Amyotrophic Lateral Sclerosis Type 1

Mendelian MONDO:0007103 Pathograph 53 Show in embeddings browser Amyotrophic Lateral Sclerosis Motor Neuron Disease Neurodegenerative Disease

Amyotrophic lateral sclerosis type 1 (ALS1) is motor neuron disease caused by pathogenic SOD1 variants. Most families show autosomal dominant inheritance, while p.Asp91Ala (legacy D90A) can segregate recessively or dominantly in different populations. Age at onset, penetrance and progression vary substantially by variant and family. Progressive upper and lower motor neuron dysfunction produces limb, bulbar and respiratory impairment; selected SOD1 genotypes also have sensory, autonomic or cerebellar findings. Experimental and human pathological evidence supports toxic properties of abnormal SOD1 rather than a universal loss of dismutase activity, but the relative contributions of protein aggregation, cellular stress and non-neuronal toxicity remain unresolved in patients. SOD1-associated inclusions usually differ from the predominant TDP-43 pathology of other ALS forms, with rare reported exceptions. Care combines SOD1-lowering tofersen where indicated with general ALS disease-modifying and supportive management.

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Classifications

Harrison's Part

Mechanistic Nosology

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Inheritance

Autosomal dominant HP:0000006

Most SOD1-associated ALS is autosomal dominant, with variant-dependent and age-dependent penetrance. An affected heterozygous parent can transmit the variant to half of offspring, but variant transmission is not a prediction of whether or when ALS will develop. Two reported juvenile p.Asp125Gly cases inherited the variant from asymptomatic fathers; those observations do not establish lifetime nonpenetrance.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:8446170 SUPPORT PRIMARY RESULT Human Clinical

"We identified 11 different SOD1 missense mutations in 13 different FALS families."

The original association identifies pathogenic SOD1 variants in familial ALS; it does not provide an allele-specific penetrance estimate.

PMID:42265995 SUPPORT Human Clinical

"whole-exome sequencing revealed the pathogenic variant p.Asp125Gly in the SOD1 gene inherited from asymptomatic fathers"

The fathers were asymptomatic when described; their ages and subsequent lifetime outcomes are not established by the cached abstract.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"ALS has a 50% chance of inheriting the ALS-related"

Within the autosomal dominant offspring subsection, this fragment gives the transmission probability; it does not quantify penetrance.

Autosomal recessive (Asp90Ala) HP:0000007

The p.Asp91Ala allele (legacy D90A) segregates recessively in described Swedish and Finnish families, although heterozygous disease occurs in other genetic backgrounds. Homozygous SOD1 variants were also found in six of 37 probands in a selected Indian SOD1-ALS cohort; homozygosity alone does not establish the same variant or inheritance mechanism as Scandinavian D90A.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:7647793 SUPPORT Human Clinical

"Here we report homozygosity for an exon 4 mutation, Asp90Ala in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland."

Establishes recessive (homozygous) inheritance for the Asp90Ala allele in Scandinavian ALS families.

PMID:41511639 SUPPORT Human Clinical

"Remarkably, a high frequency of homozygous variants (6 patients) were observed in the cohort, which were associated with earlier disease onset."

The selected Indian cohort reports six homozygous genotypes and an association with earlier onset, without establishing a general causal effect of homozygosity.

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Subtypes

SOD1 p.Ala4Val (A4V, legacy numbering; p.Ala5Val in HGVS)

The p.Ala5Val allele (legacy A4V) is associated with rapid progression in reported North American families. A historical study reported mean survival of 1.4 years from onset; this is a cohort estimate rather than an individual prognosis. Most carriers studied shared a founder haplotype. The inferred founder origin and failure to identify a nearby modifier do not exclude distant modifiers or prove that every carrier has the same course.

Show evidence (2 references)

PMID:18055113 SUPPORT Human Clinical

"Carriers of the SOD1(A4V) mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3-5 years with other dominant SOD1 mutations)."

Quantifies the survival difference that makes this allele a clinically distinct stratum.

PMID:18055113 SUPPORT Human Clinical

"It therefore appears likely that the aggressive nature of the SOD1(A4V) mutation is not a result of a modifying factor within the region around the SOD1 gene."

The authors considered a closely linked modifier unlikely within the region studied; this does not exclude modifiers elsewhere or establish purely allele-intrinsic severity.

SOD1 p.Asp90Ala homozygous (D90A/D91A, recessive Scandinavian form)

Homozygosity for p.Asp91Ala (legacy D90A) defines a well-described recessive Scandinavian form, often with slowly progressive leg-onset disease. Sensory and urinary manifestations and widespread pathology were documented in a selected nine-person autopsy series. The same variant can be associated with dominant ALS outside this recessive context, and ataxia-first presentations have occurred in both heterozygous and homozygous carriers. Normal or near-normal dismutase activity in this variant argues against a universal enzymatic-loss explanation. Transgenic coexpression and aggregate-strain experiments are retained as models, not as proof of the human recessive mechanism.

Show evidence (2 references)

PMID:36385230 SUPPORT Human Clinical

"the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement"

Defines the recessive inheritance and the extra-motor clinical features of this stratum.

PMID:36385230 SUPPORT Human Clinical

"In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns."

Neuropathological confirmation that the lesion extends beyond motor pathways in D90A homozygotes.

Discussions and Knowledge Gaps

How does transgene dosage affect translation of SOD1 model interventions to human ALS?

HUMAN MODEL MISMATCH sod1_model_dose_and_human_response

Attached to

animal_models#SOD1 G93A transgenic mouse animal_models#Low-copy SOD1 homogenate-seeding recipients

Human pathogenic alleles and high-copy transgenic models differ in expression, genotype and disease timing. Seeding susceptibility varies across model and inoculation conditions, but no isolated transgene-dose experiment explains every difference. This uncertainty does not establish why VALOR missed its 28-week clinical endpoint; timing, power, progression heterogeneity and other factors remain possible.

Which abnormal SOD1 species and downstream cellular pathways drive progression in patients?

KNOWLEDGE GAP human_sod1_toxic_mediation

Attached to

pathophysiology#Cytoplasmic SOD1 Aggregate Formation pathophysiology#Mutant SOD1 Association with Derlin-1 pathophysiology#Microglial Mutant SOD1 Contribution pathophysiology#Astrocytic Mutant SOD1 Contribution

Human tissue demonstrates SOD1 pathology, while experimental perturbations support contributions from ER stress/ASK1 and non-neuronal cells. Visible inclusions, soluble species and associated transcriptional states are not interchangeable causal entities. Relative mediation in human genotypes and the effects of lowering protein supply on pre-existing aggregates remain unresolved.

Does the disease-associated motor-neuron signature contribute to injury, reflect compensation, or contain both?

KNOWLEDGE GAP dm_state_causal_meaning

Attached to

biochemical#Disease-associated motor neuron transcriptional signature experimental_models#WTC11 motor-neuron transcription-factor perturbation

The mouse stage series and human postmortem data establish association. Some signature regulators may be protective, and forced CREB3/ATF3 expression changes only parts of the program without a death or rescue assay. Neither pseudotime, glial proximity nor computational ligand nomination proves a DM-state-to-death mechanism.

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Pathophysiology

Pathogenic SOD1 Variation

ALS1 is associated with pathogenic SOD1 coding variants, usually heterozygous but sometimes biallelic. Missense and truncating alleles can have toxic properties. Effects on stability, aggregation and dismutase activity differ by allele; normal activity in D90A and disease in high-expressing G93A mice argue against a universal simple enzyme-loss mechanism. Biallelic loss-of-function SOD1 syndromes are a distinct genetic context.

SOD1 hgnc:11179

Downstream

SOD1 Protein Supply A coding variant changes the sequence of expressed SOD1; this edge denotes variant protein production, not an increase in total abundance.

Motor Neuron Degeneration Human genetic association and disease caused by tested transgenes support pathogenic SOD1 as an upstream cause, while the relative mediation by the mapped molecular routes remains unresolved.

Extra-Motor CNS Degeneration The D90A genotype is associated with this broader pathological phenotype; the cellular toxic intermediates are unresolved.

Functional Abnormality of the Bladder Urinary manifestations occur in a selected D90A cohort; the causal autonomic pathway is not resolved by the available pathology.

Gait Ataxia Ataxia-first presentations are associated with p.Asp91Ala in the selected case series; the underlying cerebellar or sensory mechanism is not established.

Show evidence (2 references)

PMID:8446170 SUPPORT PRIMARY RESULT Human Clinical

"We identified 11 different SOD1 missense mutations in 13 different FALS families."

The initial linkage and mutation study establishes the genetic association.

PMID:7647793 SUPPORT PRIMARY RESULT Human Clinical

"The erythrocyte CuZn-SOD activity is essentially normal. Our findings suggest that this CuZn-SOD mutation causes ALS by a gain of function rather than by loss"

Human genetic evidence that ALS occurs with preserved dismutase activity, establishing gain of function in patients rather than only in transgenic models.

SOD1 Protein Supply

Transcription and translation supply SOD1 protein, including variant protein in ALS1. This upstream substrate is a treatment target; lowering it does not by itself establish removal of existing aggregates or identify the toxic molecular species.

