PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia

Laura A. Jansen, Ghayda M. Mirzaa, Gisele E. Ishak, Brian O'Roak, Joseph B. Hiatt, William H. Roden, Sonya A. Gunter, Susan L. Christian, Sarah Collins, Carissa Adams, Jean Baptiste Rivière, Judith St-Onge, Jeffrey G. Ojemann, Jay Shendure, Robert F. Hevner, William B. Dobyns

Research output: Contribution to journalArticle

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Abstract

Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer-associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum.

Original languageEnglish (US)
Pages (from-to)1613-1628
Number of pages16
JournalBrain
Volume138
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Megalencephaly
Malformations of Cortical Development
Phosphatidylinositol 3-Kinases
Mutation
Brain
Ribosomal Protein S6
Multiple Hamartoma Syndrome
Causes
Pathway
Germ-Line Mutation
Neuroimaging
Neuroglia
Astrocytes
Epilepsy
Phosphotransferases
Hemimegalencephaly
Pediatrics
Phenotype
Neurons

Keywords

  • Brain development
  • Childhood epilepsy
  • Malformations of cortical development
  • Molecular genetics

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Jansen, L. A., Mirzaa, G. M., Ishak, G. E., O'Roak, B., Hiatt, J. B., Roden, W. H., ... Dobyns, W. B. (2015). PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain, 138(6), 1613-1628. https://doi.org/10.1093/brain/awv045

PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. / Jansen, Laura A.; Mirzaa, Ghayda M.; Ishak, Gisele E.; O'Roak, Brian; Hiatt, Joseph B.; Roden, William H.; Gunter, Sonya A.; Christian, Susan L.; Collins, Sarah; Adams, Carissa; Rivière, Jean Baptiste; St-Onge, Judith; Ojemann, Jeffrey G.; Shendure, Jay; Hevner, Robert F.; Dobyns, William B.

In: Brain, Vol. 138, No. 6, 01.06.2015, p. 1613-1628.

Research output: Contribution to journalArticle

Jansen, LA, Mirzaa, GM, Ishak, GE, O'Roak, B, Hiatt, JB, Roden, WH, Gunter, SA, Christian, SL, Collins, S, Adams, C, Rivière, JB, St-Onge, J, Ojemann, JG, Shendure, J, Hevner, RF & Dobyns, WB 2015, 'PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia', Brain, vol. 138, no. 6, pp. 1613-1628. https://doi.org/10.1093/brain/awv045
Jansen, Laura A. ; Mirzaa, Ghayda M. ; Ishak, Gisele E. ; O'Roak, Brian ; Hiatt, Joseph B. ; Roden, William H. ; Gunter, Sonya A. ; Christian, Susan L. ; Collins, Sarah ; Adams, Carissa ; Rivière, Jean Baptiste ; St-Onge, Judith ; Ojemann, Jeffrey G. ; Shendure, Jay ; Hevner, Robert F. ; Dobyns, William B. / PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. In: Brain. 2015 ; Vol. 138, No. 6. pp. 1613-1628.
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abstract = "Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer-associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum.",
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AU - Hiatt, Joseph B.

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AU - Collins, Sarah

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