Amyotrophic Lateral Sclerosis

1. Disease Information

Overview. Amyotrophic lateral sclerosis (ALS), also called motor neuron disease (MND) in the UK/Commonwealth and "Lou Gehrig's disease" in the US, and maladie de Charcot in France, is a progressive, fatal neurodegenerative disorder characterized by the combined degeneration of upper motor neurons (UMN; Betz cells of the primary motor cortex and the corticospinal tracts) and lower motor neurons (LMN; anterior horn cells of the spinal cord and brainstem motor nuclei). The result is progressive muscle weakness, atrophy, spasticity, and ultimately paralysis, with death most commonly from neuromuscular respiratory failure, typically 2–4 years after symptom onset. ALS exists on a clinical–pathological continuum with frontotemporal dementia (FTD); up to ~50% of patients have some cognitive/behavioral impairment and ~13–15% meet criteria for concomitant FTD (Brown & Al-Chalabi, N Engl J Med 2017, PMID:28700839; van Es et al., Lancet 2017 seminar, PMID:28552366; Feldman et al., Lancet 2022, PMID:36116464).

Key identifiers. - MONDO: MONDO:0004976 (amyotrophic lateral sclerosis); locus-specific children include MONDO:0007103 (ALS1, SOD1). - OMIM: #105400 (ALS1, SOD1); phenotypic series PS105400 enumerates ALS1–ALS26+ loci. C9orf72 ALS-FTD = #105550 (FTDALS1). - Orphanet: ORPHA:803 (amyotrophic lateral sclerosis). - ICD-10: G12.21. ICD-11: 8B60.0. - MeSH: D000690 (Amyotrophic Lateral Sclerosis); tree under "Motor Neuron Disease" (D016472). - UMLS/SNOMED CT: 86044005 (Amyotrophic lateral sclerosis).

Synonyms / alternative names. Motor neuron disease (MND); Lou Gehrig's disease; Charcot disease; classic/classical ALS. Related MND phenotypes that some classifications group with ALS: primary lateral sclerosis (PLS) (pure UMN), progressive muscular atrophy (PMA) (pure LMN), progressive bulbar palsy (PBP) (bulbar-onset), and the ALS-FTD spectrum.

Data provenance. The KB entry should be built from aggregated disease-level resources (OMIM, Orphanet, HPO, systematic reviews, natural-history registries such as PRO-ACT, and society guidelines), not individual EHR/patient records. Genetic frequencies are drawn from familial cohorts and population databases (gnomAD, Project MinE).

2. Etiology

ALS is etiologically heterogeneous. ~90% of cases are sporadic (sALS); ~10% are familial (fALS), usually autosomal dominant. Even sporadic ALS has a substantial genetic contribution (twin-study heritability ~0.4–0.6) and is best modeled as a gene–environment, multistep process (Al-Chalabi et al., Lancet Neurol 2014 multistep model, PMID:24507800 — estimated a six-step process).

Primary causal factors. - Genetic (monogenic and oligogenic). Four genes dominate: C9orf72, SOD1, TARDBP, FUS. Together they explain up to ~60–70% of fALS and ~10% of sALS in European populations (see §4). C9orf72 hexanucleotide expansion is the single most common cause overall. - Convergent molecular mechanism. Regardless of trigger, >97% of ALS cases share cytoplasmic TDP-43 (TARDBP) mislocalization and aggregation as the pathological signature; the principal exceptions are SOD1- and FUS-mutant cases, which have SOD1- or FUS-positive/TDP-43-negative inclusions (Neumann et al., Science 2006, PMID:17023659 — identified TDP-43 as the ubiquitinated inclusion protein).

Risk factors.

Genetic risk / susceptibility. - C9orf72 G4C2 repeat expansion (>~30 repeats pathogenic; intermediate alleles debated) — largest single genetic risk factor; incomplete, age-dependent penetrance. - ATXN2 intermediate-length polyQ repeats (~27–33 CAG) — validated risk factor for sporadic ALS (Elden et al., Nature 2010, PMID:20740007). - SOD1, TARDBP, FUS rare variants (see §4). UNC13A polymorphisms modify risk and survival. - Rare-variant burden in TBK1, NEK1, KIF5A, C21orf2, OPTN, VCP, UBQLN2, CHCHD10, MATR3, PFN1, ANXA11, TIA1, SQSTM1, TUBA4A.

Environmental / demographic risk. - Age (peak onset 55–75) and male sex (M:F ~1.3–1.5:1, converging after menopause). - Family history of ALS/FTD. - Cigarette smoking — the most consistently replicated exogenous risk factor (probable causal; especially in women). - Physical activity / elite athleticism & professional sport (e.g., Italian football, US football) and military service — associated in multiple cohorts, though confounding and reverse-causation debated. - Occupational/environmental exposures: heavy metals (lead), pesticides/agrochemicals, electromagnetic fields, formaldehyde — associations of variable strength. - β-methylamino-L-alanine (BMAA), a cyanobacterial neurotoxin, implicated in the Western Pacific ALS–Parkinsonism–dementia complex (Guam ALS-PDC) (Cox et al. hypothesis; contested).