SOD1 hgnc:11179

Downstream

Cytoplasmic SOD1 Aggregate Formation Expressed variant SOD1 can enter abnormal conformational and aggregation pathways. The intervening folding, maturation and nucleation steps are allele dependent and are not resolved by tissue colocalization.

Mutant SOD1 Association with Derlin-1 Tested mutant proteins gain association with Derlin-1. Whether exposed mutant surfaces bind directly or require chaperones remains unresolved.

Microglial Mutant SOD1 Contribution Mutant protein expression in this glial lineage contributes to disease progression in conditional mouse experiments; the downstream toxic molecular species is unresolved.

Astrocytic Mutant SOD1 Contribution Mutant protein expression in this glial lineage contributes to disease progression in conditional mouse experiments; the downstream toxic molecular species is unresolved.

P2X7-Associated SOD1 Release Expressed SOD1 supplies released material under the ATP challenge; this includes wild-type as well as tested mutant protein, and does not establish spontaneous human neuron-to-neuron spread.

Show evidence (1 reference)

PMID:32640130 SUPPORT BACKGROUND Human Clinical

"Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis."

The intervention targets protein production, not correction of the DNA variant.

Cytoplasmic SOD1 Aggregate Formation

Abnormal SOD1 conformers accumulate in neurons and glia in experimental systems and human SOD1 ALS tissue. The specific harmful species and the contribution of visible inclusions versus soluble species remain unresolved. Most SOD1 pathology differs from the predominant TDP-43 proteinopathy of other ALS, although rare TDP-43-positive structures were observed in the D90A series. Neither universal dimer destabilization nor uniform TDP-43 absence is assumed.

spinal cord motor neuron CL:0011001

Animal models

SOD1 G85R with wild-type or D90A coexpression Mouse perturbs Coexpression modifies aggregate accumulation and disease kinetics.

Downstream

Seeded SOD1 Inclusion Pathology Aggregate-bearing donor tissue carries seeding activity in selected transgenic hosts. The experiment uses unpurified homogenate rather than a molecularly defined seed.

Show evidence (3 references)

PMID:17469116 SUPPORT PRIMARY RESULT Human Clinical

"Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43."

Human postmortem series establishing that ALS1 inclusions are ubiquitin-positive and TDP-43-negative.

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem."

The selected D90A autopsy series documents misfolded-SOD1 pathology.

PMID:40450581 SUPPORT PRIMARY RESULT Model Organism

"Even though the current results suggest that hSOD1 aggregation is the primary cause of disease, the identities of the principal harmful species are still unknown."

The coexpression study explicitly leaves the harmful aggregate species unresolved.

Mutant SOD1 Association with Derlin-1

Tested SOD1 mutants associate with Derlin-1 in transfected cells and mouse tissue. Recombinant-protein experiments support interaction, but reticulocyte-lysate chaperones could mediate it. This is an association with an ERAD component, without demonstrated sequestration or disassembly of the whole ERAD complex.

Downstream

Impaired ER-Associated Protein Degradation The interaction is implicated by perturbation studies, while substrate presentation or transfer rather than complex disassembly is proposed as the inhibited step.

Show evidence (2 references)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"Here we show that SOD1mut specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD."

The cellular studies identify the Derlin-1-associated route in tested mutants.

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"we cannot rule out the possibility that chaperon proteins in the reticulocyte lysate mediate the interaction between SOD1mut and Derlin-1."

The authors explicitly limit a direct-binding interpretation.

Impaired ER-Associated Protein Degradation

Overexpression of tested mutant SOD1 retards degradation of luminal NHK and transmembrane CD3delta ERAD reporters. Reduced reporter ubiquitination and retention on a Derlin-1/VIMP-containing complex suggest impaired substrate transfer. The exact blocked step is unresolved; core component association and measured cytosolic proteasomal degradation were preserved under the tested conditions.

ERAD pathway GO:0036503 ↓ DECREASED

Experimental models

Mutant SOD1 Derlin-1 and ERAD assays CELL LINE Mutant expression retards ERAD reporters.

Downstream

Endoplasmic Reticulum Stress Defective ERAD is proposed to accumulate improperly processed luminal substrates and activate the stress response. Reporter turnover and stress activation support this route, without isolating every retained endogenous substrate.

Show evidence (2 references)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"In contrast, overexpression of SOD1mut decreased the degradation of NHK to a half-life of >8 h"

The pulse-chase assay measures delayed ERAD reporter turnover.

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"Cycloheximide chase experiments showed that the degradation of CD3δ was also retarded by overexpression of SOD1mut"

A second ERAD substrate corroborates impaired degradation.

Endoplasmic Reticulum Stress

The tested mutant-SOD1 cell systems activate ER stress responses, including IRE1/PERK changes and XBP1 splicing. These stress readouts are distinct from motor neuron death: NSC34 cells showed signaling without detectable mutant-induced death under the reported conditions.

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED

Downstream

IRE1-TRAF2-ASK1 Complex Formation ER stress-associated IRE1 activation recruits the TRAF2/ASK1 complex in the tested cell system.

Show evidence (2 references)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"Derlin-1 siRNA exhibited no effect on the basal level of activation of IRE1"

Derlin-1 depletion did not simply induce or abolish every ER stress response.

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"SOD1mut-induced activation of IRE1 and ASK1 was clearly inhibited by Derlin-1 depletion"

The depletion experiment supports the mutant-associated stress pathway.

IRE1-TRAF2-ASK1 Complex Formation

In mutant-SOD1-expressing NSC34 cells, coimmunoprecipitation supports recruitment of ASK1 to IRE1 in the presence of TRAF2. This records the signaling assembly separately from kinase activation.

Downstream

ASK1 Kinase Activation IRE1/TRAF2-associated assembly is the experimentally supported route to ASK1 activation; complex formation and kinase activity were assayed separately.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut"

The experiment resolves the dependence of the measured association on TRAF2 and mutant SOD1.

ASK1 Kinase Activation

Mutant SOD1 activates ASK1 in a kinase assay. Genetic ASK1 deletion and a Derlin-1-derived competing peptide partially protect embryonic spinal-cord neurons; ASK1 deletion also mitigates neuron loss and delays terminal disease in transgenic mice. Downstream p38 and caspase routes are candidates rather than directly established effectors in this study.

Experimental models

Mutant SOD1 Derlin-1 and ERAD assays CELL LINE Mutant expression activates an ASK1 kinase readout.

Animal models

ASK1-deficient SOD1 G93A mice Mouse perturbs Genetic removal tests the contribution of ASK1 to model progression.

Downstream

Motor Neuron Degeneration ASK1 contributes to neuronal injury through incompletely resolved downstream death pathways. Protection is partial and does not prevent onset in the tested mice.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1"

The kinase assay distinguishes activation from mere complex association.

Microglial Mutant SOD1 Contribution

Lineage-restricted lowering in a deletable-transgene mouse implicates microglial mutant SOD1 in later disease progression. It does not establish a specific human microglial toxic mediator or an invariant onset/progression division across SOD1 genotypes.

microglial cell CL:0000129

Animal models

Microglial and motor-neuron conditional SOD1 reduction Mouse perturbs Microglial reduction slows later progression.

Downstream

Motor Neuron Degeneration Lineage-restricted reduction slows model progression, supporting a non-cell-autonomous contribution; specific human toxic mediators remain unknown.

Show evidence (1 reference)

PMID:16741123 SUPPORT PRIMARY RESULT Model Organism

"Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression."

The lineage perturbation establishes a later progression contribution in this mouse model.

Astrocytic Mutant SOD1 Contribution

Reducing astrocytic mutant SOD1 in a conditional mouse delays microglial activation and later disease progression without changing onset in that experiment. The mediator linking astrocytes to neuronal injury remains unresolved.

astrocyte CL:0000127

Animal models

Astrocyte conditional SOD1 reduction Mouse perturbs Perturbs an astrocytic contribution to disease progression.

Downstream

Motor Neuron Degeneration Lineage-restricted reduction slows model progression, supporting a non-cell-autonomous contribution; specific human toxic mediators remain unknown.

Show evidence (1 reference)

PMID:18246065 SUPPORT PRIMARY RESULT Model Organism

"diminished mutant expression in astrocytes did not affect onset, but delayed microglial activation and sharply slowed later disease progression"

The abstract supports an astrocyte contribution, with source detail limited to the cached abstract.

P2X7-Associated SOD1 Release

High extracellular ATP induces rapid release of SOD1-containing particulate material from transfected murine NSC34 hybrid cells; AZ10606120 inhibits this response. This pharmacological experiment supports a P2X7-associated release process, with overexpression, millimolar ATP and non-primary neuronal lineage limits.

Experimental models

ATP-triggered SOD1 donor and recipient cultures CELL LINE Antagonist-sensitive release occurs after high ATP exposure.

Show evidence (1 reference)

PMID:35478453 SUPPORT PRIMARY RESULT In Vitro

"ATP induced the rapid release of aggregated SOD1G93A from NSC-34 cells transiently transfected with SOD1G93A, a process blocked by AZ10606120 and revealing a role for P2X7 in this process."

