In DEE (KCNA2, OMIM 616366), the master switch sits on the ↑ UP branch ([F] forced below); the healthy state is the OFF well. The forced corrective direction is to lower s toward OFF branch (polarity: clear). Classification: ○ Novel direction-only lead. Direction only — no dose, no efficacy magnitude.
The disease maps to an R19 double-well whose corrective lever is read straight off the cusp (barrier 0.4873, γ 1.3962, spinodal 0.6350). The corrective direction is forced [F]; the agent names below are direction-concordant labels at grade [O] (no dose, no efficacy or safety magnitude). This is a research hypothesis offered to experts, not medical advice.
The emergence switch
The switch for DEE is an R19 double-well emerged from the real proximal-promoter DNA of KCNA2. Its geometry is fixed by measured stiffness γ (never fitted); the numbers below are read directly off that cusp.
emergent axis
↑ UP [F]
healthy branch
OFF
lesion
GOF
γ (stiffness)
1.3962
barrier
0.4873
spinodal
0.6350
s_on / s_off
1.1816 / -1.1816
fragility
0.51
corrective polarity
clear
forced direction
lower s toward OFF branch
Chemistry feasibility (DIRECTION only [O]). small-molecule recrossing of the fold is geometrically plausible (barrier 0.4873 at neutral drive; lower barrier = smaller drive to supply). [O] -- no affinity/potency/dose/efficacy asserted.
The derived corrective lever
The cusp forces a corrective direction: lower s toward OFF branch. This is the load-bearing output of the framework — it is [F] forced, and it is falsifiable. 2 lever families are derived; the lead is h-restore (drive modulator).
Mechanism. remove / oppose the drive (clear the accumulating load that pins the disease branch)
Applies to. allele-agnostic (downstream/environmental tilt)
favoured when the switch is fragile -- a small drive shift recrosses the fold
Falsifier. If clearing/opposing the accumulating gain-of-function delayed-rectifier potassium current of the mutant Kv1.2 channel does NOT relieve the disease branch in a KCNA2 model, the h-restore(clear) lever is refuted for this axis.
EXCLUDED: gain-of-function -- the lesion is not a destabilised healthy product to stiffen; the corrective move is to clear/oppose the toxic drive (h-restore)
Falsifier. If a folding-stabiliser/chaperone does NOT re-deepen the healthy well for a residual KCNA2 allele (no rescue that a null allele lacks), the gamma-restore lever is refuted; null alleles are excluded by construction.
Agents mapped onto the lever
Existing agents whose known action is direction-concordant with the derived lever (status as pinned in the corpus; no dose, no efficacy magnitude).
agent (class)
dir.
status
phase
map
potassium-channel blockade (4-aminopyridine) opposing the gain-of-function Kv1.2 current
Syrbe 2015 Nat Genet 47:393
decrease
investigational (not approved for this indication)
0
◇ in trials
⚠ Mechanism-direction only — do not self-administer; no dose (unvalidated; set by a physician / national authority); not an approved use.
Direction-only candidate leads (corpus join)
Each lead is surfaced only because its known mechanism points the same way as the derived lever, and each comes with a source and a falsifier. None is a treatment.
4-aminopyridine (potassium-channel blockade) [KCNA2 GOF DEE]○ novel leaddir: decrease · investigational (not approved for this indication)
Mechanism. Direction-concordant (decrease) agent for KCNA2; magnitude open [O]; direction-only repurposing/recovery signal, not a claim of efficacy or safety for any patient.
Prior-art. 4-aminopyridine (an approved K-channel blocker for other indications) is direction-concordant with the KCNA2 gain-of-function and under study in gain-of-function cases; direction-only, not approved for this indication.
Safety (qualitative; no magnitude). established/known-use safety reporting on record (qualitative; no magnitude)
Falsifier. If 4-aminopyridine (potassium-channel blockade) [KCNA2 GOF DEE] (a gene-specific decrease agent) clearing/opposing the accumulating load does NOT relieve the UP [F] disease branch in a KCNA2 model, the h-restore(clear) direction is refuted for 4-aminopyridine (potassium-channel blockade) [KCNA2 GOF DEE] here.
Source: Syrbe 2015 Nat Genet 47:393 (gain- and loss-of-function KCNA2 mutations cause epileptic encephalopathy)
⚠ Mechanism-direction only — do not self-administer; no dose (unvalidated; set by a physician / national authority); not an approved use.
Evidence & provenance
What is reproduced vs. cited for this page.
element
grade
basis
R19 switch & cusp geometry (this page)
[V] verified
emerged from measured promoter γ of KCNA2; deterministic, 2×sha256 identical
corrective direction
[F] forced
forced by the cusp sign; falsifiable (see lever falsifiers)
mapped agents / leads
[O] open
direction-concordance only; corpus-pinned (2026-06-21); no dose, no efficacy/safety magnitude
Reading the agent column. VALIDATION SIGNAL -- the agent is already approved / established standard for this disease, so the direction logic recovered known clinical practice. Not a new claim by this kit. GENUINE HYPOTHESIS -- no approved indication for this disease; the direction match is a direction-only, untested [O] lead. Basis field grades the evidence (investigational here / in a related condition / off-label / speculative).