Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy.

OBJECTIVE: Autosomal-recessive mutations in TBCK cause intellectual disability of variable severity. Although the physiological function of TBCK remains unclear, loss-of-function mutations are associated with inhibition of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Given that mTORC1 signaling is known to regulate autophagy, we hypothesized that TBCK-encephalopathy patients with a neurodegenerative course have defects in autophagic-lysosomal dysfunction. METHODS: Children (n = 8) of Puerto Rican (Boricua) descent affected with homozygous TBCK p.R126X mutations underwent extensive neurological phenotyping and neurophysiological studies. We quantified autophagosome content in TBCK-/- patient-derived fibroblasts by immunostaining and assayed autophagic markers by western assay. Free sialylated oligosaccharide profiles were assayed in patient's urine and fibroblasts. RESULTS: The neurological phenotype of children with TBCK p.R126X mutations, which we call TBCK-encephaloneuronopathy (TBCKE), include congenital hypotonia, progressive motor neuronopathy, leukoencephalopathy, and epilepsy. Systemic features include coarse facies, dyslipidemia, and osteoporosis. TBCK-/- fibroblasts in vitro exhibit increased numbers of LC3+ autophagosomes and increased autophagic flux by immunoblots. Free oligosaccharide profiles in fibroblasts and urine of TBCKE patients differ from control fibroblasts and are ameliorated by treatment with the mTORC1 activator leucine. INTERPRETATION: TBCKE is a clinically distinguishable syndrome with progressive central and peripheral nervous system dysfunction, consistently observed in patients with the p.R126X mutation. We provide evidence that inappropriate autophagy in the absence of cellular stressors may play a role in this disorder, and that mTORC1 activation may ameliorate the autophagic-lysosomal system dysfunction. Free oligosaccharide profiles could serve as a novel biomarker for this disorder as well as a tool to evaluate potential therapeutic interventions. Ann Neurol 2018;83:153-165.

Sending Mixed Signals: The Expanding Role of Molecular Cascade Mutations in Malformations of Cortical Development and Epilepsy.

Advances in gene sequencing techniques have led to a dramatic increase in the number of signaling cascade and cytoskeletal assembly mutations associated with malformations of cortical development and epilepsy. At the forefront of this research are novel mutations found in regulators of the PI3K/AKT/mTOR cascade and tubulin-associated malformations of cortical development. However, there is limited understanding of the consequences of these newly discovered germline and somatic mutations on cellular function or how these changes in cell biology may lead to areas-large or small-of malformed cortex and recurrent spontaneous seizures. We summarize and discuss what is currently known in this field in an effort to shine light on vast gaps in our knowledge of relatively common causes of cortical malformations.