Protective factors. - Higher BMI / hyperlipidemia are consistently associated with lower risk and better survival (a metabolic-reserve effect) — one of the most robust epidemiological signals. - Type 2 diabetes associated with reduced ALS risk in European populations (opposite in Asian populations). - Genetic protective/modifier alleles remain an active area; no well-established protective coding variant analogous to APOE exists.

Gene–environment interaction. The multistep model implies that inherited variants "use up" one or more of the ~6 steps, so mutation carriers require fewer environmental hits and present earlier — e.g., C9orf72 carriers show a lower estimated step number than sporadic patients (Al-Chalabi et al., PMID:24507800; Vucic et al. multistep replication studies).

3. Phenotypes

ALS phenotypes span motor (UMN + LMN), bulbar, respiratory, cognitive/behavioral, and constitutional domains. Suggested HPO terms (verify labels with OAK before KB entry):

Onset topography. ~⅔ spinal (limb) onset (asymmetric distal limb weakness — foot drop, hand clumsiness/split-hand), ~⅓ bulbar onset (dysarthria/dysphagia; more common in older women, worse prognosis), and a minority respiratory-onset (worst prognosis). "Flail arm" (Vulpian-Bernhardt) and "flail leg" variants and PLS/PMA represent phenotypic extremes.

Characteristics. Adult onset (median ~58–63 y; earlier in fALS, especially SOD1/FUS which can be juvenile). Course is relentlessly progressive with contiguous anatomical spread from the onset region. Severity variable but uniformly disabling.

Quality-of-life impact. Progressive loss of ambulation → wheelchair dependence; loss of speech → augmentative/alternative communication; loss of swallow → gastrostomy dependence and aspiration risk; respiratory decline → ventilatory dependence; retained cognition in most patients means awareness of decline (high depression/existential distress). Measured with ALSFRS-R (function), ALSAQ-40/ALSAQ-5 (disease-specific QoL), and generic EQ-5D/SF-36.

4. Genetic / Molecular Information

Causal genes (the "big four" + long tail; OMIM phenotypic series PS105400).

Landmark gene-discovery citations: - SOD1 — Rosen et al., Nature 1993 (first ALS gene), PMID:8446170. - TARDBP/TDP-43 mutations — Sreedharan et al., Science 2008, PMID:18309045. - FUS — Kwiatkowski et al., Science 2009, PMID:19251627; Vance et al., Science 2009, PMID:19251628. - C9orf72 G4C2 expansion — DeJesus-Hernandez et al., Neuron 2011, PMID:21944778; Renton et al., Neuron 2011, PMID:21944779. - UBQLN2 (X-linked) — Deng et al., Nature 2011, PMID:21857683. - TBK1 — Freischmidt et al., Nat Neurosci 2015, PMID:26192745. - KIF5A — Nicolas et al., Neuron 2018, PMID:29566793.

Pathogenic variants — classification & type. - SOD1: >180 mostly missense variants (e.g., p.Ala5Val/A4V — aggressive, N. American; p.Asp91Ala/D90A — often recessive, slowly progressive, Scandinavian; p.Gly94Ala/G93A — the canonical mouse model allele). ACMG classification: many pathogenic/likely pathogenic in ClinVar. Mechanism = toxic gain of function (misfolding), not loss of dismutase activity. - C9orf72: noncoding GGGGCC hexanucleotide repeat expansion in intron 1 (normal <~24; pathogenic hundreds–thousands). Repeat-primed PCR / Southern blot required (not standard NGS). - TARDBP/FUS: predominantly missense clustered in the glycine-rich/low-complexity C-terminal domain (TDP-43) and the C-terminal NLS/RGG region (FUS). - KIF5A: loss-of-splice-site / C-terminal variants.

Allele frequency / somatic vs germline. ALS variants are germline; SOD1/TARDBP/FUS pathogenic alleles are essentially absent/ultra-rare in gnomAD controls, consistent with pathogenicity. C9orf72 expansions are not captured by standard population SNV databases. Somatic mosaicism is described (e.g., FUS) but rare.

Modifier genes. ATXN2 intermediate repeats (risk + earlier onset; PMID:20740007); UNC13A (survival/cognition modifier and a cryptic-exon target of TDP-43 loss); EPHA4 (survival); KIFAP3, CAMTA1 (reported modifiers).

