{
  "title": "The Lipid Question \u2014 source-linked research and synthetic simulations",
  "research_cutoff": "2026-11-10",
  "conclusion": "SPT inhibition is plausible for a defined mechanism or subgroup; human sporadic-ALS slowing and prevention remain unproved.",
  "measured_kinetic_inputs": 0,
  "patient_data_used": false,
  "clinical_effect_estimated": false,
  "evidence": {
    "schema_version": "1.0",
    "research_cutoff": "2026-11-10",
    "cards": [
      {
        "kind": "HUMAN GENETICS",
        "year": "2021",
        "sample": "11 patients \u00b7 7 families",
        "tags": [
          "human"
        ],
        "title": "A specific genetic defect can release the SPT brake.",
        "finding": "Defined childhood ALS variants disrupt feedback and increase new sphingolipid synthesis. Correcting the mutant signal reduced abnormal synthesis in patient cells.",
        "limit": "A rare initiating mutation is not evidence that adult sporadic ALS has the same defect.",
        "detail": "Allele-selective cellular correction and systemic inhibition of normal SPT are different interventions. Clinical inhibitor benefit was not established.",
        "source_id": "HUM-S01",
        "url": "https://www.nature.com/articles/s41591-021-01346-1"
      },
      {
        "kind": "HUMAN OBSERVATION",
        "year": "2022",
        "sample": "2 plasma cohorts",
        "tags": [
          "human"
        ],
        "title": "ALS repeatedly implicates lipid metabolism.",
        "finding": "Two cohorts identified overlapping altered lipid pathways, including sphingolipids, after covariate adjustment.",
        "limit": "Replicated plasma associations do not identify CNS flux or establish that lowering production will help.",
        "detail": "Cohorts contained 125 ALS/71 controls and 225 ALS/104 controls. Samples were post-onset and nonfasting. Later Michigan reports may share participants.",
        "source_id": "SL-E06",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9762943/"
      },
      {
        "kind": "HUMAN OBSERVATION",
        "year": "October 2026",
        "sample": "104 sporadic ALS \u00b7 78 controls",
        "tags": [
          "human",
          "counter"
        ],
        "title": "The newest plasma pattern goes both ways.",
        "finding": "Selected sphingolipid species were higher in ALS and others lower. This is not a uniform excess of every sphingolipid.",
        "limit": "Blood sampling time and fasting differed; a plasma abundance does not reveal the responsible tissue or enzyme.",
        "detail": "Under the reported combined statistical/effect-size criterion, four sphingolipid species were lower and three higher. The classifier lacked external validation.",
        "source_id": "HUM-S07",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13685669/"
      },
      {
        "kind": "DISEASE MODEL",
        "year": "2020",
        "sample": "GARP-mutant wobbler mice",
        "tags": [
          "model"
        ],
        "title": "SPT inhibition helped a trafficking-defect model.",
        "finding": "Myriocin improved motor-related outcomes and survival in a model with elevated sphingosine and disrupted lysosomal trafficking.",
        "limit": "A defined mouse trafficking mutation is not human sporadic ALS.",
        "detail": "Survival groups contained 17\u201318 mice. Unchanged ceramide and sphinganine plus lower sphingomyelin underline the need to separate lipid pools.",
        "source_id": "SL-E05",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7229683/"
      },
      {
        "kind": "COUNTEREVIDENCE",
        "year": "2015",
        "sample": "SOD1-G93A mice",
        "tags": [
          "model",
          "counter"
        ],
        "title": "Reducing a different lipid-synthesis step worsened disease.",
        "finding": "Blocking glucosylceramide synthesis accelerated disease in this ALS model. Adding the ganglioside GM3 supported survival.",
        "limit": "GCS is a different target from SPT; this does not prove every level of myriocin inhibition is harmful.",
        "detail": "The result motivates preservation of complex-lipid functions. It does not calibrate the model\u2019s reference level or a human therapeutic window.",
        "source_id": "SL-E02",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC4491749/"
      },
      {
        "kind": "HUMAN OBSERVATION",
        "year": "2021",
        "sample": "23 ALS \u00b7 10 neurological controls",
        "tags": [
          "human",
          "counter"
        ],
        "title": "Blood and spinal-fluid measurements are not interchangeable.",
        "finding": "Paired plasma and cerebrospinal-fluid lipidomics showed substantially different differential-lipid patterns.",
        "limit": "Neither blood nor CSF concentration directly measures synthesis flux inside a motor neuron.",