The experiment measures ATP-triggered release and antagonist sensitivity.

Seeded SOD1 Inclusion Pathology

Spinal-cord homogenates from paralysed transgenic donors accelerate paralysis and inclusion pathology in susceptible low-copy G93A or G85R:YFP mice. Homogenate inoculation supports experimentally transmissible disease activity without proving purified-SOD1 sufficiency, a particular cell-to-cell transport mechanism or necessity for human ALS spread.

Animal models

Low-copy SOD1 homogenate-seeding recipients Mouse partially recapitulates Homogenate inoculation accelerates inclusion-associated disease in susceptible hosts.

Downstream

Motor Neuron Degeneration Homogenate inoculation accelerates the disease endpoint in susceptible mice, with pathological inclusions. This does not isolate the lethal aggregate species or prove the same route in patients.

Show evidence (2 references)

PMID:41702846 SUPPORT PRIMARY RESULT Model Organism

"injected intrathecally with seeding homogenates containing misfolded G93A or G85R SOD1 developed accelerated motor neuron disease efficiently"

The recipient experiment demonstrates acceleration in susceptible transgenic lines.

PMID:41702846 SUPPORT PRIMARY RESULT Model Organism

"The general appearance of the pathological inclusions by ubiquitin immunostaining was similar among all of the paralysed animals"

Histology supports inclusion pathology in the affected recipients.

Motor Neuron Degeneration

Loss and dysfunction of upper and lower motor neurons produce the clinical motor syndrome. Human D90A autopsy tissue directly documents severe ventral-horn neuron loss and corticospinal degeneration. Multiple experimentally supported toxic routes may contribute, but no single aggregate species or stress pathway explains every patient.

spinal cord motor neuron CL:0011001 Betz upper motor neuron CL:4023052

Experimental models

Embryonic spinal-cord SOD1 toxicity and rescue cultures PRIMARY CELL CULTURE Tests partial rescue of cultured motor neuron loss.

Animal models

SOD1 G93A transgenic mouse Mouse partially recapitulates Reproduces progressive motor neuron loss with a defined mutant SOD1 transgene.

SOD1-null mouse Mouse fails to recapitulate Does not reproduce spontaneous ALS-like motor degeneration by the reported six-month assessment.

ASK1-deficient SOD1 G93A mice Mouse perturbs ASK1 deficiency mitigates the loss of spinal motor neurons.

Low-copy SOD1 homogenate-seeding recipients Mouse partially recapitulates The inoculated mice reach an accelerated motor disease endpoint.

Borsantrazole-treated SOD1 G37R mice Mouse perturbs The intervention modifies disease-related motor and terminal outcomes in one transgenic model.

SOD1 G93A motor-neuron multiomic atlas Mouse partially recapitulates Profiles molecular states associated with vulnerable motor neurons during model progression.

Downstream

Upper Motor Neuron Dysfunction Degeneration of upper motor pathways reduces descending motor control.

Progressive Muscle Denervation Loss of lower motor neurons removes motor innervation to their muscle fibers.

Show evidence (2 references)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"Upon microscopic investigation, all nine patients had severe loss of motor neurons in the ventral horn to the point of rarefaction of the tissue and the appearance of cavities."

Direct human pathology supports lower motor neuron loss in the selected D90A series.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Motor symptoms occur as the result of degeneration of both upper and lower motor neurons."

The clinical overview links motor-system pathology to the syndrome.

Upper Motor Neuron Dysfunction

Damage to corticospinal and corticobulbar motor control contributes to pyramidal signs and some bulbar manifestations. Upper and lower motor involvement vary by genotype and stage.

Downstream

Spasticity Impaired upper motor control produces this pyramidal sign; its presence varies by stage and phenotype.

Hyperreflexia Impaired upper motor control produces this pyramidal sign; its presence varies by stage and phenotype.

Extensor Plantar Response Impaired upper motor control produces this pyramidal sign; its presence varies by stage and phenotype.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"UMN signs in ALS include hyperreflexia, extensor plantar response, and increased muscle tone."

General ALS physiology identifies the consequences of upper motor neuron dysfunction.

Progressive Muscle Denervation

Loss of lower motor neuron output progressively denervates skeletal muscle. Weakness, wasting, cramps and fasciculations can result; the distribution varies among limb, bulbar and respiratory muscles. Fasciculations are not treated as proof that compensatory reinnervation itself causes the syndrome.

Downstream

Progressive Muscle Weakness Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.

Lower Limb Muscle Weakness Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.

Skeletal Muscle Atrophy Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.

Fasciculations Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.

Muscle Cramps Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.

Dysarthria Denervation affecting the relevant bulbar or respiratory muscles contributes to impaired function; bulbar symptoms may also involve upper motor pathways.

Dysphagia Denervation affecting the relevant bulbar or respiratory muscles contributes to impaired function; bulbar symptoms may also involve upper motor pathways.

Dysphonia Denervation affecting the relevant bulbar or respiratory muscles contributes to impaired function; bulbar symptoms may also involve upper motor pathways.

Respiratory Insufficiency Denervation affecting the relevant bulbar or respiratory muscles contributes to impaired function; bulbar symptoms may also involve upper motor pathways.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"LMNs, located in the brain stem and spinal cord, innervate striated muscle. LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations."

General ALS physiology connects lower motor neurons to their muscle manifestations.

Extra-Motor CNS Degeneration

In the selected D90A homozygous series, degeneration includes dorsal columns and circumscribed cortical areas. SOD1 inclusions coexist with these lesions, without an experiment establishing that visible inclusions cause them. These findings are genotype- and cohort-scoped.

Downstream

Somatic Sensory Dysfunction Dorsal-column injury is anatomically consistent with the vibration-sense deficits in the same series, although no intervention isolates the responsible lesion.

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns."

Direct pathology establishes involvement outside the motor pathways.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Digestive 1

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"Dysarthria preceded dysphagia and dysphonia."

The selected human D90A series directly documents progressive bulbar symptoms.

Genitourinary 1

Functional Abnormality of the Bladder HP:0000009

Show evidence (1 reference)

PMID:36385230 SUPPORT Human Clinical

"may also include sensory, autonomic, and urinary bladder involvement"

Reports bladder involvement as a recognised feature of the D90A homozygous phenotype.

Limbs 1

Lower Limb Muscle Weakness HP:0007340

Show evidence (2 references)

PMID:41511639 SUPPORT Human Clinical

"Most patients presented with a lower limb onset (67.6%) and a lower motor neuron phenotype."

Quantifies lower-limb onset as the predominant presentation in this cohort.

PMID:42265995 SUPPORT Human Clinical

"lower limb onset of weakness, lower motor neuron examination findings, and rapid progression over months to involve all body regions"

Independent report of the same onset pattern in juvenile-onset SOD1-ALS, showing it is not confined to one cohort or one allele.

Musculoskeletal 4

Progressive Muscle Weakness HP:0003323

Course: PROGRESSIVE

Sequelae: Respiratory Insufficiency

Show evidence (2 references)

PMID:42265995 SUPPORT Human Clinical

"rapid progression over months to involve all body regions"

Documents the generalisation this node describes. The cited cases are juvenile p.Asp125Gly, where progression is unusually rapid, so the quote establishes the pattern of spread rather than its typical rate.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination"

The full ALS overview supports clinical progression as a general ALS feature, applied here with SOD1-specific variation.

Skeletal Muscle Atrophy HP:0003202

Course: PROGRESSIVE

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations."

The ALS overview identifies this lower motor neuron manifestation; no SOD1-specific frequency is inferred.

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"the two patients with the most severe motor neuron cell loss and muscle wasting (patients #8–9)"

Direct human observations corroborate muscle wasting in the D90A cohort.

Spasticity HP:0001257

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"Upper motor neuron signs (primarily brisk deep-tendon reflexes, Hoffmann’s sign, Babinski’s sign, and spasticity) preceded lower motor neuron signs when a new region (leg, arm, trunk, or bulbar) became involved."

The D90A series directly observes the pyramidal signs; the temporal order is cohort-specific.

Muscle Cramps Muscle spasm HP:0003394

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"All patients described the onset of motor dysfunction as a sense of stiffness and complained of severe muscular cramps in the legs, unsteadiness or clumsiness, and general fatigue."

Direct clinical observations support cramps in this selected genotype-specific cohort.

Nervous System 7

Fasciculations HP:0002380

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations."

The ALS overview identifies this lower motor neuron manifestation; no SOD1-specific frequency is inferred.

PMID:41670738 SUPPORT PRIMARY RESULT Human Clinical

"The patient had difficulty standing on the tiptoes, and widespread fasciculations were present."

Direct patient examination supports fasciculations in SOD1 ALS.

Hyperreflexia HP:0001347

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

The D90A series directly observes the pyramidal signs; the temporal order is cohort-specific.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"Dysarthria preceded dysphagia and dysphonia."

The selected human D90A series directly documents progressive bulbar symptoms.

