PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia
Open accessAbstract
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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Somatic activating mutations in the PI3K/AKT pathway are associated with hemimegalencephaly and focal cortical dysplasia syndromes marked by cortical dyslamination, dysmorphic neurons and loss of radial neuronal orientation.
“Somatic activating mutations in the PI3K/AKT pathway are associated with hemimegalencephaly and focal cortical dysplasia syndromes that are marked by cortical dyslamination, dysmorphic neurons and loss of radial neuronal orientation [50, 105, 106].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [105]
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- Authors
- Jansen, L. A., Mirzaa, G. M., Ishak, G. E., O'Roak, B. J., Hiatt, J. B., Roden, W. H., Gunter, S. A., Christian, S. L., Collins, S., Adams, C., Rivière, J.-B., St-Onge, J., Ojemann, J. G., Shendure, J., Hevner, R. F., & Dobyns, W. B.
- Affiliations
- Seattle Children's Research Institute (US)
- University of Washington (US)
- Seattle Children's Hospital (US)
- University of Virginia (US)
- Université de Bourgogne (FR)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-02-25
- Volume
- 138
- Issue
- 6
- Pages
- 1613-1628
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4614119
- OpenAlex
- W2111043432
- Cited by
- 364
- References
- 76
- Citations by year
- 2026: 10 · 2025: 31 · 2024: 24 · 2023: 34 · 2022: 40 · 2021: 42 · 2020: 32 · 2019: 44 · 2018: 40 · 2017: 29 · 2016: 26 · 2015: 10 · 2014: 1 · 2013: 1
- FWCI
- 34.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA160080, R21CA160080)
- National Institute of General Medical Sciences (T32GM007266)
- National Institute of Neurological Disorders and Stroke (K02NS072162, R01NS085081, R01NS058721)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- malformations of cortical development, hemimegalencephaly, megalencephaly, PTEN germline mutation, PTEN hamartoma tumor syndrome, mosaicism, S6 phosphorylation, Akt phosphorylation
- MeSH terms
- Adolescent, Brain, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Mutation, Signal Transduction, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Genetic Predisposition to Disease, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Malformations of Cortical Development, Class I Phosphatidylinositol 3-Kinases, Megalencephaly, Neuroimaging, Hemimegalencephaly
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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