Somatic mosaicism of the PI3K‐AKT‐MTOR pathway is associated with hemimegalencephaly in fetal brains

It is known that somatic activation of PI3K–AKT–MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosa...

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Published inNeuropathology Vol. 43; no. 2; pp. 190 - 196
Main Authors Itoh, Kyoko, Pooh, Ritsuko, Shimokawa, Osamu, Fushiki, Shinji
Format Journal Article
LanguageEnglish
Published Melbourne John Wiley & Sons Australia, Ltd 01.04.2023
Wiley Subscription Services, Inc
Subjects
1-Phosphatidylinositol 3-kinase
AKT protein
AKT1
AKT1 protein
Brain - pathology
Cell differentiation
Cell proliferation
Dysplasia
Fetuses
hemimegalencephaly
Hemimegalencephaly - genetics
Hemimegalencephaly - metabolism
Hemimegalencephaly - pathology
heterotopia
Humans
Mosaicism
Mutation
Nests
Neural stem cells
Phosphatidylinositol 3-Kinases - metabolism
PIK3CA
Polymicrogyria
Polymicrogyria - metabolism
Polymicrogyria - pathology
Progenitor cells
Proto-Oncogene Proteins c-akt - metabolism
TOR protein
TOR Serine-Threonine Kinases - metabolism
heterotopia
polymicrogyria
AKT1
PIK3CA
hemimegalencephaly
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Summary:It is known that somatic activation of PI3K–AKT–MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated‐S6 ribosomal protein (P‐RPS6) (Ser240/244) were observed in the polymicrogyria‐like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K–AKT–MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K‐AKT–MTOR pathway.
ISSN:0919-6544
1440-1789
DOI:10.1111/neup.12875