Epigenetics. C9orf72 promoter/repeat hypermethylation can reduce expression and modestly protect; global and locus-specific DNA-methylation changes and histone modifications at C9orf72 reported (search ENCODE/Roadmap; DiseaseMeth). Epigenetic DNA methylation "clocks" show accelerated biological aging in ALS.

Chromosomal abnormalities. The C9orf72 repeat maps to chromosome 9p21; ALS is otherwise not a large-CNV/aneuploidy disorder. Large structural variants are rare contributors.

5. Environmental Information

• Toxins / occupational exposures (search CTD): lead and other heavy metals, pesticides/organochlorines, agrochemicals, solvents/formaldehyde, and cyanotoxin BMAA (CHEBI candidate; Guam ALS-PDC). Electromagnetic-field/electric-shock exposure hypothesized.
• Lifestyle: cigarette smoking (probable causal risk); vigorous/high-level physical activity and contact/professional sport; military deployment (Gulf War veterans). High premorbid BMI/lipids protective (§2).
• Infectious agents: No established infectious cause. Human endogenous retrovirus HERV-K (HML-2) reactivation has been proposed as a mechanistic contributor (TDP-43 can transactivate HERV-K), motivating antiretroviral trials (e.g., Triumeq/Lighthouse); enteroviral hypotheses unconfirmed. This is best curated as a hypothesis/knowledge-gap, not established etiology.

6. Mechanism / Pathophysiology

ALS is a convergent, multi-mechanism motor-neuron proteinopathy. The dominant unifying lesion is nuclear clearance and cytoplasmic aggregation of TDP-43, causing both loss of nuclear RNA-processing function and cytoplasmic gain of toxicity (Neumann et al., PMID:17023659; reviews Taylor, Brown & Ravits, Nature 2016 "Decoding ALS," PMID:27830784).

Causal chain (upstream → downstream), with GO/CL suggestions:

1. Genetic/environmental trigger (mutation, aging, oxidative burden) →
2. RNA-metabolism dysregulation & TDP-43/FUS mislocalization — impaired splicing, mRNA transport, stress-granule dynamics; loss of TDP-43 nuclear function → cryptic-exon inclusion (e.g., in STMN2 and UNC13A), a key emerging mechanism.
3. GO:0008380 (RNA splicing); GO:0006406 (mRNA export from nucleus); GO:0010494 (cytoplasmic stress granule); GO:0006913 (nucleocytoplasmic transport).
4. Proteostasis failure & protein aggregation — misfolded SOD1, TDP-43, FUS, DPR aggregates; impaired autophagy and ubiquitin–proteasome clearance (OPTN, SQSTM1, UBQLN2, VCP, TBK1 converge here).
5. GO:0006914 (autophagy); GO:0000045 (autophagosome assembly); GO:0043161 (proteasome-mediated ubiquitin-dependent protein catabolic process); GO:0031625 (ubiquitin protein ligase binding).
6. Nucleocytoplasmic transport defects — C9orf72 DPRs (esp. arginine-rich poly-GR/PR) disrupt the nuclear pore.
7. C9orf72-specific triad: (a) RNA foci sequestering RNA-binding proteins; (b) RAN-translated dipeptide repeat proteins (poly-GA, -GP, -GR, -PR, -PA) that are toxic (Mori et al., Science 2013, PMID:23393093; Ash et al., Neuron 2013, PMID:23415312); (c) C9orf72 haploinsufficiency impairing autophagy/immune function.
8. Glutamate excitotoxicity — deficient astrocytic EAAT2/GLT-1 glutamate uptake → excess synaptic glutamate → Ca²⁺-mediated excitotoxic motor-neuron injury (the rationale for riluzole).
9. GO:0051966 (regulation of glutamatergic synaptic transmission); CHEBI:14321 (glutamate); CHEBI:29108 (calcium).
10. Mitochondrial dysfunction & oxidative stress — impaired bioenergetics, ROS; SOD1 links directly (though toxicity is misfolding-driven, not enzyme loss).
11. GO:0006979 (response to oxidative stress); GO:0004784 (superoxide dismutase activity); CHEBI:18421 (superoxide); CHEBI:16240 (hydrogen peroxide).
12. Axonal transport & cytoskeletal defects — KIF5A, DCTN1, PFN1, TUBA4A, NEFH; distal ("dying-back") axonopathy and neuromuscular-junction denervation as an early event.
13. Non–cell-autonomous neuroinflammation — reactive astrocytes and microglia drive progression; mutant SOD1 in glia accelerates disease independent of neuronal SOD1 (Boillée et al., Science 2006, microglial contribution, PMID:16741123).
14. GO:0150076 (neuroinflammatory response); GO:0006954 (inflammatory response); CL:0000129 (microglial cell); CL:0000127 (astrocyte).
15. Motor-neuron degeneration & apoptosis → denervation → muscle atrophy/paralysis → respiratory failure.
    • GO:0043065 (positive regulation of apoptotic process); CL:0000100 (motor neuron); CL:0011001 (spinal cord motor neuron); CL:0000598 (pyramidal neuron, for corticomotoneurons).

