SMPDL3B-Deficient Mechanistic Chain

1. Post-viral innate activation with EV-glycome shift (Pesqueira-Sanchez et al., 2025; GLA synthesis)

Post-viral or chronic inflammatory stress elevates innate immune tone across immune and endothelial compartments. Pattern-recognition pathways remain sensitized rather than resolving.

2. Increased EV burden with high-mannose surface glycosylation (Pesqueira-Sanchez et al., 2025; Hoel et al., 2021)

Extracellular vesicle (EV) production increases, with a shift toward mannose-rich EV surface glycans. GNA-binding EVs indicate abnormal vesicle biogenesis and glycan processing rather than acute inflammation.

3. Persistent ER–Golgi secretory pathway stress (Yoon et al., 2016; GLA synthesis)

The EV-glycome pattern reflects chronic ER/Golgi processing strain, with incomplete restoration of protein folding, lipid trafficking, and post-translational modification capacity.

Unlike transient inflammatory activation, this pattern reflects a chronic cellular stress state, reinforcing abnormal EV release and signaling.

4. NAD⁺ depletion and loss of metabolic–epigenetic buffering (Fan et al., 2021; integrated NAD⁺/SIRT1 literature)

Sustained cellular stress reduces NAD⁺ availability, suppressing SIRT1 activity, a key regulator of transcriptional resilience, lipid homeostasis, and stress tolerance.

This represents a buffering failure, not an inflammatory spike: the cell loses its ability to maintain adaptive transcriptional programs under load.

5. c-Myc–dependent transcriptional insufficiency (Fan et al., 2021)

Reduced SIRT1 activity destabilizes c-Myc–dependent transcription, impairing expression programs involved in membrane maintenance, lipid-raft regulation, and cellular stress tolerance.

This creates a low-capacity baseline state rather than an acutely triggered one.

6. Chronically low SMPDL3B expression (deficiency phenotype) (Moreau et al., 2025)

Baseline SMPDL3B expression remains persistently low, reflecting transcriptional insufficiency rather than proteolytic cleavage or shedding.

7. Membrane microdomain instability and loss of innate restraint (Heinz et al., 2015)

Low SMPDL3B weakens lipid-raft organization and membrane microdomain control. Innate immune receptors become poorly buffered, increasing reactivity to otherwise modest stimuli.

This raises cellular reactivity by reducing membrane buffering capacity, without requiring strong upstream triggers.

8. Endothelial fragility and nitric-oxide signaling instability (Wirth & Scheibenbogen, 2021; GLA synthesis)

Endothelial cells become structurally fragile. Nitric-oxide signaling loses robustness, permeability control weakens, and vascular tone becomes inconsistent rather than adaptively regulated.

Rather than fixed vasoconstriction or vasodilation, the system becomes brittle, with reduced buffering against normal physiological stress.

9. Perfusion failure under everyday physiological load (Wirth & Scheibenbogen, 2021; GLA synthesis)

Orthostasis, exertion, heat, or meals precipitate regional hypoperfusion, particularly affecting cerebral, muscular, renal, and splanchnic beds.

This represents a distribution failure, not a primary cardiac or pulmonary limitation.

10. Intermittent ischemic metabolism (Hoel et al., 2021; integrated metabolic literature)

Tissues shift episodically toward ischemic and anaerobic metabolism. Oxygen delivery and metabolite clearance become unreliable, producing delayed rather than immediate symptom escalation.

These shifts may be subtle during exertion but become evident hours later.

11. ATP strain and calcium handling failure (Wirth & Steinacker, 2020; GLA synthesis)

Reduced ATP availability impairs calcium extrusion and buffering. Intracellular Ca²⁺ accumulates, increasing mitochondrial workload and vulnerability.

This step is load-dependent and explains delayed symptom escalation rather than immediate collapse.

12. Delayed mitochondrial ROS amplification (PEM timing) (Naviaux et al., 2016; GLA synthesis)

Mitochondrial stress produces delayed ROS bursts, typically hours after exertion, aligning with post-exertional malaise rather than immediate fatigue.

ROS further destabilizes membranes and signaling without defining the baseline defect.

13. Secondary lipid and kinase amplifiers during flares (Moreau et al., 2025; integrated lipid signaling literature)

ROS can transiently increase PKC / PI-PLC signaling, worsening membrane fragility and innate sensitivity without defining the baseline deficient state.

Importantly, these amplifiers deepen crashes but do not define the primary deficient state.

14. Renal hypoperfusion and volume dysregulation (Wirth & Scheibenbogen, 2021; Miwa & Fujita, 2016)

Renal perfusion instability reduces effective circulating volume, lowering preload and exacerbating orthostatic intolerance.

In the context of chronically low SMPDL3B expression and upstream perfusion instability, renal blood-flow regulation becomes less buffered, reinforcing orthostatic intolerance and lowering the threshold for crash initiation.

15. Hepatic metabolic load and FGF21 elevation (Hoel et al., 2021; GLA synthesis)

Sustained systemic stress increases hepatic metabolic demand. FGF21 elevation reflects impaired metabolic flexibility and ongoing metabolic load rather than adaptive fasting responses.

This contributes to poor recovery kinetics and prolonged post-exertional symptoms.

16. Autonomic sympathetic bias locks the pattern (Wirth & Scheibenbogen, 2021; Freeman et al., 2011)

Baroreflex impairment and sympathetic dominance further destabilize perfusion control, reducing flow reserve and lowering the crash threshold.

The system becomes locked into a low-tolerance, high-reactivity state.