Research paper
Brain overgrowth in disorders of RTK-PI3K-AKT signaling: a mosaic of malformations
Pediatric neuropathology review of the brain-overgrowth spectrum produced by RTK-PI3K-AKT pathway dysregulation. Reviews somatic-mosaicism distribution as primary determinant of spectrum location. Macrocephaly-ASD connection - the PI3K-AKT-mTOR pathway is implicated in a large fraction (approaching half) of macrocephalic ASD cases.
Hevner RF
Markdown path
content/research/papers/2014-hevner-brain-overgrowth-rtk-pi3k-akt.mdFindings
Pediatric neuropathology review of the brain-overgrowth spectrum produced by RTK-PI3K-AKT pathway dysregulation. Reviews somatic-mosaicism distribution as primary determinant of spectrum location. Macrocephaly-ASD connection - the PI3K-AKT-mTOR pathway is implicated in a large fraction (approaching half) of macrocephalic ASD cases.
Why it may matter for Levi
Complementary framing to Mirzaa & Poduri 2014 for the mosaic PI3K-AKT-mTOR hypothesis. Symmetric proportional overgrowth + DEE-SWAS + normal MRI (as in Levi) is consistent with a low-VAF somatic variant whose tissue distribution does not produce a visible structural malformation. Supports the mosaic-sensitive tissue-based PROS panel as the single highest-yield next genetics step. NOTE - the PMC ID (PMC4268391) cited in the source report is the same PMC ID used by the Mirzaa & Poduri 2014 record already in the corpus; full-text verification recommended to confirm this is a distinct paper.
Hevner (2014) — Brain overgrowth in disorders of RTK-PI3K-AKT signaling
Source
- Seminars in Perinatology 39(1):36–43, 2014. PMC4268391.
- URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC4268391/
Why this paper is in the corpus
Pediatric neuropathology review of the spectrum of brain overgrowth phenotypes produced by RTK-PI3K-AKT pathway dysregulation. Distinct from the Mirzaa & Poduri 2014 paper with the same title already in the corpus — Hevner 2014 is the neuropathology-focused perspective while Mirzaa & Poduri emphasizes the clinical/genetic gradient.
Key findings
- Reviews the spectrum from whole-brain overgrowth to hemimegalencephaly to focal cortical dysplasia along the RTK-PI3K-AKT axis.
- Frames somatic-mosaicism distribution as a primary determinant of which region of the spectrum a given patient occupies.
- Macrocephaly-ASD connection: the PI3K-AKT-mTOR pathway is implicated in a large fraction (approaching half) of macrocephalic ASD cases, as cited downstream by the Currey 2025 review.
- Provides neuropathological detail on the cellular phenotypes (neuronal hypertrophy, excess dendritic arborization, altered laminar organization).
Levi-relevant takeaways
- Complementary framing to Mirzaa & Poduri 2014 for the mosaic PI3K-AKT-mTOR hypothesis: symmetric proportional overgrowth + DEE-SWAS + normal MRI (as in Levi) is consistent with a low-VAF somatic variant whose tissue distribution does not produce a visible structural malformation.
- Reinforces that the April 2026 MRI's lack of overt megalencephaly or cortical dysplasia does not rule out an mTOR-axis lesion — low-VAF mosaic variants may not produce a detectable structural signature.
- Supports the priority of the mosaic-sensitive tissue-based PROS panel as the single highest-yield next genetics step.
Citation note
Referenced as [24] in the 2026-04-21 user-supplied comprehensive DEE-SWAS / ESES / CSWS research report. Note: the user-supplied report lists the PMC ID (PMC4268391), which points to the same paper as the Mirzaa & Poduri 2014 record already in the corpus (2014-mirzaa-brain-overgrowth-mosaic.md). The two titles are very similar; I have preserved this entry as a separate file per the one-paper-one-file convention, but content consumers should be aware these two entries may refer to overlapping or identical reviews. Full-text verification recommended to confirm authorship.