Prion-like spread. Misfolded SOD1 and TDP-43 propagate template-directed misfolding cell-to-cell, consistent with the clinically observed contiguous anatomical spread from the onset focus.

Protein dysfunction detail. SOD1 = destabilized/misfolded metalloenzyme (Cu/Zn) forming toxic oligomers (UniProt P00441). TDP-43 (UniProt Q13148) and FUS (UniProt P35637) are RNA/DNA-binding proteins with low-complexity/prion-like domains that drive aberrant liquid–liquid phase separation into pathological solid aggregates.

Molecular profiling. Transcriptomics of ALS motor cortex/spinal cord (GEO datasets) show splicing dysregulation and cryptic exons; single-nucleus RNA-seq reveals selective vulnerability and glial activation states; CSF/plasma neurofilament (NfL, pNfH) is the leading fluid proteomic biomarker (see §10). CRISPR functional-genomics screens (DepMap-style, and DPR-toxicity screens) implicate nucleocytoplasmic-transport and ER-stress modifiers.

7. Anatomical Structures Affected

Organ / system level. Primary target = the motor system of the central and peripheral nervous system. - Primary motor cortex / precentral gyrus (Betz cells) — UBERON:0001384 (primary motor cortex); UBERON:0002026 (precentral gyrus). - Corticospinal (pyramidal) tract / lateral corticospinal tract — UBERON:0002718 (lateral corticospinal tract). - Spinal cord anterior (ventral) horn — UBERON:0002240 (spinal cord); ventral/anterior horn gray matter. - Brainstem motor nuclei (hypoglossal, facial, trigeminal motor) — bulbar involvement. - Frontotemporal cortex — in ALS-FTD (UBERON:0001870 frontal cortex; UBERON:0001871 temporal lobe). - Secondary: skeletal muscle (denervation atrophy; UBERON:0001134 skeletal muscle tissue), diaphragm (UBERON:0001103) → respiratory system; downstream complications in respiratory and GI (aspiration) systems.

Characteristically spared (important negative features for KB): extraocular muscles/oculomotor neurons, Onuf's nucleus (sphincter/continence), sensory pathways, and autonomic function — usually preserved until very late.

Tissue / cell level. - Lower motor neurons — CL:0011001 (spinal cord motor neuron); CL:0000100 (motor neuron). - Upper motor neurons / Betz cells (corticomotoneurons) — CL:0000598 (pyramidal neuron). - Astrocytes — CL:0000127; microglia — CL:0000129; oligodendrocytes — CL:0000128 (contribute to non-cell-autonomous injury). - Skeletal muscle fiber — CL:0000188 (denervated).

Subcellular level (GO cellular component). Cytoplasmic inclusions (GO:0005737 cytoplasm); stress granules (GO:0010494); nucleus/nuclear clearance of TDP-43 (GO:0005634); mitochondrion (GO:0005739); neuromuscular junction (GO:0031594); nuclear pore/envelope (GO:0005643).

Localization / lateralization. Onset is characteristically focal and asymmetric (one limb), with contiguous ipsilateral and contralateral spread; the split-hand sign (preferential thenar/first-dorsal-interosseous wasting) is a recognized focal LMN pattern.

8. Temporal Development

Onset. Adult, typically 55–75 y (median ~58–63); insidious, focal, painless weakness. Juvenile/early-onset forms occur with FUS, SOD1, ALS2, SETX, SPG11.

Progression & staging. Relentlessly progressive; rate is variable but individually near-linear on ALSFRS-R. Two validated clinical staging systems: - King's staging (anatomical spread: stages 1–4A/4B by number of regions involved + gastrostomy/NIV milestones) — Roche et al., Brain 2012, PMID:22042175. - MiToS staging (functional loss across 4 domains) — Chiò et al., 2015.

Rate / course. Median survival ~2–4 years from symptom onset (from diagnosis shorter). Course is progressive, non-remitting (no relapsing-remitting phase; spontaneous remission essentially unknown/"reversal" cases extraordinarily rare and debated).

Prognostic tempo determinants (see §11): bulbar/respiratory onset, older age, short diagnostic delay (fast progression), FTD, low FVC, high ΔALSFRS-R slope, low BMI → faster. PLS and flail-limb variants, SOD1-D90A, and young onset → slower (survival can be many years to decades).

Critical intervention windows. Early NfL-guided and genetically-guided treatment initiation (tofersen data suggest earlier = better). Presymptomatic intervention is now being tested (ATLAS trial: tofersen in presymptomatic SOD1 carriers with rising NfL).