        "detail": "This small observational study included exploratory comparisons. It supports a compartment distinction rather than a validated treatment-selection test.",
        "source_id": "HUM-S09",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8361390/"
      },
      {
        "kind": "EXPOSURE CHECK",
        "year": "2004",
        "sample": "Short systemic mouse experiment",
        "tags": [
          "model",
          "counter"
        ],
        "title": "A peripheral change does not prove brain target engagement.",
        "finding": "Systemic myriocin changed hepatic SPT activity and sphinganine without changing the measured brain SPT activity in this experiment.",
        "limit": "This is not human oral pharmacokinetics or proof that the molecule never enters the brain.",
        "detail": "Route, formulation, duration and tissue assays matter. Relevant human exposure and target engagement need to be demonstrated directly.",
        "source_id": "HUM-S11",
        "url": "https://pubmed.ncbi.nlm.nih.gov/14700532/"
      },
      {
        "kind": "PREPRINT \u00b7 ONE CASE",
        "year": "2022",
        "sample": "One child \u00b7 SPTLC1 p.Leu38Arg",
        "tags": [
          "human"
        ],
        "title": "A biomarker observation started a clinical question.",
        "finding": "A fungal preparation was followed by lower circulating sphingolipids in a child with a specific genetic mechanism.",
        "limit": "No control, established functional recovery, survival effect or prevention result.",
        "detail": "Treatment evidence remains preprint-level. The accessible peer-reviewed successor supports genetics, but its treatment passage was not verified.",
        "source_id": "HUM-S02",
        "url": "https://www.medrxiv.org/content/10.1101/2022.02.07.22269609v1.full"
      },
      {
        "kind": "TRIAL REGISTRY",
        "year": "Checked 10 November 2026",
        "sample": "Planned phase 2 \u00b7 estimated 84",
        "tags": [
          "human"
        ],
        "title": "A selected sporadic-ALS treatment trial is registered.",
        "finding": "A C. cicadae preparation is planned against placebo in sporadic ALS with elevated plasma sphingolipids.",
        "limit": "No posted results. This is a whole fungal preparation, not purified myriocin or an ALS-prevention trial.",
        "detail": "The record last updated May 20, 2026 still reports Not Yet Recruiting. Estimated start dates do not establish that enrollment began.",
        "source_id": "HUM-S04",
        "url": "https://clinicaltrials.gov/study/NCT07467746"
      }
    ],
    "sources": [
      {
        "id": "HUM-S01",
        "title": "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis",
        "url": "https://www.nature.com/articles/s41591-021-01346-1",
        "label": "Human genetics",
        "note": "A defined rare mechanism; cellular correction is not a clinical trial."
      },
      {
        "id": "HUM-S03",
        "title": "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS",
        "url": "https://pubmed.ncbi.nlm.nih.gov/37348646/",
        "label": "Human genetics \u00b7 2023",
        "note": "Abstract inspected; published treatment passage remains unverified."
      },
      {
        "id": "SL-E06",
        "title": "Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9762943/",
        "label": "Two human plasma cohorts \u00b7 2022",
        "note": "Association after onset; potential overlap with later cohorts."
      },
      {
        "id": "HUM-S07",
        "title": "Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13685669/",
        "label": "Sporadic ALS plasma \u00b7 2026",
        "note": "Mixed species directions and sampling-time limitations."
      },
      {
        "id": "SL-E05",
        "title": "Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7229683/",
        "label": "Myriocin in wobbler mice \u00b7 2020",
        "note": "Direct intervention in a defined trafficking model."
      },
      {
        "id": "SL-E02",
        "title": "Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC4491749/",
        "label": "GCS perturbation / GM3 \u00b7 2015",
        "note": "Different enzyme; complex-lipid function matters."
      },
      {
        "id": "SL-E03",
        "title": "Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase",
        "url": "https://academic.oup.com/hmg/article/24/25/7390/2384791",
        "label": "Muscle / denervation \u00b7 2015",
        "note": "Injury can itself drive a lipid-metabolism response."
      },
      {
        "id": "HUM-S09",
        "title": "Lipidomic traits of plasma and cerebrospinal fluid in amyotrophic lateral sclerosis correlate with disease progression",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8361390/",
        "label": "Paired human plasma / CSF \u00b7 2021",
        "note": "Compartment specificity; concentration is not flux."