Somatic Sensory Dysfunction HP:0003474

Show evidence (2 references)

PMID:36385230 SUPPORT Human Clinical

"In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns."

Neuropathological substrate for the sensory involvement in this stratum.

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"Loss of sense of vibration, first at the ankles and later also in the hands, was observed early in all patients."

Clinical sensory examination complements the anatomical pathology in this selected series.

Gait Ataxia HP:0002066

Show evidence (2 references)

PMID:42614182 SUPPORT Human Clinical

"All patients presented with progressive gait ataxia as their initial and predominant symptom, with upper and lower motor neuron signs emerging months to years later and ultimately meeting criteria for ALS."

Case series documenting ataxia-onset SOD1-ALS in Asp91Ala carriers.

PMID:42614182 SUPPORT Human Clinical

"Diagnostic latencies from ataxia onset to recognition of ALS ranged from 3 to 9 years."

Quantifies the diagnostic delay that makes this presentation clinically consequential.

Extensor Plantar Response Babinski sign HP:0003487

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

The D90A cohort directly documents Babinski signs; timing is scoped to this series.

Emotional Lability HP:0000712

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"None of the patients showed overt signs of FTD, but five had prominent emotional lability in the later stages of the disease."

Documents a selected-cohort count without converting it to general ALS1 frequency.

Respiratory 1

Respiratory Insufficiency HP:0002093

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:40328546 SUPPORT REVIEW SYNTHESIS Human Clinical

"Respiratory involvement has been identified as a cardinal feature of amyotrophic lateral sclerosis (ALS) since its earliest descriptions in the 19th century."

Establishes respiratory involvement as a cardinal ALS feature; the terminal mechanism in this entry is denervation of the respiratory muscles.

Voice 1

Dysphonia HP:0001618

Show evidence (1 reference)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"Dysarthria preceded dysphagia and dysphonia."

Directly supports voice impairment in the reported cohort.

🧬

Genetic Associations

SOD1

Gene: SOD1 hgnc:11179 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:8446170 SUPPORT Human Clinical

"We identified 11 different SOD1 missense mutations in 13 different FALS families."

The original report establishing SOD1 as the ALS1 disease gene.

PMID:41661214 SUPPORT BACKGROUND Human Clinical

"Over 200 ALS-associated SOD1 variants induce varying disease progression rates"

Sources the variant count and the fact that allele identity modulates progression rate.

PMID:9029070 SUPPORT Human Clinical

"The presence of one mutation, A4V, correlated with shorter survival. G37R, G41D, and G93C mutations predicted longer survival."

The historical cohort associates particular variants with survival differences; the result is neither a universal ranking nor an individual prediction.

💊

Medical Actions

Tofersen

Action: Pharmacotherapy NCIT:C15986

Agent: tofersen NCIT:C166584

Platform: Antisense oligonucleotide RNase H knockdown Targeting: Unconjugated Chemistry: 2′-MOE

RNA target: SOD1 hgnc:11179 SOD1 mRNA

Tofersen is an intrathecal antisense oligonucleotide that promotes RNase H-mediated degradation of SOD1 mRNA and reduces SOD1 protein production. EAN guidance recommends it for progressive ALS caused by pathogenic SOD1 variants, with discussion of treatment burden and serious adverse events. US accelerated approval was based on reduced plasma NfL. In the 108-participant randomized VALOR phase, the 28-week primary clinical endpoint in the prespecified faster-progression subgroup (60 of 108 participants) was not met despite reduced CSF SOD1 and plasma NfL. The extension retained the original randomized early/delayed groups, but everyone could receive active drug after week 28; later comparisons therefore lack an untreated control. At week 148, earlier initiation was associated with numerically less decline, with imprecise survival estimates. Four uncontrolled Icelandic p.Gly94Ser cases provide additional clinical observations, not proof of universal stabilization. Myelitis/radiculitis, raised intracranial pressure with papilledema, and aseptic meningitis require specific safety discussion and evaluation.

Mechanism Target:

INHIBITS SOD1 Protein Supply — Reducing SOD1 mRNA lowers protein supply; this does not directly correct the variant or prove clearance of existing aggregates.

Show evidence (2 references)

PMID:36129998 SUPPORT Human Clinical

"Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo."

Demonstrates target engagement via a CSF surrogate, together with a fall in a neuroaxonal injury marker.

PMID:42406382 SUPPORT Human Clinical

"reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84%"

The abstract reports cross-sectional tissue reductions in three recently treated autopsy donors, not a within-person serial measurement or clearance of inclusions.

Show evidence (7 references)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"In patients with progressive ALS caused by pathogenic mutations in superoxide dismutase 1 (SOD1), offer tofersen as first‐line treatment."

The guideline supports treatment for progressive pathogenic-variant SOD1 ALS.

PMID:32640130 SUPPORT PRIMARY RESULT Human Clinical

"In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks."

First-in-human demonstration that intrathecal tofersen lowers CSF SOD1 in ALS1.

PMID:36129998 SUPPORT PRIMARY RESULT Human Clinical

"In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events."

The randomized phase found biomarker reductions without significant benefit on the primary clinical endpoint at 28 weeks; this limits efficacy claims without refuting target engagement or the treatment indication.

+ 4 more references

Riluzole

Action: Pharmacotherapy NCIT:C15986

Agent: riluzole CHEBI:8863

Platform: Small molecule

Riluzole is recommended as general ALS therapy from diagnosis, including SOD1-associated disease. Its modest survival evidence comes from broader ALS populations and does not establish a separate SOD1-specific effect. Tolerability and adverse effects should guide dose adjustment or discontinuation.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Offer lifelong riluzole to all people with ALS at diagnosis."

General ALS guidance supports use in ALS1 without implying a genotype-specific efficacy estimate.

Edaravone

Action: Pharmacotherapy NCIT:C15986

Agent: edaravone CHEBI:31530

Platform: Small molecule

Edaravone is an ALS therapy available in intravenous and oral formulations in the US. Its pivotal efficacy trial selected early-stage Japanese patients with preserved function and respiration; these trial criteria are not the full US labeled indication. EAN 2024 guidance recommends against routine use outside clinical trials, so clinical use depends on jurisdiction, evidence assessment and shared decisions. A distinct SOD1-specific benefit has not been established, and its therapeutic mechanism in patients remains unknown despite antioxidant activity.

Show evidence (3 references)

url:https://www.radicavahcp.com/pdfs/radicava-prescribing-information.pdf SUPPORT REVIEW SYNTHESIS Other

"RADICAVA and RADICAVA ORS are indicated for the treatment of amyotrophic lateral sclerosis (ALS)."

The US label does not restrict the indication to the pivotal trial subgroup.

url:https://www.radicavahcp.com/pdfs/radicava-prescribing-information.pdf SUPPORT REVIEW SYNTHESIS Other

"The mechanism by which RADICAVA and RADICAVA ORS exert their therapeutic effect in patients with ALS is unknown."

The label limits claims about the human therapeutic mechanism.

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Based on the available evidence, the panel currently does not recommend the use of intravenous or oral edaravone outside the context of a clinical trial."

The European guideline recommendation differs from US availability; this is not a claim that the drug is unapproved everywhere.

Multidisciplinary ALS Care

Coordinated specialist ALS care, generally reviewed every 3–6 months according to progression, integrates respiratory, nutritional, mobility, communication and psychosocial needs. This is general ALS guidance applied to ALS1.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Provide coordinated care for people with ALS using a clinic‐based, specialist ALS MDT approach."

The guideline supports coordinated ALS care rather than a SOD1-specific intervention trial.

Noninvasive Ventilation

Offer noninvasive ventilation when symptoms, signs or investigations support respiratory insufficiency, with efforts to accommodate bulbar dysfunction. Discuss invasive ventilation in advance according to preferences and clinical circumstances. Diaphragmatic pacing is not recommended.

Mechanism Target:

BYPASSES Respiratory Insufficiency — Ventilatory support compensates for respiratory impairment; it does not reverse motor neuron degeneration.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"NIV should be offered to all patients with ALS with either symptoms, signs, or laboratory investigations supportive of respiratory insufficiency."

Ventilatory support compensates for respiratory impairment; it does not reverse motor neuron degeneration.

Show evidence (2 references)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"NIV should be offered to all patients with ALS with either symptoms, signs, or laboratory investigations supportive of respiratory insufficiency."

Ventilatory support compensates for respiratory impairment; it does not reverse motor neuron degeneration.

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Do not use diaphragmatic pacing for the treatment of ALS."

The guideline distinguishes ventilatory support from ineffective diaphragm pacing.

Nutritional Support and Gastrostomy

Assess swallowing, nutrition and feeding effort and discuss gastrostomy early, revisiting the decision as disease progresses. In respiratory insufficiency, introduce NIV and perform gastrostomy with the patient established on NIV. Tube feeding supports nutritional delivery without restoring bulbar motor function.

Mechanism Target:

BYPASSES Dysphagia — Gastrostomy can bypass impaired oral swallowing to provide nutrition, with timing individualized.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Discuss gastrostomy at an early stage, and at regular intervals as ALS progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking, and risk of choking."