9. Inheritance and Population

Epidemiology. - Incidence: ~1.5–2.7 per 100,000 person-years in European-ancestry populations (Europe age-standardized ~1.0–2.6/100,000/yr); lower reported rates in East Asian and admixed populations. US age-adjusted incidence ~1.5–1.7/100,000 (recent CDC/registry data). - Prevalence: ~4.5–9 per 100,000; a 2023 systematic review/model projects global prevalence rising substantially by 2040 with population aging (Global prevalence & incidence systematic review, Neurology 2023 — see PMC10424837 / DOI 10.1212/WNL.0000000000207474). Registry-based projections (Italy) estimate prevalence ~11.7/100,000 in 2024 rising toward ~15.7/100,000 by 2040. - Lifetime risk ~1 in 300–400.

Inheritance & genetic-counseling parameters. - Pattern: Predominantly autosomal dominant in fALS (SOD1, C9orf72, TARDBP, FUS, TBK1, KIF5A); X-linked (UBQLN2); autosomal recessive (some SOD1-D90A, ALS2/alsin, SPG11); and multifactorial/oligogenic/polygenic in sporadic disease. - Penetrance: Incomplete and age-dependent — notably C9orf72 (near-complete only by ~80 y) and SOD1 (allele-dependent; A4V high, D90A variable/recessive). ATXN2 = risk factor, not fully penetrant. - Expressivity: Highly variable — same C9orf72 expansion can yield pure ALS, pure FTD, or ALS-FTD within one family. - Anticipation: C9orf72 shows repeat instability and some evidence of anticipation, but it is not a classic clean anticipation disorder. - Oligogenic inheritance: Increasingly recognized (e.g., co-occurring C9orf72 + ATXN2 or + TBK1 variants worsen/modify phenotype) — relevant to the dismech digenic/oligogenic curation pattern. - Founder effects: SOD1-D90A (Scandinavian/Finnish recessive founder haplotype); C9orf72 shares a common founder haplotype across European populations. - Consanguinity: relevant for recessive juvenile forms (ALS2, SPG11) in consanguineous populations.

Population demographics. Higher measured burden in European-ancestry populations; male predominance (M:F ~1.2–1.5:1, attenuating with age). Geographic clusters historically: Western Pacific ALS-PDC (Guam Chamorro, Kii Peninsula Japan, West Papua) — declining, environmentally linked.

10. Diagnostics

ALS is a clinical diagnosis (UMN + LMN signs, progressive spread, exclusion of mimics) supported by electrophysiology; no single confirmatory test.

Diagnostic criteria. - Gold Coast criteria (2020/2021) — current consensus; simplified dichotomous (ALS vs not-ALS), higher sensitivity (~93–96%) than revised El Escorial (Airlie House) and Awaji-shima criteria (Shefner et al., Clin Neurophysiol 2020, PMID:32410883). - Prior systems: revised El Escorial, Awaji (incorporates EMG as clinical-equivalent).

Electrophysiology (core). Needle EMG shows active + chronic denervation/reinnervation (fibrillations, positive sharp waves, fasciculation potentials, large/unstable motor units) in ≥2 body regions; nerve conduction studies exclude conduction block/neuropathy; motor unit number estimation (MUNE) and transcranial magnetic stimulation (threshold tracking → cortical hyperexcitability) as research/supportive tools.

Laboratory & biomarkers. - Neurofilaments — the key fluid biomarker: elevated serum/CSF neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) support diagnosis, correlate with progression rate, and are used as pharmacodynamic/prognostic markers. NfL reduction was the surrogate endpoint for tofersen's accelerated approval (Miller et al., N Engl J Med 2022 VALOR, PMID:36170501). - Routine labs to exclude mimics: CK (mildly elevated), TSH, PTH, serum protein electrophoresis, anti-GM1 (to exclude multifocal motor neuropathy), HIV, Lyme, heavy metals, hexosaminidase A, VLCFA, CSF. - LOINC codes exist for NfL and the exclusionary panel.

Imaging. MRI brain/spinal cord primarily to exclude structural mimics (cervical spondylotic myelopathy, structural lesions); may show corticospinal-tract T2/FLAIR hyperintensity and motor-cortex "iron" hypointensity. Advanced DTI/functional MRI and PET (e.g., TSPO neuroinflammation) are research tools.

Genetic testing. Increasingly standard given gene-targeted therapy: at minimum C9orf72 repeat-primed PCR and SOD1 sequencing (therapeutically actionable), plus ALS gene panels / exome (TARDBP, FUS, TBK1, etc.). Testing now recommended for all ALS patients per updated consensus (actionability + trial eligibility + reproductive counseling). C9orf72 requires repeat-expansion testing (not captured by standard NGS).

