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Published January 1, 2022 | Version v1
Journal article Open

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Creators

  • 1. Erasmus MC, Sophia Childrens Hosp, Dept Child Neurol, NL-3015 CN Rotterdam, Netherlands
  • 2. UCL, UCL Queen Sq Inst Neurol, Dept Neuromuscular Disorders, London WC1N 3BG, England
  • 3. Erasmus MC, Dept Clin Genet, NL-3015 CN Rotterdam, Netherlands
  • 4. Univ Helsinki, Folkhalsan Res Ctr, Dept Med & Clin Genet, Med, Helsinki 00290, Finland
  • 5. Univ Helsinki, Dept Pathol, Med, Helsinki 00100, Finland
  • 6. Cairo Univ Children Hosp, Kasr Al Ainy Sch Med, Div Neurol & Metab, Cairo, Egypt
  • 7. Univ Sao Paulo, Clin Ctr Med Genet Fed, Dept Morphol & Genet, Sao Paulo, SP, Brazil
  • 8. Centogene GmbH, D-18055 Rostock, Germany
  • 9. Leiden Univ Med Ctr, Dept Clin Genet, K5S,POB 9600, NL-2300 RC Leiden, Netherlands
  • 10. Univ Alberta, Dept Med Genet, Edmonton, AB, Canada
  • 11. Univ Alberta, Div Pediat Neurol, Edmonton, AB, Canada
  • 12. Technion Israel Inst Technol, Carmel Med Ctr, Genet Inst, Ruth & Bruce Rappaport Fac Med, Haifa, Israel
  • 13. Carmel Hosp, Pediat Neurol Unit, Haifa, Israel

Description

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.

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