Gastrostomy can bypass impaired oral swallowing to provide nutrition, with timing individualized.

Show evidence (2 references)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

Gastrostomy can bypass impaired oral swallowing to provide nutrition, with timing individualized.

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"If there is respiratory insufficiency, perform the gastrostomy with the patient established on NIV."

Respiratory support is part of safe gastrostomy planning in people with respiratory impairment.

Cough Augmentation

Manual assisted cough or breath stacking can assist ineffective cough, with mechanical cough assistance considered when needed. This is a general ALS supportive intervention.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Offer cough augmentation techniques, such as manual assisted cough, to people with ALS who cannot cough effectively."

The guideline recommends augmenting an ineffective cough.

Communication Support

Speech-language assessment and augmentative or alternative communication equipment should be provided promptly, with adaptation as abilities change. Communication aids compensate for impaired speech rather than restoring the underlying motor neurons.

Mechanism Target:

BYPASSES Dysarthria — Communication equipment bypasses impaired speech production to support communication.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life."

Communication equipment bypasses impaired speech production to support communication.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life."

Communication equipment bypasses impaired speech production to support communication.

Rehabilitation and Mobility Support

Exercise, positioning and assistive or orthotic support are individualized to function, fatigue and preferences. Goals include joint mobility, comfort and participation; a SOD1-specific disease-modifying effect is not established.

Show evidence (2 references)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Choose a programme that is appropriate to the person's level of function and tailored to their needs, abilities, and preferences."

The guideline supports individualized physical rehabilitation rather than fixed-intensity exercise.

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"If a person needs orthoses to help with muscle problems, they should be referred to orthotics services without delay, and the orthoses should be provided without delay."

Orthoses support function when muscle weakness causes a need.

Spasticity Management

Physical therapy and, where appropriate, baclofen, tizanidine, gabapentin or other guideline-listed agents can relieve stiffness and spasticity. Choice depends on comorbidity, tolerability and functional consequences.

Mechanism Target:

INHIBITS Spasticity — These symptomatic treatments reduce spasticity without reversing the causal motor neuron disease.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Consider cannabinoids, baclofen, tizanidine, or gabapentin to treat muscle stiffness, spasticity, or increased tone."

These symptomatic treatments reduce spasticity without reversing the causal motor neuron disease.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Consider cannabinoids, baclofen, tizanidine, or gabapentin to treat muscle stiffness, spasticity, or increased tone."

These symptomatic treatments reduce spasticity without reversing the causal motor neuron disease.

Muscle Cramp Management

Symptomatic treatment of troublesome cramps may include agents such as mexiletine or baclofen, selected with attention to comorbidities and adverse effects. Cardiac risk requires particular consideration for relevant drugs.

Mechanism Target:

INHIBITS Muscle Cramps — The general ALS guideline supports symptomatic cramp treatment.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Consider sodium blockers (ranolazine, quinine sulfate, mexiletine, carbamazepine), gabapentine, pregabalin, and baclofen for the management of cramps as symptomatic treatment."

The general ALS guideline supports symptomatic cramp treatment.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Consider sodium blockers (ranolazine, quinine sulfate, mexiletine, carbamazepine), gabapentine, pregabalin, and baclofen for the management of cramps as symptomatic treatment."

The general ALS guideline supports symptomatic cramp treatment.

Emotional Lability Management

Emotional lability should be distinguished from depression or frontotemporal cognitive/behavioral symptoms. SSRIs, tricyclic antidepressants or dextromethorphan/quinidine may be considered according to comorbidity and tolerability.

Mechanism Target:

INHIBITS Emotional Lability — General ALS recommendations support symptom reduction for emotional lability.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Consider selective serotonin reuptake inhibitor (SSRI) antidepressants, tricyclic antidepressants, or DMQ for treating emotional lability in people with ALS."

General ALS recommendations support symptom reduction for emotional lability.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Consider selective serotonin reuptake inhibitor (SSRI) antidepressants, tricyclic antidepressants, or DMQ for treating emotional lability in people with ALS."

General ALS recommendations support symptom reduction for emotional lability.

Saliva and Secretion Management

If troublesome sialorrhea develops, consider anticholinergic treatment with attention to adverse effects and coexisting bulbar problems; refractory severe symptoms may warrant specialist botulinum toxin. This care indication does not establish a disease-wide frequency of sialorrhea in SOD1 ALS.

Show evidence (1 reference)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Consider anticholinergics (e.g., amitriptyline, atropine, glycopyrrolate, oxybutynin, scopolamine) as first‐line treatment."

The recommendation applies to the guideline section on symptomatic sialorrhea management.

Psychological and Palliative Support

Offer psychological support, caregiver support and individualized advance care planning throughout the disease course. Discuss ventilation, feeding and end-of-life preferences at a time and in a manner appropriate to the individual.

Show evidence (2 references)

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Offer the person and their family/carers information about sources of emotional and psychological support, including support groups and online forums, and respite care."

The guideline supports psychosocial care for patients and carers.

PMID:38470068 SUPPORT REVIEW SYNTHESIS Human Clinical

"Be prepared to discuss end‐of‐life issues whenever people wish to do so"

The guideline supports ongoing access to preference-sensitive end-of-life discussion.

Genetic Counseling and Predictive Testing

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Genetic counseling addresses variant-specific inheritance, age-dependent penetrance, reproductive options, implications for relatives and the psychosocial consequences of predictive testing. Testing an unaffected relative requires informed counseling; a positive result does not predict an individual onset date. ATLAS is evaluating biomarker-triggered presymptomatic therapy in a selected carrier group, rather than establishing routine presymptomatic treatment.

Show evidence (2 references)

PMID:35585374 SUPPORT BACKGROUND Human Clinical

"During screening for enrollment in Part A of the study, genetic counseling sessions are required before a DNA sample is collected for testing and at the time that the results are communicated."

The ATLAS protocol illustrates pre- and post-test counseling rather than a demonstrated preventive treatment benefit.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Potential consequences of such testing (including, but not limited to, socioeconomic changes, the need for long-term follow up and evaluation arrangements for individuals with a positive test result)"

The counseling section explicitly includes these possible consequences of predictive testing.

🔬

Biochemical Markers

Neurofilament light chain (INCREASED)

Pathograph Readouts

Readout Of Motor Neuron Degeneration Positive Monitoring

Higher NfL can reflect neuroaxonal injury and has prognostic and pharmacodynamic use. It is not disease-specific and does not by itself establish neuronal rescue or determine when an individual carrier will develop ALS.

Show evidence (2 references)

PMID:42698373 SUPPORT Human Clinical

"NEFL was the most robust biomarker in plasma and CSF"

Ranks NfL first among 363 profiled proteins across case status, risk, survival and functional decline. The cohort is ALS broadly (198 patients), not SOD1-specific.

PMID:36129998 SUPPORT Human Clinical

"Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo."

The SOD1-specific NfL result, and the biomarker change that carried the accelerated approval.

Show evidence (1 reference)

PMID:35585374 SUPPORT BACKGROUND Human Clinical

"an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease"

The ATLAS design paper summarizes prior presymptomatic natural-history observations, chiefly in rapidly progressing variants; this is not a universal carrier prediction rule.

Disease-associated motor neuron transcriptional signature

Show evidence (2 references)

PMID:42335888 SUPPORT PRIMARY RESULT Human Clinical

"Using models that accounted for sample identity, we found a statistically significant increase in average DM score in pan-ALS versus control (Figure 7E) and in SOD1 versus control (Figure S11C)."

Sample-aware human analysis supports the signature in the SOD1 subgroup.

PMID:42335888 SUPPORT PRIMARY RESULT Human Clinical

"only 150 bona fide alpha motor neurons (excluding cluster 11) passed quality control across all conditions"

The low number of surviving nuclei limits the human comparison.

🔬

Diagnosis

Clinical and electrodiagnostic diagnosis of ALS

Diagnosis integrates progressive motor impairment, clinical upper/lower motor neuron findings, electromyography when appropriate, and exclusion of alternative causes. Gold Coast criteria permit UMN and LMN involvement in one region or LMN involvement in at least two. In five general suspected-ALS cohorts (3007 participants), pooled sensitivity was 0.96 and specificity 0.68, with very low certainty for specificity; these are not SOD1-specific test characteristics.

electromyography NCIT:C38056

Show evidence (4 references)

PMID:42618698 SUPPORT PRIMARY RESULT Human Clinical

"GCC demonstrated higher sensitivity than rEEC and Awaji criteria: 0.96 (95% confidence interval [CI] 0.93-0.98) versus 0.87 (95% CI 0.78-0.92) and 0.87 (95% CI 0.78-0.93), respectively."

Individual-participant meta-analysis quantifying the sensitivity advantage of the Gold Coast criteria.

PMID:42618698 SUPPORT PRIMARY RESULT Human Clinical

"Specificity was imprecise and heterogeneous, supporting use with mimic exclusion and longitudinal reassessment."

Supports this node's claim as stated, which already says the criteria buy sensitivity at the cost of specificity and are therefore applied with mimic exclusion and longitudinal reassessment. It is a caveat the claim absorbs, not a contradiction of it, so it is graded SUPPORT rather than REFUTE.