Pathology (confirmatory at autopsy). Loss of anterior-horn and Betz cells; ubiquitin/p62-positive, TDP-43-positive cytoplasmic inclusions (Bunina bodies, skein-like inclusions); TDP-43 immunohistochemistry (Neumann et al., PMID:17023659). SOD1- and FUS-cases are TDP-43-negative.

Differential diagnosis. Multifocal motor neuropathy with conduction block, cervical spondylotic myelopathy, inclusion-body myositis, Kennedy disease (SBMA), spinal muscular atrophy, myasthenia gravis, ALS mimics (paraneoplastic, thyrotoxic), and monomelic amyotrophy (Hirayama).

Screening. No population screening. Cascade genetic testing / presymptomatic testing offered in known-mutation families (with counseling); presymptomatic NfL monitoring is emerging in SOD1 carriers (ATLAS).

11. Outcome / Prognosis

• Survival: median ~2–4 years from symptom onset; ~50% die within 30 months of onset; ~10–20% survive >5 years, ~5–10% >10 years. Respiratory failure is the leading cause of death.
• Mortality: essentially a uniformly fatal disease; disease-specific mortality dominates.
• Prognostic factors (worse): bulbar or respiratory onset, older age at onset, short diagnosis delay / steep ALSFRS-R slope, low/declining FVC, low BMI and weight loss, cognitive impairment/FTD, high baseline NfL. Better: limb onset, young age, PLS/flail variants, SOD1-D90A, high BMI. The validated ENCALS survival model integrates these predictors.
• Morbidity / disability: progressive tetraparesis, anarthria, dysphagia (malnutrition, aspiration pneumonia), ventilatory dependence, communication loss, and (in a subset) dementia — profound disability captured by ICF and ALSFRS-R.
• QoL measures: ALSAQ-40/-5, EQ-5D, SF-36; caregiver burden is high.
• Prognostic biomarkers: NfL/pNfH (rate + survival), ALSFRS-R slope, FVC/SNIP, and genotype (C9orf72 → shorter survival + FTD risk).

12. Treatment

No cure; management is multidisciplinary and largely disease-modifying-modest + supportive. Multidisciplinary ALS-clinic care itself improves survival and QoL (MAXO:0000950 supportive care; multidisciplinary care).

Disease-modifying pharmacotherapy. - Riluzole (CHEBI:8863) — anti-glutamatergic (Na⁺-channel/glutamate-release inhibitor). First and only globally licensed drug; prolongs survival/time-to-tracheostomy by ~2–3 months (Bensimon et al., N Engl J Med 1994, PMID:8302340). Oral tablet, liquid, and film formulations. MAXO: pharmacotherapy. - Edaravone (CHEBI:31530) — free-radical scavenger; IV and oral; slowed ALSFRS-R decline in a defined early-stage subgroup (Writing Group/Edaravone ALS-19 Study Group, Lancet Neurol 2017, PMID:28522181). Benefit debated; approved in US/Japan/others, not by EMA. - Tofersen (Qalsody) — antisense oligonucleotide (ASO), RNase-H knockdown of SOD1 mRNA; intrathecal. FDA accelerated approval April 2023 for SOD1-ALS — the first therapy targeting a genetic cause of ALS, approved on NfL reduction as surrogate; VALOR + open-label extension (Miller et al., N Engl J Med 2022, PMID:36170501). This maps directly to the dismech antisense_oligonucleotide_therapy module (RNase-H arm, target_gene SOD1) and therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE, aso_mechanism: RNASE_H_KNOCKDOWN. - Sodium phenylbutyrate/taurursodiol (AMX0035, Relyvrio/Albrioza) — approved 2022, then withdrawn from market in 2024 after the confirmatory PHOENIX phase 3 failed. Curate as historical/withdrawn (important accuracy point).

Pharmacogenomics / precision. SOD1 and C9orf72 genotype now gate therapy (tofersen for SOD1; investigational C9orf72 ASOs). This is genotype-guided precision neurology.

Advanced / investigational therapeutics. - C9orf72-targeted ASOs (e.g., BIIB078 — failed; afinersen; next-generation candidates) and RNA-targeting/gene therapies. - Gene therapy / gene editing (AAV-delivered, CRISPR) for SOD1/C9orf72 — preclinical/early clinical. - Cell therapy — mesenchymal stromal cell (NurOwn/debamestrocel — failed primary endpoint; FDA rejected), neural progenitor approaches. - Other trials: HERV-K antiretrovirals (Triumeq), CuATSM, pridopidine, DNL343 (integrated stress-response inhibitor), tofersen presymptomatic (ATLAS), masitinib, ANX005, and platform trials (HEALEY ALS Platform Trial, MND-SMART, TRICALS).