      },
      {
        "id": "SL-E08",
        "title": "Evidence for alterations in lipid profiles and biophysical properties of lipid rafts from spinal cord in sporadic ALS",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10879240/",
        "label": "Sporadic ALS spinal membrane fractions \u00b7 2024",
        "note": "Small terminal study; denominator inconsistency retained in local notes."
      },
      {
        "id": "SL-E09",
        "title": "Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity",
        "url": "https://www.nature.com/articles/s42003-024-07231-0",
        "label": "Neuronal and glial cell biology \u00b7 2024",
        "note": "Cell-type and lipid-species effects differ."
      },
      {
        "id": "HUM-S11",
        "title": "Myriocin, a serine palmitoyltransferase inhibitor, alters regional brain neurotransmitter levels without concurrent inhibition of the brain sphingolipid biosynthesis in mice",
        "url": "https://pubmed.ncbi.nlm.nih.gov/14700532/",
        "label": "Systemic mouse pharmacodynamics \u00b7 2004",
        "note": "Peripheral effect did not establish measured brain SPT inhibition."
      },
      {
        "id": "HUM-S12",
        "title": "Disruption of sphingolipid homeostasis by myriocin, a mycotoxin, reduces thymic and splenic T-lymphocyte populations",
        "url": "https://pubmed.ncbi.nlm.nih.gov/15297021/",
        "label": "Mouse immunotoxicology \u00b7 2004",
        "note": "Exposure-specific immune effects; not a human incidence estimate."
      },
      {
        "id": "HUM-S13",
        "title": "Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC5833386/",
        "label": "Conditional intestinal SPT deletion \u00b7 2018",
        "note": "Essential functions; deletion is not partial drug inhibition."
      },
      {
        "id": "HUM-S02",
        "title": "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS",
        "url": "https://www.medrxiv.org/content/10.1101/2022.02.07.22269609v1.full",
        "label": "Single-case preprint \u00b7 2022",
        "note": "Biomarker observation, without controlled clinical benefit."
      },
      {
        "id": "HUM-S04",
        "title": "NCT07467746: Research of Traditional Chinese Medicine Oral Preparation of C. Cicadae in the Treatment of ALS Patients With Elevated Plasma Sphingolipids",
        "url": "https://clinicaltrials.gov/study/NCT07467746",
        "label": "Official trial registry \u00b7 retrieved 2026-11-10",
        "note": "Last posted 2026-05-20; no posted results."
      },
      {
        "id": "HUM-S06",
        "title": "Longitudinal Metabolomics in Amyotrophic Lateral Sclerosis Implicates Impaired Lipid Metabolism",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12174748/",
        "label": "Longitudinal metabolomics / exploratory MR \u00b7 2025",
        "note": "Attrition, nominal testing and cohort overlap limit causal claims."
      },
      {
        "id": "SL-E14",
        "title": "ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis",
        "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12974560/",
        "label": "Synthesis / salvage experiments \u00b7 2026",
        "note": "Fixed-rate simulations omit adaptive feedback observed in cells."
