Patient
Understanding SMPDL3B Phenotypes
Researcher
1) What are these phenotypes?
Some people with ME/CFS or Long COVID get sick because their system doesn’t have enough stability to recover, while others get sick because their system overreacts to stress.
- One is about not enough control.
- The other is about too much defense.
They can look similar on the surface, but they behave differently underneath.
1) What are these phenotypes?
These phenotypes represent distinct control-failure architectures involving SMPDL3B regulation at the membrane level.
- Deficient: chronically reduced SMPDL3B expression/anchoring → fragile lipid rafts → low control bandwidth.
- Shedding: adequate baseline SMPDL3B with stress-activated PI-PLC cleavage → episodic destabilization via defensive overshoot.
They can converge symptomatically while diverging mechanistically.
2) SMPDL3B-Deficient phenotype
In this pattern, the body starts with very little reserve. Even small stress can drain energy and make it harder to bounce back.
Pushing through does not build strength — it often uses up what little control is left. This is why crashes can get deeper and last longer.
2) SMPDL3B-Deficient phenotype
Baseline suppression of SMPDL3B expression or anchoring produces persistent lipid-raft instability and limited recovery bandwidth.
Stress increases Ca²⁺ flux and ROS, suppresses NAD⁺ availability, and further destabilizes SMPDL3B anchoring. Amplification accelerates control loss rather than restoring stability, yielding threshold erosion and prolonged PEM.
3) SMPDL3B-Shedding phenotype
In this pattern, the body over-protects itself. When stress appears, the system reacts strongly and “shuts things down” too much, then slowly relaxes again.
The problem isn’t lack of ability — it’s that the defense response overshoots.
3) SMPDL3B-Shedding phenotype
Defined by stress-activated PI-PLC–mediated cleavage of GPI-anchored SMPDL3B. Defensive activation overshoots necessity, removing too much SMPDL3B and driving oscillatory membrane/immune instability.
Symptoms arise primarily from excess defense, not baseline SMPDL3B depletion.
4) Why crashes (PEM) happen
Crashes often happen after activity, when the body tries and fails to recover.
- In one pattern, there isn’t enough control to reset.
- In the other, the system stays stuck in defense mode too long.
4) Why crashes (PEM) happen
Delayed PEM reflects post-stress control failure rather than immediate workload.
- Deficient: recovery failure from insufficient regulatory bandwidth with ROS/NAD⁺ suppression reinforcing instability.
- Shedding: delayed recovery from prolonged defensive signaling and overshoot in SMPDL3B shedding.
5) Pacing — why it helps but can also hurt
Pacing is about protecting your system, not pushing it. But pacing must match your pattern:
- Some people need very strict protection.
- Others do better with gentle, flexible movement.
Doing the wrong kind of pacing can make symptoms worse.
5) Pacing — phenotype-specific logic
Pacing is a control-preservation strategy (control ≠ capacity).
- Deficient: pacing prevents reserve depletion and ischemia–ROS cycling, protecting remaining control bandwidth.
- Shedding: overly rigid/fear-driven pacing can increase anticipatory autonomic stress and PI-PLC activation, worsening defensive shedding.
6) Autonomic lock-in (late-stage illness)
In more severe illness, both patterns can start to look the same: constant symptoms, no clear recovery, and the nervous system stuck “on”.
This doesn’t mean they started the same way.
6) Autonomic lock-in (late-stage illness)
Autonomic lock-in is a shared endpoint of control collapse, not mechanistic equivalence.
- Deficient: lock-in via progressive control exhaustion.
- Shedding: lock-in via chronic defensive activation and failure to exit threat mode.
7) One-line summaries
- Deficient: “My system runs out of control when pushed.”
- Shedding: “My system protects too hard and won’t let go.”
7) One-line summaries
- Deficient: fails when demand exceeds control capacity.
- Shedding: fails when defensive response overshoots necessity.
This page describes a working, provisional model used to discuss different instability patterns in ME/CFS,
Long COVID, and other post-infectious illnesses. It is not a diagnosis. The goal is to better match pacing, support strategies,
and expectations to the system’s control behavior.
Quick reference
SMPDL3B Deficient vs Shedding
Both patterns converge on perfusion instability → ischemic metabolism → delayed ROS → PEM, but differ in how SMPDL3B vulnerability is expressed under stress.
Pattern expression is clearest earlier in illness. These patterns describe how the system fails, not how severe the illness is.
Deficient (baseline-low, capacity-limited)
- Your system operates from a lower available capacity, even on “good” days.
- Symptoms tend to feel more constant or slowly drifting, rather than sharply reactive.
- Crashes usually occur when the system is pushed beyond what it can supply, often with delayed onset.
- Once destabilized, the body has difficulty rebuilding reserve, so recovery is slow and fragile.
In simple terms: the system runs close to its limits, so pushing function too early drains recovery capacity.
Shedding-dominant (dynamic, tolerance-limited)
- You may feel relatively okay at baseline, but stability can drop suddenly under stress.
- Flares are often abrupt and reactive (exertion, illness, emotional or physiological stress).
- Re-challenging or over-stabilizing too quickly can provoke sharp crashes.
- Partial recovery may occur, but the system is easily destabilized again if tolerance is exceeded.
In simple terms: the system can function — but becomes unstable if stress or stabilization rises too fast.
Important note (later-stage illness):
In more severe or long-standing illness, both deficient and shedding patterns can become housebound or bed-bound
and may enter a shared depolarized state. At this stage, symptoms can appear similar across both patterns
(low exertion thresholds, limited recovery) — not because the patterns are the same, but because regulatory control has collapsed.
Subtle differences may still exist in what triggers crashes (pushing vs over-constraint), but they are harder to distinguish in late stages.
Diagram A (preview): interpret as “capacity,” not symptom severity. Deficient = baseline-low + slower reset. Shedding = state-shift dips + re-challenge vulnerability.
Deficient (baseline-low)
Shedding-dominant (dynamic loss)