Symptomatic / supportive care (core of management). - Respiratory: non-invasive ventilation (NIV) improves survival and QoL (Bourke et al., Lancet Neurol 2006, PMID:16488378); tracheostomy/invasive ventilation as chosen; cough-assist/secretion management. MAXO: mechanical ventilation / respiratory therapy. - Nutrition: percutaneous endoscopic gastrostomy (PEG) for dysphagia/weight maintenance; high-calorie diet (MAXO: gastrostomy / dietary intervention MAXO:0000088). - Sialorrhea: anticholinergics, botulinum toxin, salivary-gland radiotherapy. - Spasticity/cramps: baclofen, tizanidine, mexiletine (cramps). - Pseudobulbar affect: dextromethorphan/quinidine (Nuedexta). - Rehabilitation: physical (MAXO:0000011), occupational, and speech therapy / AAC communication devices; mobility aids. - Palliative & advance-care planning: hospice, symptom control, respect for ventilation/withdrawal decisions.

Treatment outcomes. Approved drugs yield modest slowing (months), not reversal; combination riluzole + edaravone + supportive care is common. Adverse events: riluzole — transaminitis, asthenia, nausea; edaravone — gait disturbance, bruising, hypersensitivity; tofersen — CSF pleocytosis, myelitis/radiculitis (serious neurologic AEs), headache.

13. Prevention

• Primary prevention: No proven strategy; modifiable-risk-factor reduction (smoking cessation) is reasonable. No vaccine/immunization (not infectious).
• Secondary prevention / early detection: No population screening. In known-mutation families, presymptomatic genetic testing + NfL surveillance enables early/pre-symptomatic intervention trials (ATLAS in SOD1). Cascade testing with genetic counseling.
• Tertiary prevention (complication avoidance): early NIV, PEG, aspiration-pneumonia prevention, DVT/pressure-sore prevention, multidisciplinary clinic follow-up — these prevent complications and extend survival.
• Genetic counseling & reproductive options: risk assessment for AD/X-linked/recessive/oligogenic inheritance; preimplantation genetic testing (PGT) and prenatal diagnosis available for known familial mutations (NSGC/ACMG frameworks).
• Public-health/environmental: in historical Guam ALS-PDC, dietary/environmental change coincided with declining incidence (BMAA hypothesis).

14. Other Species / Natural Disease

• Taxonomy of models/natural disease: human (NCBITaxon:9606); models in mouse (NCBITaxon:10090), rat (NCBITaxon:10116), zebrafish (NCBITaxon:7955), Drosophila (NCBITaxon:7227), C. elegans (NCBITaxon:6239), pig, and non-human primate.
• Natural / veterinary disease: Canine degenerative myelopathy (DM) is a naturally-occurring SOD1-associated progressive spinal-cord/motor disorder (notably in German Shepherds, Pembroke Welsh Corgis, Boxers), caused by SOD1 c.118G>A (p.E40K) and a second SOD1 variant — a recognized large-animal ortholog model of SOD1-ALS (OMIA entry for degenerative myelopathy/SOD1 in Canis lupus familiaris). Equine motor neuron disease (EMND), linked to vitamin-E deficiency/oxidative stress, is a naturally-occurring LMN disease in horses resembling sporadic ALS. (Both = MODEL_ORGANISM evidence per dismech rules; document breed with VBO where possible.)
• Comparative biology / evolutionary conservation: SOD1, TARDBP, FUS, C9orf72 orthologs are deeply conserved; core mechanisms (proteostasis, RNA metabolism, oxidative stress) are conserved from yeast to human, enabling cross-species modeling (Alliance of Genome Resources).
• Transmission / zoonosis: none — ALS is not infectious or zoonotic (prion-like propagation is intracellular templating, not transmissible between individuals).

15. Model Organisms

Rodent (mammalian) — dominant models. - SOD1-G93A transgenic mouse — the classic ALS model; recapitulates progressive motor-neuron loss, paralysis, and shortened lifespan (Gurney et al., Science 1994, PMID:8209258). SOD1-G37R, G85R, D90A lines also used. Rat SOD1-G93A/H46R models for larger-CNS studies (intrathecal dosing, CSF sampling). - TDP-43 models (TARDBP overexpression/knock-in, e.g., Q331K, M337V) — reproduce TDP-43 pathology but overexpression toxicity confounds interpretation. - FUS transgenic/knock-in models — cytoplasmic FUS pathology, motor deficits. - C9orf72 models — BAC-transgenic mice carrying the human expansion (RNA foci + DPRs; variable motor phenotype across labs), AAV-(G4C2)n models, and C9orf72-knockout mice (immune/autophagy phenotype, models haploinsufficiency arm).

Genetic-model types available. Knockout, knock-in, transgenic (BAC), conditional (cell-type-specific to dissect neuron vs astrocyte vs microglia contributions), and humanized lines (MGI/IMPC/IMSR resources).

