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Research paper

Mechanisms of brain overgrowth in autism spectrum disorder with macrocephaly

Review of molecular mechanisms underlying macrocephaly-ASD, with PI3K-AKT-mTOR as a major mechanistic hub. The pathway is implicated in nearly half of macrocephalic ASD cases. Additional genes (CHD8, PTEN, TSC1/2) contribute to the broader landscape.

Indexed context

Currey L, et al.

autismmacrocephalybrain-overgrowthpi3k-akt-mtorchd8review

Markdown path

content/research/papers/2025-currey-asd-macrocephaly-brain-overgrowth.md

Findings

Review of molecular mechanisms underlying macrocephaly-ASD, with PI3K-AKT-mTOR as a major mechanistic hub. The pathway is implicated in nearly half of macrocephalic ASD cases. Additional genes (CHD8, PTEN, TSC1/2) contribute to the broader landscape.

Why it may matter for Levi

Quantitative prior for the macrocephaly-ASD-mTOR association. Levi is at the 99th percentile for head circumference from ~12 months with ASD and DEE-SWAS - phenotype matches the population discussed. Supports keeping mosaic PI3K-AKT-mTOR at the top of Levi's differential despite three negative germline workups and structurally unremarkable MRI. Reinforces mosaic-sensitive PROS panel + methylation / episignature panel for CHD8 and related chromatinopathies.

Paper text

Currey et al. (2025) — Mechanisms of brain overgrowth in ASD with macrocephaly

Source

Why this paper is in the corpus

Review of the molecular mechanisms underlying the macrocephaly-ASD phenotype, with particular emphasis on the PI3K-AKT-mTOR pathway as a major mechanistic hub. Supports the clinical reasoning that tall stature and overgrowth in the context of neurodevelopmental regression should trigger an mTOR-axis workup.

Key findings

  • The PI3K-AKT-mTOR pathway is implicated in nearly half of macrocephalic ASD cases.
  • Multiple upstream regulators converge on mTOR hyperactivation as the common downstream lesion.
  • Additional genes (CHD8, PTEN, TSC1/2, and others) contribute to the broader macrocephaly-ASD genotype-phenotype landscape.
  • Reinforces the mTORopathy framework for macrocephalic-ASD-plus-epilepsy presentations.

Levi-relevant takeaways

  • Quantitative prior for the macrocephaly-ASD-mTOR association. Levi is at the 99th percentile for head circumference from ~12 months, with ASD and DEE-SWAS — the phenotype matches the population discussed in this review.
  • Supports keeping the mosaic PI3K-AKT-mTOR hypothesis at the top of Levi's differential despite three negative germline workups and a structurally unremarkable MRI.
  • Reinforces the priority of the mosaic-sensitive tissue-based PROS panel and, as a parallel branch, the methylation / episignature panel for CHD8 and related chromatinopathies.

Citation note

Referenced as [26] in the 2026-04-21 user-supplied comprehensive DEE-SWAS / ESES / CSWS research report.