440 @default.
• W4226371602 creator A5064126742 @default.
• W4226371602 creator A5067291160 @default.
• W4226371602 creator A5068072022 @default.
• W4226371602 creator A5069447810 @default.
• W4226371602 creator A5071894755 @default.
• W4226371602 creator A5073562468 @default.
• W4226371602 creator A5073730516 @default.
• W4226371602 creator A5073825641 @default.
• W4226371602 creator A5075161655 @default.
• W4226371602 creator A5075869390 @default.
• W4226371602 creator A5077774398 @default.
• W4226371602 creator A5080944859 @default.
• W4226371602 creator A5081514191 @default.
• W4226371602 creator A5084629922 @default.
• W4226371602 creator A5085467135 @default.
• W4226371602 creator A5086289111 @default.
• W4226371602 date "2022-06-09" @default.
• W4226371602 modified "2023-10-04" @default.
• W4226371602 title "Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis" @default.
• W4226371602 cites W1508637318 @default.
• W4226371602 cites W1803309642 @default.
• W4226371602 cites W1969450042 @default.
• W4226371602 cites W2011911021 @default.
• W4226371602 cites W2058876049 @default.
• W4226371602 cites W2062562477 @default.
• W4226371602 cites W2111964251 @default.
• W4226371602 cites W2112126161 @default.
• W4226371602 cites W2118008075 @default.
• W4226371602 cites W2129886727 @default.
• W4226371602 cites W2143431207 @default.
• W4226371602 cites W2148432790 @default.
• W4226371602 cites W2159962592 @default.
• W4226371602 cites W2160458150 @default.
• W4226371602 cites W2164616239 @default.
• W4226371602 cites W2203673180 @default.
• W4226371602 cites W2401710715 @default.
• W4226371602 cites W2464372814 @default.
• W4226371602 cites W2570018090 @default.
• W4226371602 cites W2581649032 @default.
• W4226371602 cites W2593534345 @default.
• W4226371602 cites W2606454401 @default.
• W4226371602 cites W2735735717 @default.
• W4226371602 cites W2743536512 @default.
• W4226371602 cites W2779197700 @default.
• W4226371602 cites W2797610904 @default.
• W4226371602 cites W2806957581 @default.
• W4226371602 cites W2884004932 @default.
• W4226371602 cites W2929961692 @default.
• W4226371602 cites W2936477178 @default.
• W4226371602 cites W2947122456 @default.
• W4226371602 cites W2952766192 @default.
• W4226371602 cites W2994417971 @default.
• W4226371602 cites W3003439637 @default.
• W4226371602 cites W3012090331 @default.
• W4226371602 cites W3038787796 @default.
• W4226371602 cites W3107908899 @default.
• W4226371602 cites W3110941466 @default.
• W4226371602 cites W3149642365 @default.
• W4226371602 cites W4234505218 @default.
• W4226371602 doi "https://doi.org/10.1093/brain/awac145" @default.
• W4226371602 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35675510" @default.
• W4226371602 hasPublicationYear "2022" @default.

• next