Non-mammalian & cellular. - Zebrafish (sod1, tardbp, fus, c9orf72 morphants/mutants) — rapid axonal/NMJ phenotyping. - Drosophila and C. elegans — DPR-toxicity and modifier screens (large-scale genetic screens defined nucleocytoplasmic-transport and RNA-metabolism modifiers). - iPSC-derived motor neurons from patient fibroblasts — the leading human in vitro platform (TDP-43 mislocalization, hyperexcitability, survival assays); iPSC-derived astrocytes/microglia and organoids/assembloids for non-cell-autonomous and NMJ modeling. Immortalized lines (NSC-34) for biochemistry.

Phenotype recapitulation & limitations. SOD1 mice reproduce the motor phenotype well but SOD1 accounts for a minority of human ALS and lacks TDP-43 pathology; C9orf72 mouse motor phenotypes are inconsistent between labs (a documented HUMAN_MODEL_MISMATCH: robust molecular pathology without reliable neurodegeneration/paralysis). No single model captures the full sporadic-ALS, TDP-43-centric human disease — a key knowledge gap and a driver of the shift toward patient iPSC systems. (Model databases: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, Cellosaurus.)

Consolidated Ontology-Term Suggestions (for KB population)

• MONDO: MONDO:0004976 (ALS); MONDO:0007103 (ALS1/SOD1).
• HP (phenotypes): HP:0003323, HP:0003202, HP:0002380, HP:0003394, HP:0001257, HP:0001347, HP:0001260, HP:0002015, HP:0002307, HP:0002878/HP:0002093, HP:0002094, HP:0001824, HP:0000749, HP:0002145, HP:0100543.
• GO (processes/CC): GO:0008380, GO:0006406, GO:0010494, GO:0006913, GO:0006914, GO:0043161, GO:0006979, GO:0004784, GO:0051966, GO:0150076, GO:0043065; components GO:0005737, GO:0031594, GO:0005643.
• CL (cells): CL:0000100, CL:0011001, CL:0000598, CL:0000127, CL:0000129, CL:0000188.
• UBERON (anatomy): UBERON:0001384, UBERON:0002026, UBERON:0002718, UBERON:0002240, UBERON:0001103, UBERON:0001134.
• CHEBI (chemicals): CHEBI:8863 (riluzole), CHEBI:31530 (edaravone), CHEBI:14321 (glutamate), CHEBI:29108 (calcium), CHEBI:18421 (superoxide), CHEBI:16240 (hydrogen peroxide).
• HGNC (genes): hgnc:11179 (SOD1), hgnc:28337 (C9orf72), hgnc:11571 (TARDBP), hgnc:4010 (FUS), hgnc:11584 (TBK1), hgnc:6323 (KIF5A). (Verify all with OAK — lowercase hgnc: per repo convention.)
• MAXO (treatments): pharmacotherapy (riluzole/edaravone/tofersen), mechanical/non-invasive ventilation, gastrostomy, physical therapy (MAXO:0000011), dietary intervention (MAXO:0000088), supportive/palliative care (MAXO:0000950).

Key Landmark Citations (verified real; snippets to be re-fetched before KB commit)

Sources (web-verified during research)

• Global Prevalence and Incidence of ALS: A Systematic Review, Neurology 2023 (PMC)
• Study Forecasts Uptick in ALS Prevalence — NeurologyLive
• Updates on Disease Mechanisms and Therapeutics for ALS, Cells 2024 (PMC)
• Biogen: FDA Accelerated Approval of QALSODY (tofersen)
• Tofersen — StatPearls (NCBI Bookshelf)
• Renton et al. 2011, C9ORF72 — PubMed 21944779
• DeJesus-Hernandez et al. 2011, C9ORF72 (PMC)
• Bensimon 1994 riluzole — PubMed 8302340
• Edaravone ALS-19 Study Group — citation 28522181
• Amylyx: Removal of RELYVRIO/ALBRIOZA from market
• Diagnosing ALS: the Gold Coast criteria and the role of EMG (PMC)
• ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now? (PMC)

Curation flags for the KB entry: 1. Model as Complex disease with a monogenic subtype layer (SOD1, C9orf72, TARDBP, FUS, TBK1, KIF5A…) — good candidate for has_subtypes + oligogenic inheritance modeling (C9orf72+ATXN2/TBK1). 2. antisense_oligonucleotide_therapy module conformance (tofersen, RNase-H, SOD1) is a natural fit. 3. Record AMX0035/Relyvrio as withdrawn (2024) — accuracy-critical. 4. Flag C9orf72 mouse HUMAN_MODEL_MISMATCH and sporadic-ALS/TDP-43 model gap as discussions (kind: HUMAN_MODEL_MISMATCH / KNOWLEDGE_GAP). 5. All snippets require just fetch-reference verification before commit; treat HERV-K/BMAA as hypotheses, not established etiology.