RESUMEN
Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (nâ¯=â¯2), GNAO1 (nâ¯=â¯1), STXBP1 (nâ¯=â¯1), SLC35A2 (nâ¯=â¯1), TBL1XR1 (nâ¯=â¯1), and KIF1A (nâ¯=â¯1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.
Asunto(s)
Cinesinas/genética , Receptores Citoplasmáticos y Nucleares/genética , Canales de Potasio Shab/genética , Espasmos Infantiles/genética , Preescolar , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Humanos , Lactante , Proteínas de Transporte de Monosacáridos/genética , Mutación/genética , Proteínas Represoras/genética , Espasmos Infantiles/diagnósticoRESUMEN
GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for ~4% of unsolved MAE cases.
Asunto(s)
Epilepsias Mioclónicas/genética , Epilepsia Generalizada/genética , Proteínas Transportadoras de GABA en la Membrana Plasmática/genética , Animales , Epilepsias Mioclónicas/patología , Epilepsia Generalizada/patología , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Ratones , MutaciónRESUMEN
OBJECTIVE: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic spasms. METHODS: We performed DEPDC5 resequencing in 130 patients with spasms, segregation analysis of variants of interest, and detailed clinical assessment of patients with possibly and likely pathogenic variants. RESULTS: We identified 3 patients with variants in DEPDC5 in the cohort of 130 patients with spasms. We also describe 3 additional patients with DEPDC5 alterations and epileptic spasms: 2 from a previously described family and a third ascertained by clinical testing. Overall, we describe 6 patients from 5 families with spasms and DEPDC5 variants; 2 arose de novo and 3 were familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. CONCLUSIONS: While recent molecular findings in epileptic spasms emphasize the contribution of de novo mutations, we highlight the relevance of inherited mutations in the setting of a family history of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed phenotypic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alterations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 epilepsies more with the recognized features of other mTORopathies.
