ClinVar

In 2 sisters with developmental and epileptic encephalopathy-16 (DEE16; 615338), Milh et al. (2013) identified compound heterozygosity for 2 mutations in exon 2 of the TBC1D24 gene: a c.686T-C transition, resulting in a phe229-to-ser (F229S) substitution at a highly conserved residue in the TBC domain, and c.468C-A transversion, resulting in a cys156-to-ter substitution (C156X; 613577.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in several large exome databases and segregated with the disorder in the family. The patients developed clonic seizures early in the second month of life and thereafter developed prolonged, almost continuous seizures of different types with severe neurologic deterioration and lack of psychomotor development. The clinical diagnosis was consistent with malignant migrating partial seizures of infancy (MMPSI). Coimmunoprecipitation studies showed that the F229S mutation impaired the interaction of TBC1D24 with ARF6 (600464), and overexpression of the mutant protein in primary cortical neurons abolished the ability of TBC1D24 to increase neurite length and arborization, consistent with a loss of function.