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Epileptic Encephalopathy Secondary to Homozygous TBC1 Domain-Containing Kinase (TBCK) Mutation in Four Patients of Puerto Rican Descent

Objective: TBCK Syndrome is a rare autosomal recessive disorder characterized by congenital hypotonia, intellectual disability, motor impairment and intractable epilepsy. Mutations within TBCK lead to mTORC1 complex inactivation, causing subsequent accumulation of autophagic vesicles within fibroblasts. To date, there are 35 cases of TBCK reported worldwide. We present four TBCK cases with the p.R126X (p.ARG126*) mutation, a variant predominating amongst children of Puerto Rican-descent, recently denominated as TBCK-Encephaloneuropathy or Boricua Syndrome. Methods: We describe four unrelated Puerto-Rican patients with no known consanguinity diagnosed with epilepsy during the year 2021 at our institution. Patient 1 is an 8-month-old female with global developmental delay, hypotonia, tongue fasciculations and epilepsy. Patient 2 is a 3-year-old male with global developmental delay, and hypotonia, who presented in status epilepticus. Patient 3 is a 3-year-old female with hypotonia, left hemiparesis, global developmental delay, presenting in status epilepticus. Patient 4 is a 2-year-old female with global developmental delay, hypotonia, facial diplegia, with a second episode of status epilepticus within 6 months. Results: Genetic testing demonstrated the same homozygous pathogenic variants c.376C>T (p.ARG126*) within the TBCK gene in all four patients. All patients had congenital hypotonia, delayed motor milestones, profound intellectual disability, and expressive language delay prior to the diagnosis of epilepsy. Conclusions: Pediatric patients of Puerto-Rican descent with a history of hypotonia, global developmental delays and new onset epilepsy should be evaluated for TBCK mutations, as prompt recognition can help providers facilitate appropriate medical management and prognosis counseling.
Keywords: TBCK Syndrome, Epileptic Encephalopathy, Boricua TBCK Mutation