Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia.

Lee WS, Baldassari S, Chipaux M, Adle-Biassette H, Stephenson SEM, Maixner W, Harvey AS, Lockhart PJ, Baulac S, Leventer RJ · 2021 · Annals of Clinical and Translational Neurology · Atlas ID LEE2021

What this study shows

Three patients with cortical malformations carried brain-restricted somatic RHEB variants (p.Y35L in two, p.E40V in one) that were absent from blood. The size of the malformation followed the variant load: 2.6% in a small transmantle FCD, 8.9% in a lobar FCD, 17.6% in hemimegalencephaly. Dysmorphic neurons and balloon cells stained strongly for pS6, a readout of raised mTOR activity, while non-mTOR FCD type I and control tissue did not. In the two patients with enough tissue, laser capture microdissection found the variants enriched in these abnormal cells. Only three patients, two of them reported earlier; the effect of the variants on Rheb itself was not tested in this paper.

Abstract

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Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues. Laser capture microdissection showed enrichment of RHEB variants in dysmorphic neurons and balloon cells.

Read the full abstract on PubMed →

At a glance

Evidence type	H Human study Marked H because it is direct evidence from a human clinical trial or human cohort; the code names the kind of study, not its quality -- a small, well-run trial is still H.
Study type	3 - Human Observational
Model system	Human (3 patients with focal cortical dysplasia or hemimegalencephaly; resected brain tissue)
Journal	Annals of Clinical and Translational Neurology
Year	2021
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1002/acn3.51286 · PMID 33434304 · Free full text (PMC7886042)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	None (observational case series)
Target	RHEB (somatic gain-of-function variants) / mTOR activity in dysplastic brain
Model	Human
Effect	Lesion size tracked RHEB variant load (2.6%, 8.9%, 17.6%); strong pS6 in dysmorphic neurons and balloon cells
Sample size	3 patients (1 new, 2 previously described)
Limitations	Three patients only. Variant effect on Rheb function not tested here. pS6 is an indirect readout of mTOR activity. No microdissection in patient 1 (insufficient tissue); pS6 cell density could not be compared for patient 1.

In the Atlas

Links in the pathway map

Supports Rheb activates mTORC1

Cite this paper

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Lee, W. S., Baldassari, S., Chipaux, M., Adle-Biassette, H., Stephenson, S. E. M., Maixner, W., Harvey, A. S., Lockhart, P. J., Baulac, S., & Leventer, R. J. (2021). Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia. Annals of Clinical and Translational Neurology. https://doi.org/10.1002/acn3.51286

@article{LEE2021,
  author       = {Lee, W. S. and Baldassari, S. and Chipaux, M. and Adle-Biassette, H. and Stephenson, S. E. M. and Maixner, W. and Harvey, A. S. and Lockhart, P. J. and Baulac, S. and Leventer, R. J.},
  title        = {{Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia}},
  journal      = {Annals of Clinical and Translational Neurology},
  year         = {2021},
  doi          = {10.1002/acn3.51286},
  note         = {PMID: 33434304},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record LEE2021) [Data set]. https://mtor-atlas.org/study/LEE2021/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_LEE2021,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record LEE2021},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/LEE2021/},
  doi          = {10.5281/zenodo.22059963}
}

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