Early-onset epileptic encephalopathies (EOEEs) are a group of rare devastating epileptic syndromes of infancy characterized by severe drug-resistant seizures and electroencephalographic abnormalities. The current study aims to determine the genetic etiology of a familial form of EOEE fulfilling the diagnosis criteria for malignant migrating partial seizures of infancy (MMPSI). We identified two inherited novel mutations in TBC1D24 in two affected siblings. Mutations severely impaired TBC1D24 expression and function, which is critical for maturation of neuronal circuits. The screening of TBC1D24 in an additional set of eight MMPSI patients was negative. TBC1D24 loss of function has been associated to idiopathic infantile myoclonic epilepsy, as well as to drug-resistant early-onset epilepsy with intellectual disability. Here, we describe a familial form of MMPSI due to mutation in TBC1D24, revealing a devastating epileptic phenotype associated with TBC1D24 dysfunction. We identified novel inherited mutations in TBC1D24 in two siblings affected by Malignant Migrating Partial Seizures of Infancy (MMPSI), a rare devastating early onset epileptic encephalopaties of heterogeneous genetic origin. TBC1D24 is a novel epilepsy gene encoding a neuronal protein known to interact with ARF6 and to regulate neurite development. The pathogenic TBC1D24 variants are located in the ARF6 binding domain and severely impaired TBC1D24 expression and function.
- Autosomal recessive
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