PMID:42618698 SUPPORT BACKGROUND Human Clinical

"Upper and lower motor neuron dysfunction in at least one body region, with both present in the same region when only one region is involved; or lower motor neuron dysfunction in at least two body regions"

The reproduced Gold Coast definition specifies the regional motor-neuron requirement.

+ 1 more reference

Exclusion of structural and treatable mimics

Investigations should exclude structural and treatable mimics based on the clinical presentation. Cervical myelopathy may resemble or coexist with ALS; an MRI lesion must account for the distribution and progression of findings. EMG/NCS distribution, clinical examination and follow-up are complementary. The narrative review does not establish a frequency ranking of mimics.

cervical spine magnetic resonance imaging NCIT:C16809

Show evidence (2 references)

PMID:42625715 SUPPORT REVIEW SYNTHESIS Human Clinical

"MRI is indispensable but not self-interpreting, EMG/NCS is most useful when interpreted by distribution rather than positivity alone"

The narrative review supports distribution-based interpretation and exclusion of a clinically relevant structural mimic; it is not a new diagnostic-accuracy cohort.

PMID:42625715 SUPPORT REVIEW SYNTHESIS Human Clinical

"both may present with upper-limb weakness, hand wasting, hyperreflexia, gait disturbance, and cervical MRI abnormalities"

The narrative review supports distribution-based interpretation and exclusion of a clinically relevant structural mimic; it is not a new diagnostic-accuracy cohort.

SOD1 genetic testing

Molecular testing identifies an ALS-causing SOD1 variant in a person with a compatible motor neuron syndrome. Testing may be part of an ALS multigene panel, with variant classification and inheritance interpreted in context. A variant of uncertain significance alone does not establish ALS1. A pathogenic result informs counseling and eligibility for SOD1-directed therapy; presymptomatic testing is a separate counseling decision.

SOD1 genetic testing NCIT:C15709

Show evidence (2 references)

PMID:41661214 SUPPORT BACKGROUND Human Clinical

"Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene."

The therapeutic indication makes identification of the causal SOD1 variant clinically relevant; it does not make every detected variant diagnostic.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT REVIEW SYNTHESIS Human Clinical

"A three-generation family history should be obtained, with attention paid to relatives with neurologic signs and symptoms, particularly cognitive impairment,"

The overview supports a structured family history alongside molecular evaluation.

📈

Progression

Variable onset and progression

SOD1 ALS ranges from rare juvenile rapidly progressive cases to adult-onset disease lasting decades. In the selected nine-person D90A homozygous autopsy series, onset ranged from 38 to 60 years and symptomatic duration from 5 to 33 years. Variant, family, treatment and ascertainment affect course; these are not universal age or survival bounds.

Show evidence (2 references)

PMID:36385230 SUPPORT PRIMARY RESULT Human Clinical

"Patient age at onset of first symptom ranged from 38 to 60 years (mean 49 years) and duration of symptomatic illness ranged from 5 to 33 years (mean 17 years)."

The autopsy series defines its own selected genotype-specific course.

PMID:42265995 SUPPORT Human Clinical

"rapid progression over months to involve all body regions"

📊

Related Datasets

RNA Expression Profiling in Lymphoblastoid Cell Lines from Mutated and Non-Mutated Amyotrophic Lateral Sclerosis Patients geo:GSE271030

RNA-seq of patient-derived lymphoblastoid cell lines in which SOD1-mutated patients are one of four genotype subgroups (alongside FUS, TARDBP and C9ORF72) compared with sporadic ALS and matched controls. Included because the study stratifies by causal gene and so contains an ALS1 arm; it is not a SOD1-only dataset, and the authors report that expression profiles were genotype-specific, which is what makes the SOD1 arm separable rather than pooled.

human BULK RNA SEQ

PMID:38967638

Patient-derived lymphoblastoid lines provide a non-neuronal genotype-stratified transcriptomic resource. Expression differences do not by themselves establish motor-neuron causal pathways.

Show evidence (2 references)

GEO:GSE271030 SUPPORT In Vitro

"a transcriptomic profiling of Sporadic ALS (SALS) and mutated patients (FUS, TARDBP, C9ORF72 and SOD1), and matched controls was realized"

The repository record states that SOD1-mutated patients are one of the profiled genotype subgroups, which is what makes this dataset relevant to ALS1.

GEO:GSE271030 SUPPORT In Vitro

"Gene expression profiles of LCLs were genetic-background specific, indeed only 12 genes were commonly deregulated in all groups."

Reports that expression profiles differed by genetic background, with almost no shared deregulated genes. This is what makes the SOD1 arm worth analysing separately rather than pooling it into a generic ALS signature; it is not itself a SOD1-specific result.

An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS [scRNA-Seq] geo:GSE306676

Stage-stratified single-nucleus RNA sequencing of spinal motor-neuron populations in SOD1 G93A mice and controls.

mouse SINGLE CELL RNA SEQ

PMID:42335888

Cross-sectional stage samples and inferred molecular trajectories do not constitute same-cell lineage tracing or establish the DM signature as a cause of death.

Show evidence (1 reference)

PMID:42335888 SUPPORT PRIMARY RESULT Model Organism

"Raw and processed sequencing data have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession numbers GEO: GSE306676 for the snRNA-seq data and GEO: GSE306675 for the multiome (paired snATAC/snRNA-seq) data."

The primary publication identifies the deposited assay and accession.

An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS [multiome] geo:GSE306675

Paired single-nucleus ATAC and RNA sequencing of SOD1 G93A mouse spinal tissue across disease stages.

mouse MULTI OMICS

PMID:42335888

Cross-sectional stage samples and inferred molecular trajectories do not constitute same-cell lineage tracing or establish the DM signature as a cause of death.

Show evidence (1 reference)

PMID:42335888 SUPPORT PRIMARY RESULT Model Organism

The primary publication identifies the deposited assay and accession.

🔬

Clinical Trials

NCT02623699 PHASE_III COMPLETED

The phase III VALOR component of a multipart tofersen study randomized 108 symptomatic adults. The primary 28-week clinical endpoint in the 60-participant faster-progression subgroup was not met, while CSF SOD1 and plasma NfL fell. Its linked extension is recorded separately as NCT03070119.

Show evidence (1 reference)

clinicaltrials:NCT02623699 SUPPORT Other

"The primary objective of Part C of this study is to evaluate the clinical efficacy of tofersen administered to adults with ALS and a confirmed SOD1 mutation."

Registry record establishing the trial that supports SOD1-directed therapy in this entry.

NCT04856982 PHASE_III ACTIVE_NOT_RECRUITING

ATLAS evaluates tofersen initiated before clinical onset in selected adult SOD1-variant carriers with elevated neurofilament. The registry remained active, not recruiting, on 2026-09-21. Preventive efficacy is unresolved; the published protocol is not an outcome report.

Show evidence (1 reference)

clinicaltrials:NCT04856982 SUPPORT Other

"The primary objective of this study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF)."

Registry record for the presymptomatic-initiation trial referenced in the genetic counseling treatment entry.

NCT03070119 PHASE_III COMPLETED

Open-label extension of prior tofersen studies. The long-term VALOR comparison retained initial randomized early/delayed assignment, although both groups could receive active drug after crossover. The registry covers a broader extension population than the 95 VALOR participants entering its extension.

Show evidence (1 reference)

clinicaltrials:NCT03070119 SUPPORT BACKGROUND Other

"The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 (tofersen) in participants with amyotrophic lateral sclerosis (ALS) and confirmed superoxide dismutase 1 (SOD1) mutation."

The registry identifies the extension scope.

🧫

Experimental Models

Mutant SOD1 Derlin-1 and ERAD assays CELL_LINE

NSC34 and HEK293 systems express tested SOD1 mutants and ERAD components. Interaction assays, NHK/CD3delta turnover, ubiquitination, stress signaling and ASK1 kinase activity interrogate separate steps.

Pathograph links

Impaired ER-Associated Protein Degradation partially recapitulates observes: cellular Mutant expression retards ERAD reporters.

Limitations: Overexpression and model substrates may not quantify the corresponding endogenous human-neuron burden. Direct binding is not proven in the reticulocyte-lysate assay; measured core-complex associations remain intact.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"Cycloheximide chase experiments showed that the degradation of CD3δ was also retarded by overexpression of SOD1mut"

Transfected-cell assays measure slower ERAD substrate turnover.

ASK1 Kinase Activation partially recapitulates observes: molecular Mutant expression activates an ASK1 kinase readout.

Limitations: NSC34 stress signaling did not itself result in the motor neuron death measured in the separate primary-culture preparation.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1"

Direct kinase activity is measured.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"Cycloheximide chase experiments showed that the degradation of CD3δ was also retarded by overexpression of SOD1mut"

Transfected-cell assays measure slower ERAD substrate turnover.

Embryonic spinal-cord SOD1 toxicity and rescue cultures PRIMARY_CELL_CULTURE

Mixed E12.5 mouse spinal-cord cultures express G93A or G85R SOD1; the Derlin-1 CT4 peptide or ASK1 deficiency partially preserves SMI32-positive motor neurons.

