TY  - JOUR
EP  - 2312
Y1  - 2022/07//
SP  - 2301
IS  - 7
VL  - 145
N1  - © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article
distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
JF  - Brain
UR  - https://doi.org/10.1093/brain/awac116
PB  - Oxford University Press (OUP)
N2  - 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 harboring 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), 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: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.
A1  - van der Knoop, Marieke M
A1  - Maroofian, Reza
A1  - Fukata, Yuko
A1  - van Ierland, Yvette
A1  - Karimiani, Ehsan G
A1  - Lehesjoki, Anna-Elina
A1  - Muona, Mikko
A1  - Paetau, Anders
A1  - Miyazaki, Yuri
A1  - Hirano, Yoko
A1  - Selim, Laila
A1  - de França, Marina
A1  - Fock, Rodrigo Ambrosio
A1  - Beetz, Christian
A1  - Ruivenkamp, Claudia AL
A1  - Eaton, Alison J
A1  - Morneau-Jacob, Francois D
A1  - Sagi-Dain, Lena
A1  - Shemer-Meiri, Lilach
A1  - Peleg, Amir
A1  - Haddad-Halloun, Jumana
A1  - Kamphuis, Daan J
A1  - Peeters-Scholte, Cacha MPCD
A1  - Hiz Kurul, Semra
A1  - Horvath, Rita
A1  - Lochmüller, Hanns
A1  - Murphy, David
A1  - Waldmüller, Stephan
A1  - Spranger, Stephanie
A1  - Overberg, David
A1  - Muir, Alison M
A1  - Rad, Aboulfazl
A1  - Vona, Barbara
A1  - Abdulwahad, Firdous
A1  - Maddirevula, Sateesh
A1  - Povolotskaya, Inna S
A1  - Voinova, Victoria Y
A1  - Gowda, Vykuntaraju K
A1  - Srinivasan, Varunvenkat M
A1  - Alkuraya, Fowzan S
A1  - Mefford, Heather C
A1  - Alfadhel, Majid
A1  - Haack, Tobias B
A1  - Striano, Pasquale
A1  - Severino, Mariasavina
A1  - Fukata, Masaki
A1  - Hilhorst-Hofstee, Yvonne
A1  - Houlden, Henry
TI  - Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy
AV  - public
KW  - ADAM22
KW  -  LGI1
KW  -  developmental and epileptic encephalopathy
KW  -  refractory seizures
ID  - discovery10146747
ER  -