{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:52:26Z","timestamp":1787795546276,"version":"build-2784847793"},"reference-count":23,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T00:00:00Z","timestamp":1516752000000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Autosomal\u2010recessive mutations in <jats:italic>TBCK<\/jats:italic> cause intellectual disability of variable severity. Although the physiological function of TBCK remains unclear, loss\u2010of\u2010function 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\u2010encephalopathy patients with a neurodegenerative course have defects in autophagic\u2010lysosomal dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Children (n\u2009=\u20098) of Puerto Rican (Boricua) descent affected with homozygous <jats:italic>TBCK<\/jats:italic> p.R126X mutations underwent extensive neurological phenotyping and neurophysiological studies. We quantified autophagosome content in TBCK<jats:sup>\u2212\/\u2212<\/jats:sup> patient\u2010derived fibroblasts by immunostaining and assayed autophagic markers by western assay. Free sialylated oligosaccharide profiles were assayed in patient's urine and fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The neurological phenotype of children with <jats:italic>TBCK<\/jats:italic> p.R126X mutations, which we call TBCK\u2010encephaloneuronopathy (TBCKE), include congenital hypotonia, progressive motor neuronopathy, leukoencephalopathy, and epilepsy. Systemic features include coarse facies, dyslipidemia, and osteoporosis. TBCK<jats:sup>\u2212\/\u2212<\/jats:sup> fibroblasts in vitro exhibit increased numbers of LC3<jats:sup>+<\/jats:sup> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>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\u2010lysosomal 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\u2013165<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25130","type":"journal-article","created":{"date-parts":[[2017,12,28]],"date-time":"2017-12-28T15:42:58Z","timestamp":1514475778000},"page":"153-165","source":"Crossref","is-referenced-by-count":44,"title":["Homozygous boricua <i>TBCK<\/i> mutation causes neurodegeneration and aberrant autophagy"],"prefix":"10.1002","volume":"83","author":[{"given":"Xilma R.","family":"Ortiz\u2010Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Neurology The Children's Hospital of Philadelphia Philadelphia PA"},{"name":"Department of Neurology Perelman School of Medicine, University of Pennsylvania Philadelphia PA"},{"name":"Center for Mitochondrial and Epigenomic Medicine The Children's Hospital of Philadelphia Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus A.","family":"Tintos\u2010Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neurology The Children's Hospital of Philadelphia Philadelphia PA"},{"name":"Center for Mitochondrial and Epigenomic Medicine The Children's Hospital of Philadelphia Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine The Perelman School of Medicine, University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kierstin","family":"Keller","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine The Children's Hospital of Philadelphia Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine The Perelman School of Medicine, University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueli","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine The Perelman School of Medicine, University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Reghan","family":"Foley","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana X.","family":"Bharucha\u2010Goebel","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda MD"},{"name":"Division of Neurology Children's National Health System Washington DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudha K.","family":"Kessler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neurology The Children's Hospital of Philadelphia Philadelphia PA"},{"name":"Department of Neurology Perelman School of Medicine, University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina W.","family":"Yum","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neurology The Children's Hospital of Philadelphia Philadelphia PA"},{"name":"Department of Neurology Perelman School of Medicine, University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter B.","family":"Crino","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Maryland School of Medicine Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine The Perelman School of Medicine, University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas C.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine The Children's Hospital of Philadelphia Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine The Perelman School of Medicine, University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten G.","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda 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