Pathograph links

Motor Neuron Degeneration perturbs observes: cellular Tests partial rescue of cultured motor neuron loss.

Limitations: Mixed neurons and glia do not isolate a purely neuron-autonomous effect; lentiviral overexpression and embryonic cells differ from adult human ALS. Rescue is incomplete.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"SOD1mut-induced motor neuron death was significantly attenuated by coexpression of Derlin-1(CT4)"

The competing peptide partly protects neurons in embryonic spinal cultures.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT In Vitro

"SOD1mut-induced motor neuron death was significantly attenuated by coexpression of Derlin-1(CT4)"

The competing peptide partly protects neurons in embryonic spinal cultures.

ATP-triggered SOD1 donor and recipient cultures CELL_LINE

Transfected NSC34 cells exposed to 3–5 mM ATP release particulate material. Recipient NSC34 cells and EOC13 microglia show ER stress reporter activity and TNF release respectively.

Pathograph links

P2X7-Associated SOD1 Release partially recapitulates observes: cellular Antagonist-sensitive release occurs after high ATP exposure.

Limitations: NSC34 is a murine hybrid line, not a primary human motor neuron. A single antagonist without receptor knockout supports pharmacological involvement; low LDH only limits overt lysis under the tested conditions.

Show evidence (1 reference)

PMID:35478453 SUPPORT PRIMARY RESULT In Vitro

"ATP induced the rapid release of aggregated SOD1G93A from NSC-34 cells transiently transfected with SOD1G93A, a process blocked by AZ10606120 and revealing a role for P2X7 in this process."

The donor-cell assay tests release after an acute ATP challenge.

Released 20000-g pellets contain mixed material. EGFP control preparations can also provoke responses, so purified SOD1 necessity and recipient death are not demonstrated. Release includes tested wild-type SOD1. The CELL_LINE classification reflects separate donor and recipient cell-line assays with transfer of released material, rather than an assumption of direct mixed-cell coculture.

Show evidence (1 reference)

PMID:35478453 SUPPORT PRIMARY RESULT In Vitro

"ATP induced the rapid release of aggregated SOD1G93A from NSC-34 cells transiently transfected with SOD1G93A, a process blocked by AZ10606120 and revealing a role for P2X7 in this process."

The donor-cell assay tests release after an acute ATP challenge.

WTC11 motor-neuron transcription-factor perturbation IPSC_DERIVED_MODEL

Lentiviral CREB3 or ATF3 overexpression in WTC11 hNIL motor neurons induces portions of the disease-associated transcriptional signature. RNA is assessed 14 days after transduction.

These are engineered non-patient cells. No SOD1 variant, neuron-death endpoint, functional rescue or validated therapeutic mechanism is tested. The model is left without a degeneration join because changing an associated program does not establish that the program causes cell death.

Show evidence (2 references)

PMID:42335888 SUPPORT PRIMARY RESULT In Vitro

"CREB3 expression was associated with upregulation of approximately 20% of DM-upregulated genes (precision ~15%), while ATF3 expression was associated with downregulation of approximately 5% of DM-downregulated genes (precision ~34%)."

Forced transcription-factor expression partially reproduces the associated gene-expression program.

PMID:42335888 SUPPORT PRIMARY RESULT In Vitro

"For each condition, three independent wells were transduced and processed as technical replicates."

The replicate unit is a technical well, not an independent patient.

🐁

Animal Models

SOD1 G93A transgenic mouse

High-level expression of the G93A variant, which has little effect on enzyme activity, causes progressive paralysis and spinal motor neuron loss.

Species

Mouse

Genotype

High-expression human SOD1 G93A transgene

Publication

PMID:8209258

Pathograph links

Motor Neuron Degeneration partially recapitulates observes: organism Reproduces progressive motor neuron loss with a defined mutant SOD1 transgene.

Limitations: Supraphysiological transgene dosage differs from endogenous human alleles. Prior poor response of high-copy lines to homogenate seeding has no definitive explanation and does not refute their motor degeneration.

Show evidence (1 reference)

PMID:8209258 SUPPORT PRIMARY RESULT Model Organism

"The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age."

The original report documents spinal motor neuron loss and paralysis.

Show evidence (1 reference)

PMID:8209258 SUPPORT PRIMARY RESULT Model Organism

"The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age."

The original report documents spinal motor neuron loss and paralysis.

SOD1-null mouse

Complete SOD1 deficiency did not produce overt motor deficits by six months, but increased motor neuron vulnerability after axonal injury. This tests simple absence of the enzyme rather than every possible loss-of-function contribution to ALS.

Species

Mouse

Genotype

Homozygous Sod1 knockout

Publication

PMID:8673102

Pathograph links

Motor Neuron Degeneration fails to recapitulate observes: organism Does not reproduce spontaneous ALS-like motor degeneration by the reported six-month assessment.

Limitations: The observation period and injury dependence preclude an absolute lifetime or stress-independent negative claim. ALS1 includes several inheritance contexts, not only heterozygous missense alleles.

Show evidence (1 reference)

PMID:8673102 SUPPORT PRIMARY RESULT Model Organism

"These animals develop normally and show no overt motor deficits by 6 months in age."

The negative result is limited to the described development and observation period.

Show evidence (2 references)

PMID:8673102 SUPPORT PRIMARY RESULT Model Organism

"These animals develop normally and show no overt motor deficits by 6 months in age."

The negative result is limited to the described development and observation period.

PMID:8673102 SUPPORT PRIMARY RESULT Model Organism

"These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury."

The injury result demonstrates a physiological protective role.

Microglial and motor-neuron conditional SOD1 reduction

Lineage-directed reduction separates motor-neuron contributions to onset/early progression from a microglial contribution to later progression in the tested transgenic model.

Species

Mouse

Genotype

Deletable mutant human SOD1 transgene with lineage-restricted excision

Publication

PMID:16741123

Pathograph links

Microglial Mutant SOD1 Contribution perturbs observes: organism Microglial reduction slows later progression.

Limitations: The cached source is abstract-only; exact Cre specificity and quantitative excision details are not imported. The phase division is not assumed universal in human ALS.

Show evidence (1 reference)

PMID:16741123 SUPPORT PRIMARY RESULT Model Organism

"Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression."

The conditional model distinguishes the microglial progression contribution.

Show evidence (1 reference)

PMID:16741123 SUPPORT PRIMARY RESULT Model Organism

"Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression."

The conditional model distinguishes the microglial progression contribution.

Astrocyte conditional SOD1 reduction

Reduced astrocytic mutant expression delays microglial activation and later disease progression in the reported mouse study.

Species

Mouse

Genotype

Deletable mutant human SOD1 transgene with astrocytic reduction

Publication

PMID:18246065

Pathograph links

Astrocytic Mutant SOD1 Contribution perturbs observes: organism Perturbs an astrocytic contribution to disease progression.

Limitations: The cached abstract does not resolve the secreted or contact-dependent mediator. Delayed microglial activation alone does not prove that microglia completely mediate the benefit.

Show evidence (1 reference)

PMID:18246065 SUPPORT PRIMARY RESULT Model Organism

"diminished mutant expression in astrocytes did not affect onset, but delayed microglial activation and sharply slowed later disease progression"

Astrocytic reduction modifies the measured progression and activation outcomes.

Show evidence (1 reference)

PMID:18246065 SUPPORT PRIMARY RESULT Model Organism

"diminished mutant expression in astrocytes did not affect onset, but delayed microglial activation and sharply slowed later disease progression"

Astrocytic reduction modifies the measured progression and activation outcomes.

ASK1-deficient SOD1 G93A mice

In male low-copy G1L mice, ASK1 deletion extends survival and partly preserves spinal motor neurons without delaying motor onset; a high-copy comparison also shows a survival extension without onset change.

Species

Mouse

Genotype

SOD1 G93A transgene crossed with Ask1-null mice

Publication

PMID:18519638

Pathograph links

ASK1 Kinase Activation perturbs observes: organism Genetic removal tests the contribution of ASK1 to model progression.

Limitations: Protection is partial, sex and transgene context are restricted, and a constitutive knockout is not a clinical drug intervention. The study does not establish aggregate-independent protection.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT Model Organism

"the mean survival of SOD1G93A/ASK1−/− mice was 38.4 ± 2.7 wk (±SEM) and significantly longer than the 34.9 ± 1.6 wk survival of control SOD1G93A mice"

ASK1 deletion delays the terminal endpoint in the male low-copy model.

Motor Neuron Degeneration perturbs observes: organism ASK1 deficiency mitigates the loss of spinal motor neurons.

Limitations: The result does not identify every downstream death effector or imply prevention of ALS onset.

Show evidence (1 reference)

PMID:18519638 SUPPORT PRIMARY RESULT Model Organism

"These findings indicated that the absence of ASK1 mitigates motor neuron death in ALS mice."

Direct histology complements the survival endpoint.

