期刊
BRAIN
卷 145, 期 7, 页码 2301-2312出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awac116
关键词
ADAM22; LGI1; refractory seizures; developmental and epileptic encephalopathy
资金
- Wellcome Trust [WT093205 MA, WT104033AIA]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- JSPS/MEXT KAKENHI [19H03331, 19K22439, 21K19390, 19K16269, 20H00459, 20H04915]
- Japan Agency for Medical Research and Development [21wm0525022h0001]
- University of Tubingen [2545-1-0]
- Ministry of Science, Research and Art Baden-Wurttemberg
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [418081722, 433158657]
- Russian Ministry of Health [121061500066-2]
- Canadian Institutes of Health Research (Foundation ) [FDN-167281]
- Canadian Institutes of Health Research and Muscular Dystrophy Canada
- Canada Foundation for Innovation [CFI-JELF 38412]
- Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health) [950-232279]
- TUBITAK (Turkish Scientific and Technological Research Council) [216S771]
- Wellcome Trust Investigatornd [MR/V009346/1, MR/N025431/1]
- European Research Council [309548]
- Newton Fund (UK/Turkey) [MR/N027302/1]
- Addenbrookes Charitable Trust [G100142]
- Evelyn Trust
- Stoneygate Trust
- Lily Foundation
- MRC [MR/S005021/1]
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]
The paper provides a detailed description of the clinical features of ADAM22 deficiency, including treatment-resistant epilepsy, global developmental delay, intellectual disability, and hypotonia. The deleteriousness of ADAM22 variants is confirmed through functional studies.
Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Van der Knoop et al. describe the clinical features of 21 individuals with biallelic pathogenic variants in ADAM22 and confirm the deleteriousness of the variants with functional studies. Clinical hallmarks of this rare disorder comprise progressive encephalopathy and infantile-onset refractory epilepsy.
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