PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia.
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.
1 University of Virginia, Neurology, Charlottesville, VA, USA 2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA laura.jansen@virginia.edu.
Laura A
LA
Jansen
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA 3 University of Washington, Paediatrics, Seattle, WA, USA.
Ghayda M
GM
Mirzaa
4 Seattle Children's Hospital, Radiology, Seattle, WA, USA.
Gisele E
GE
Ishak
5 University of Washington, Genome Sciences, Seattle, WA, USA 6 Oregon Health and Science University, Molecular and Medical Genetics, Portland, OR, USA.
Brian J
BJ
O'Roak
5 University of Washington, Genome Sciences, Seattle, WA, USA.
Joseph B
JB
Hiatt
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA.
William H
WH
Roden
1 University of Virginia, Neurology, Charlottesville, VA, USA.
Sonya A
SA
Gunter
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA.
Susan L
SL
Christian
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA.
Sarah
S
Collins
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA.
Carissa
C
Adams
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA 7 Université de Bourgogne, Equipe Génétique des Anomalies du Développement, Dijon, France.
Jean-Baptiste
JB
Rivière
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA 7 Université de Bourgogne, Equipe Génétique des Anomalies du Développement, Dijon, France.
Judith
J
St-Onge
8 University of Washington, Neurosurgery, Seattle, WA, USA.
Jeffrey G
JG
Ojemann
5 University of Washington, Genome Sciences, Seattle, WA, USA.
Jay
J
Shendure
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA 8 University of Washington, Neurosurgery, Seattle, WA, USA.
Robert F
RF
Hevner
2 Seattle Children's Research Institute, Centre for Integrative Brain Research, Seattle, WA, USA 3 University of Washington, Paediatrics, Seattle, WA, USA.
William B
WB
Dobyns
D000293:Adolescent; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D065705:Hemimegalencephaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058627:Megalencephaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D059906:Neuroimaging; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
brain development; childhood epilepsy; malformations of cortical development; molecular genetics