This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "pi3k_akt_mtor_cortical_overgrowth#PI3K-AKT-mTOR Pathway Hyperactivation in Neural Progenitors"). Conforming nodes should substitute the disorder-specific activating lesion: somatic mosaic PIK3CA (hemimegalencephaly, CLOVES/PROS), germline or postzygotic PIK3R2 or AKT3 (MCAP/MPPH megalencephaly spectrum), brain somatic MTOR (focal cortical dysplasia type II), or CCND2 stabilization (MPPH). Existing dismech entries CLOVES_Syndrome.yaml and Tuberous_Sclerosis_Complex.yaml model upstream/parallel arms of this pathway and could add conforms_to references to the "PI3K-AKT-mTOR Pathway Hyperactivation in Neural Progenitors" node; TSC reaches the same mTORC1 hyperactivation node through TSC1/TSC2 loss rather than a PI3K-activating variant. A non-cell-autonomous AKT3-FOXG1-Reelin branch (restricted AKT3-mutant progenitors misexpressing Reelin and misrouting neighboring wild-type neurons; Romero et al. 2018 review sections 2.2.1.8/2.2.8) is a candidate additional node shared with the Reelin lamination module (epic #4098), but is deferred here pending verification of its primary sources and is intentionally not asserted without quotable primary-paper evidence.
PI3K-AKT-mTOR Pathway Hyperactivation in Neural Progenitors
trigger
The conserved initiating lesion is constitutive activation of the PI3K-AKT-mTOR growth-signaling cascade in neural progenitor cells. Activating variants in three core components of the PI3K-AKT pathway - PIK3CA (p110-alpha catalytic subunit), PIK3R2 (p85-beta regulatory subunit), and AKT3 - or in the downstream kinase MTOR drive ligand-independent signaling. These variants are frequently post-zygotic somatic (mosaic) events confined to the developing brain, producing mosaic hyperactivation in a clone of progenitors and their progeny.
Downstream
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Progenitor Hyperproliferation and Cell-Cycle Dysregulation
Constitutive PI3K-AKT-mTOR signaling drives excess progenitor proliferation and delayed cell-cycle exit.
Progenitor Hyperproliferation and Cell-Cycle Dysregulation
amplifier
Hyperactive PI3K-AKT-mTOR signaling increases biosynthesis, cell growth, and proliferation of neural progenitors while dysregulating cell-cycle control. Stabilization of cyclin D2 (CCND2) - normally targeted for proteasomal degradation downstream of GSK-3-beta, which is inhibited by AKT - links the pathway to G1/S cell-cycle progression and expands the progenitor pool, increasing the neuronal output that is subsequently malpositioned.
Downstream
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Cortical Overgrowth
Expansion of the progenitor pool and increased cell growth enlarge cortical tissue volume.
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Impaired Neuronal Migration and Cortical Lamination
Excess and abnormally specified neurons fail to migrate and laminate normally, producing dyslamination.
Cortical Overgrowth
effector
Progenitor hyperproliferation and increased cell growth enlarge the cortex, producing megalencephaly when diffuse and hemimegalencephaly when the activating mosaic clone is confined to one hemisphere. The degree and distribution of overgrowth track the timing and spatial extent of the somatic-mosaic activating event.
Downstream
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Epileptogenic Cortical Dysplasia and Seizures
Overgrown, abnormally organized cortex forms an epileptogenic substrate.
Impaired Neuronal Migration and Cortical Lamination
effector
Beyond overgrowth, PI3K-AKT-mTOR hyperactivation perturbs radial neuronal migration and inside-out cortical lamination, yielding dyslamination and a polymicrogyria-like or focal cortical dysplasia cortical architecture. The migration defect is mechanistically separable from the proliferative overgrowth and contributes the malformed (as opposed to merely enlarged) component of the phenotype.
Downstream
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Epileptogenic Cortical Dysplasia and Seizures
Dyslaminated, dysmorphic-neuron-containing cortex is intrinsically epileptogenic.
Epileptogenic Cortical Dysplasia and Seizures
outcome
The overgrown, dyslaminated cortex containing cytomegalic dysmorphic neurons (and, in focal cortical dysplasia type II, balloon cells) forms an epileptogenic substrate that generates medically refractory seizures. Persistent mTOR hyperactivation in these abnormal neurons shifts the cortical network toward excitation, and the seizures are frequently intractable to antiseizure medication but responsive to mTOR inhibition, identifying the pathway as a treatment target. This terminal step conforms to the conserved epilepsy excitation-inhibition imbalance module, with the mTOR-pathway cortical malformation as the disorder-specific driver of the imbalance.