      }
    ]
  },
  "model_manifest": {
    "schemaVersion": "1.0",
    "generatedOn": "2026-11-10",
    "modelVersion": "1.0.0",
    "engineSha256": "d825ecb7b6f376c9bd66523e4a71ae5e9e5388f7d208c75ade3e7f91eb653718",
    "kind": "synthetic_assumption_exploration",
    "measuredInputCount": 0,
    "fittedToData": false,
    "timeUnit": "normalized time; not days",
    "poolUnit": "dimensionless proxy amount",
    "interpretation": "All numeric inputs are deliberate assumptions. Ensemble intervals are spread across assumed settings, not confidence intervals or probabilities of human benefit.",
    "reproducibleCommand": "node model/generate.mjs",
    "outputs": [
      {
        "file": "browser-model.js",
        "bytes": 12014,
        "sha256": "d825ecb7b6f376c9bd66523e4a71ae5e9e5388f7d208c75ade3e7f91eb653718"
      },
      {
        "file": "scenarios.json",
        "bytes": 1525673,
        "sha256": "21bb2b20ca92dc13420aeaf287bcdaa25519d44e03de9ec2cf5542d23f91cf79"
      },
      {
        "file": "ensemble.json",
        "bytes": 1019357,
        "sha256": "c221c567b9259458b46fad8b4b18718fde73f1629c141ad76cc99738d2981c0b"
      },
      {
        "file": "sensitivity.json",
        "bytes": 30189,
        "sha256": "8321aadda878aa9233d231321845c294f93c5fcdcbd33679f414bb90922040d8"
      },
      {
        "file": "validation.json",
        "bytes": 3153,
        "sha256": "24cc975dcaa1204ec31be5731bb7eab643ff4e9ec3071ea340fb826e77d18a26"
      }
    ]
  },
  "numerical_validation": {
    "schemaVersion": "1.0",
    "generatedOn": "2026-11-10",
    "modelVersion": "1.0.0",
    "engineSha256": "d825ecb7b6f376c9bd66523e4a71ae5e9e5388f7d208c75ade3e7f91eb653718",
    "kind": "synthetic_assumption_exploration",
    "measuredInputCount": 0,
    "fittedToData": false,
    "timeUnit": "normalized time; not days",
    "poolUnit": "dimensionless proxy amount",
    "interpretation": "All numeric inputs are deliberate assumptions. Ensemble intervals are spread across assumed settings, not confidence intervals or probabilities of human benefit.",
    "passed": true,
    "checkCount": 19,
    "checks": [
      {
        "name": "Balanced system remains at its analytic equilibrium",
        "passed": true
      },
      {
        "name": "Zero inhibition is an exact null comparison",
        "passed": true
      },
      {
        "name": "No SPT source means SPT inhibition has no effect",
        "passed": true
      },
      {
        "name": "Intervention after the horizon has no effect",
        "passed": true
      },
      {
        "name": "Zero-length exposure has no effect",
        "passed": true
      },
      {
        "name": "Source-free, loss-free closed recycling conserves initial mass",
        "passed": true
      },
      {
        "name": "In a loss-free system, added source equals accumulated total mass",
        "passed": true
      },
      {
        "name": "Blocked GSL synthesis gives the known exponential decay of G",
        "passed": true
      },
      {
        "name": "No sources and complete SPT inhibition allow all pools to decay",
        "passed": true
      },
      {
        "name": "Singular equilibrium is explicitly unavailable rather than invented",
        "passed": true
      },
      {
        "name": "High loss/conversion rates retain nonnegative states and mass balance",
        "passed": true
      },
      {
        "name": "Matched high pools cannot identify de novo versus salvage input",
        "passed": true
      },
      {
        "name": "Linear steady-state source-share prediction matches numerical simulation",
        "passed": true
      },
      {
        "name": "A lower base pool can coexist with worse assumed essential-pool shortfall",
        "passed": true
      },
      {
        "name": "Mass conservation is satisfied in every preset and multiple exposure windows",
        "passed": true
      },
      {
        "name": "Halving step size converges for event-aligned state and burden outputs",
        "passed": true
      },
      {
        "name": "Washout restores the untreated steady state, without an invented lasting cure",
        "passed": true
      },
      {
        "name": "Zero horizon returns the initial state and no integrated exposure",
        "passed": true
      },
      {
        "name": "Invalid parameters, dose-like inputs and impossible exposures are rejected",
        "passed": true
      }
    ],
    "scope": "Numerical implementation, conservation and structural limits only. Not validation against human ALS data.",
    "ensembleSampleCount": 512,
    "presetCount": 6,
    "regimenCount": 144,
    "maximumEnsembleMassResidual": 2.6716406864579767e-12,
    "stepHalvingMaximumFinalStateDifference": 1.27675647831893e-13,
    "browserCopyMatchesCanonical": true,
    "numericalValidationOnly": true
  },
  "methods_file": "model-methods.md",
  "caveats": [
    "All numeric model rates, initial amounts, references and ensemble ranges are assumptions.",
    "The model contains no neural-survival, ALSFRS-R, lifespan, dose or incident-ALS mapping.",
    "Numerical validation is separate from biological and clinical validation.",
    "A reduction in an intermediate and a shortfall relative to an assumed G reference have no validated clinical interpretation.",
    "Whole fungal products and purified myriocin are different interventions.",
    "Human observations, mouse experiments, a single-case preprint and a registered trial are different evidence levels."
  ]
}