Abstracts

Rationale: Mutations in the TBC1D24 gene were first reported in a family with infantile onset of prolonged myoclonic seizures. Subsequent reports have associated TBC1D24 mutations with a variety of autosomal recessive infantile onset neurologic disorders. We describe 4 non-related children with intractable infantile myoclonic epilepsy and intellectual disability who had TBC1D24 mutations identified on genetic testing in a large pediatric epilepsy center. Common factors in the clinical presentation which should prompt practitioners to test for a TBC1D24 associated epilepsy syndrome are described. Methods: Children with pharmacoresistant epilepsy seen at UT Southwestern Medical Center, in the Comprehensive Epilepsy Center at Children’s Medical Center, Dallas are routinely evaluated for genetic disorders. Factors that prompt detailed genetic investigation include early onset of seizures, associated intellectual disability and normal neuroimaging studies. Three children who met these criteria had testing which revealed homozygous or compound heterozygous TBC1D24 mutations. Based on a clinical presentation similar to the initial cases a fourth child was tested and found to have a homozygous mutation identical to one of the earlier patients. Chart review was performed for all four children to determine common features of the clinical presentation. Results: All children were of Hispanic ethnic origin and had early infantile onset of prolonged, focal myoclonic seizures lasting up to several hours. In most cases this prompted an evaluation for focal epilepsy, but the normal initial EEG and neuroimaging were not supportive of a lesional etiology. With repeated events, the focal myoclonus shifted from side to side. It was usually not associated with loss of awareness, even when prolonged, and was usually not associated with any ictal EEG change. This presentation and seizure semiology were distinctive, and are consistent with similar cases described in the literature.  All children eventually developed other seizures types with loss of awareness, and 2 had prolonged periods of altered awareness thought to represent non-convulsive status epilepticus. All children appeared to have a normal initial neurologic examination and only mild developmental delay. One had sensorineural hearing loss. All walked by age 2 and all but the child with hearing loss had several  words by age 2. With age the developmental trajectory slowed. In one case there was developmental regression leading to an erroneous diagnosis of lysosomal storage disease. The other 3 cases had no regression but developed ataxia around age 2 years. At last exam the older children had no ataxia but all had moderate to severe intellectual disability and short stature.  Conclusions: 4 patients with TBC1D24 mutations are described who presented with a characteristic syndrome of early infantile onset prolonged focal myoclonic seizures. The normal early development, maintained awareness during seizures and lack of ictal EEG correlate distinguished these cases from other early infantile epileptic encephalopathies.  With age, cerebellar findings, developmental stagnation and acquired short stature became evident. Recognition of this distinctive presentation should prompt evaluation for TBC1D24 mutation. Early diagnosis will avert unnecessary testing, help determine prognosis and guide genetic counseling. Funding: None