Genetic testing in adults with developmental and epileptic encephalopathy – what do we know?

Abstract

Knowledge of underlying genetic causes of developmental and epileptic encephalopathies (DEE) in adults is still limited when compared to the routine diagnostic approach in similarly affected children. A well-documented longitudinal study of adults with DEE is of utmost importance to understand the natural history of the respective entity. This information is of great value especially for genetic counselling of newly diagnosed children with identical genetic diagnoses and may impact treatment and management of affected individuals. In our meta-analysis we provide an overview of the most recurrent genetic findings across an adult DEE cohort ( n = 1 , 020 n=1,020 ). The gene mostly associated with a pathogenic or likely pathogenic variant in adult DEE is SCN1A, followed by MECP2 and CHD2. Studies employing exome sequencing and calling of both single nucleotide variants and copy number variants are associated with diagnostic yields of almost 50 %. Finally, we highlight three remarkable cases, each representing the oldest individual ever published with their genetic diagnosis, i. e., Angelman syndrome, Miller–Dieker syndrome, and CAMK2A-related disorder, and describe lessons learned from each of these adults.

Genetic diagnostics in epilepsies: recommendations of the Commission Epilepsy and Genetics of German Society of Epileptology (German ILAE Chapter)

“…Hier kann die diagnostische Ausbeute bis zu 60 % erreichen [35]. Gleichzeitig sollte das Alter bei Einleitung der Diagnostik die Entscheidung nicht beeinflussen -auch Erwachsene können die retrospektive Erstdiagnose beispielsweise einer DEE erhalten und so von der Diagnostik profitieren [23,30,31,36,37] geklärt. Eine multizentrische retrospektive Fallserie aus deutschen Epilepsiezentren erbrachte gute Ergebnisse in einigen Fällen mit Tuberöser Sklerose (TSC1/2) oder genetischen hypothalamischen Hamartomen (GLI3, PTEN), während Personen mit Kanalopathien bzw.…”

Classification of missense variants in the N-methyl-d-aspartate receptor GRIN gene family as gain- or loss-of-function

“…Among genes unambiguously associated with neurological disease, ion channels are disproportionately represented ( 1–5 ). Four genes ( GRIN1 , GRIN2A , GRIN2B and GRIN2D ) that encode N -methyl- d -aspartate receptor (NMDAR) subunits ( 6 ) have been associated with GRIN -related disorders that belong to the top 10 diagnoses among individuals with developmental and epileptic encephalopathy ( 7 ). In addition, GRIN2A variants have been linked to schizophrenia ( 8 ).…”