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Case Reports
. 2015 May 19;84(20):2029-32.
doi: 10.1212/WNL.0000000000001594. Epub 2015 Apr 15.

Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR

Richard J Leventer  1 , Thomas Scerri  2 , Ashley P L Marsh  2 , Kate Pope  2 , Greta Gillies  2 , Wirginia Maixner  2 , Duncan MacGregor  2 , A Simon Harvey  2 , Martin B Delatycki  2 , David J Amor  2 , Peter Crino  2 , Melanie Bahlo  2 , Paul J Lockhart  2
Affiliations
Case Reports

Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR

Richard J Leventer et al. Neurology. .

Abstract

Objective: To define causative somatic mutations in resected brain tissue from an infant with intractable epilepsy secondary to hemispheric cortical dysplasia.

Methods: Whole-exome sequencing was conducted on genomic DNA derived from both resected brain tissue and peripheral blood leukocytes. Comparison of the brain vs blood sequencing results was performed using bioinformatic methods designed to detect low-frequency genetic variation between tissue pairs.

Results: Histopathology of the resected tissue showed dyslamination and dysmorphic neurons, but no balloon cells, consistent with focal cortical dysplasia type IIa. mTOR activation was observed by immunohistochemistry in the dysplasia. A missense mutation (c.4487T>G; p.W1456G) was detected in the FAT domain of MTOR in DNA from the dysplasia but not in lymphocytes. The mutation is predicted damaging (i.e., leading to mTOR activation) and was observed as a low-level mosaic with 8% of cells being heterozygous for the variant.

Conclusions: We report the novel finding of an MTOR mutation associated with nonsyndromic cortical dysplasia. Somatic-specific mutations in MTOR and related genes should be considered in a broader spectrum of patients with hemispheric malformations and more restricted forms of cortical dysplasia.

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Figures

Figure 1
Figure 1. MRI and PET imaging features
(A) Axial T2-weighted image performed at age 7 months showing blurring of the gray–white junction, simplified sulcation, and hypointense white matter signal for age maximal in the right frontal and central regions consistent with extensive focal cortical dysplasia (white arrows). (B) Interictal fluorodeoxyglucose-PET image consistent with severe hypometabolism of the majority of the right hemisphere. (C) Axial T2-weighted image performed 3 months after right hemispherotomy demonstrating the areas from which tissue was resected.
Figure 2
Figure 2. Histopathology, phospho-S6 immunostaining, and MTOR mutation location
(A) Low-power and (B) high-power photomicrographs of dysplastic cortex stained with hematoxylin & eosin. (A) Cortical dyslamination and numerous dysmorphic cytomegalic neurons. (B) Dysmorphic cytomegalic neurons in greater detail with margination of Nissl substance, prominent nucleoli, and irregular cytoplasmic profiles (black arrows). No balloon cells were seen. (C) Positive phospho-S6 immunostaining (Ser235/236, rabbit polyclonal, 1:200; Cell Signaling) in dysmorphic cytomegalic neurons (black arrowheads), consistent with mTOR pathway activation (scale bar: A = 200 μm; B and C = 100 μm). (D) Schematic representation of the location of the p.W1456G variant and the MTOR domain structure. The location of the HEAT repeats, FAT domain, rapamycin-biding domain (FRB), kinase domain, and FATC motif are indicated. Protein coordinates were derived from the GeneCards human gene database (http://www.genecards.org/).
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