Show evidence (2 references)

PMID:18519638 SUPPORT PRIMARY RESULT Model Organism

"the mean survival of SOD1G93A/ASK1−/− mice was 38.4 ± 2.7 wk (±SEM) and significantly longer than the 34.9 ± 1.6 wk survival of control SOD1G93A mice"

ASK1 deletion delays the terminal endpoint in the male low-copy model.

PMID:18519638 SUPPORT PRIMARY RESULT Model Organism

"ASK1 deficiency also extended the survival of SOD1G93A(high) mice but not the time of onset"

The onset/progression distinction is preserved in the reported additional model.

Low-copy SOD1 homogenate-seeding recipients

Adult intrathecal inoculation uses 4 microliters containing 2 microliters of 10% spinal-cord homogenate and lidocaine. Donors, recipient genotypes, ages and passage histories vary across comparisons. Paralysis leading to humane euthanasia is the primary endpoint.

Species

Mouse

Genotype

VLE G93A on B6SJL and homozygous G85R:YFP Line 230 on FVB/NJ

Publication

PMID:41702846

Pathograph links

Seeded SOD1 Inclusion Pathology partially recapitulates observes: organism Homogenate inoculation accelerates inclusion-associated disease in susceptible hosts.

Limitations: Inocula are not purified or seed-titer normalized. Age, route, batch and passage vary together; long incubation overlaps spontaneous disease in some older animals. Conditional incubation analyses exclude asymptomatic animals. An internal six-versus-five denominator discrepancy prevents a universal seeding-rate estimate.

Show evidence (1 reference)

PMID:41702846 SUPPORT PRIMARY RESULT Model Organism

"injected intrathecally with seeding homogenates containing misfolded G93A or G85R SOD1 developed accelerated motor neuron disease efficiently"

The study tests disease induction in susceptible transgenic recipients.

Motor Neuron Degeneration partially recapitulates observes: organism The inoculated mice reach an accelerated motor disease endpoint.

Limitations: The experiment does not prove necessity of cell-to-cell propagation in human ALS or isolate which aggregate species kills neurons.

Show evidence (1 reference)

PMID:41702846 SUPPORT PRIMARY RESULT Model Organism

"injected intrathecally with seeding homogenates containing misfolded G93A or G85R SOD1 developed accelerated motor neuron disease efficiently"

The study tests disease induction in susceptible transgenic recipients.

Show evidence (2 references)

PMID:41702846 SUPPORT PRIMARY RESULT Model Organism

"injected intrathecally with seeding homogenates containing misfolded G93A or G85R SOD1 developed accelerated motor neuron disease efficiently"

The study tests disease induction in susceptible transgenic recipients.

PMID:41702846 SUPPORT PRIMARY RESULT Model Organism

"The primary humane endpoint for all injections was overt paralysis of at least one hindlimb."

Defines the operational endpoint rather than spontaneous death.

SOD1 G85R with wild-type or D90A coexpression

Both double-transgenic lines have earlier onset and shorter endpoint survival than G85R alone. Wild-type coexpression aggravates the phenotype more than D90A; D90A also prolongs onset-to-endpoint duration. Insoluble pools contain both expressed proteins and show strain-A epitope profiles.

Species

Mouse

Genotype

G85R/WT or G85R/D90A double transgenes on C57BL/6J

Publication

PMID:40450581

Pathograph links

Cytoplasmic SOD1 Aggregate Formation perturbs observes: organism Coexpression modifies aggregate accumulation and disease kinetics.

Limitations: WT expression is about 2.5-fold higher than D90A, confounding a purely sequence-based comparison. Coaccumulation does not directly demonstrate hybrid-fibril nucleation. No WT/D90A human heterozygous genotype was tested, so human recessivity remains a proposed explanation.

Show evidence (2 references)

PMID:40450581 SUPPORT PRIMARY RESULT Model Organism

"In both cases, the lifespans of the combined Tg mice were shortened, but the effect of coexpression of hSOD1WT was far greater than that of hSOD1D90A"

Both coexpression combinations aggravate the endpoint relative to G85R alone; D90A is less aggravating, not protective.

+ 1 more reference

Show evidence (1 reference)

PMID:40450581 SUPPORT PRIMARY RESULT Model Organism

"In both cases, the lifespans of the combined Tg mice were shortened, but the effect of coexpression of hSOD1WT was far greater than that of hSOD1D90A"

Both coexpression combinations aggravate the endpoint relative to G85R alone; D90A is less aggravating, not protective.

Borsantrazole-treated SOD1 G37R mice

Presymptomatic daily intraperitoneal borsantrazole, 10 mg/kg from day 90, was compared with vehicle in 12 mice per group, six of each sex. The study reports delayed onset, less weight loss and a longer humane-endpoint survival. Borsantrazole remains an experimental compound.

Species

Mouse

Genotype

High-copy SOD1 G37R line 42

Publication

PMID:42503607

Pathograph links

Motor Neuron Degeneration perturbs observes: organism The intervention modifies disease-related motor and terminal outcomes in one transgenic model.

Limitations: There is no human efficacy result or in vivo edaravone comparator. Small sex subgroups do not establish a treatment-by-sex interaction. End-stage male spinal proteomics is exploratory and does not prove antioxidant, NRF2 or autophagy mediation; limited mouse safety assays do not establish clinical safety.

Show evidence (1 reference)

PMID:42503607 SUPPORT PRIMARY RESULT Model Organism

"the mean age of survival differed significantly between the vehicle‐treated (177.9 days) and the BSZ‐treated group (193 days)."

The primary model reports a 15.1-day difference in mean terminal age.

Show evidence (1 reference)

PMID:42503607 SUPPORT PRIMARY RESULT Model Organism

"the mean age of survival differed significantly between the vehicle‐treated (177.9 days) and the BSZ‐treated group (193 days)."

The primary model reports a 15.1-day difference in mean terminal age.

SOD1 G93A motor-neuron multiomic atlas

Single-nucleus and spatial analyses identify a disease-associated alpha-motor-neuron transcriptional state across separately sampled disease stages. Human postmortem data include 12 SOD1 ALS donors and support related signature changes.

Species

Mouse

Genotype

High-copy SOD1 G93A transgene

Publication

PMID:42335888

Pathograph links

Motor Neuron Degeneration partially recapitulates observes: organism Profiles molecular states associated with vulnerable motor neurons during model progression.

Limitations: Pseudotime and cross-stage sampling do not trace individual neurons to death. The DM program includes potentially protective responses and is not an established causal intermediate or survival predictor. Human analysis retains only 150 bona fide alpha nuclei across all conditions, with neuronal fragments as a separate assay.

Show evidence (1 reference)

PMID:42335888 SUPPORT PRIMARY RESULT Model Organism

"mid-stage (~P100), end-stage (~P125), and age-matched, non-transgenic control mice"

Defines a cross-sectional stage series rather than repeated sampling of the same neurons.

Show evidence (1 reference)

PMID:42335888 SUPPORT PRIMARY RESULT Model Organism

"mid-stage (~P100), end-stage (~P125), and age-matched, non-transgenic control mice"

Defines a cross-sectional stage series rather than repeated sampling of the same neurons.

{ }

Source YAML

click to show

name: Amyotrophic Lateral Sclerosis Type 1
creation_date: '2026-09-05T00:00:00Z'
category: Mendelian
description: Amyotrophic lateral sclerosis type 1 (ALS1) is motor neuron disease caused by pathogenic SOD1 variants. Most families show autosomal dominant inheritance, while p.Asp91Ala (legacy D90A) can segregate recessively or dominantly in different populations. Age at onset, penetrance and progression vary substantially by variant and family. Progressive upper and lower motor neuron dysfunction produces limb, bulbar and respiratory impairment; selected SOD1 genotypes also have sensory, autonomic or cerebellar findings. Experimental and human pathological evidence supports toxic properties of abnormal SOD1 rather than a universal loss of dismutase activity, but the relative contributions of protein aggregation, cellular stress and non-neuronal toxicity remain unresolved in patients. SOD1-associated inclusions usually differ from the predominant TDP-43 pathology of other ALS forms, with rare reported exceptions. Care combines SOD1-lowering tofersen where indicated with general ALS disease-modifying and supportive management.
disease_term:
  preferred_term: amyotrophic lateral sclerosis type 1
  term:
    id: MONDO:0007103
    label: amyotrophic lateral sclerosis type 1
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:8446170
      reference_title: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord.
      explanation: Places the disease in the nervous system, supporting the neurologic chapter assignment.
  mechanistic_category:
  - classification_value: proteotoxic disease
    evidence:
    - reference: PMID:17469116
      reference_title: Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions
      explanation: Ubiquitinated protein inclusions in affected neurons are the pathological basis for classifying ALS1 as a proteotoxic disease.
parents:
- Amyotrophic Lateral Sclerosis
- Motor Neuron Disease
- Neurodegenerative Disease
synonyms:
- ALS1
- SOD1-ALS
- SOD1-related amyotrophic lateral sclerosis
- amyotrophic lateral sclerosis 1
- familial amyotrophic lateral sclerosis due to SOD1 mutation
has_subtypes:
- name: A4V
  display_name: SOD1 p.Ala4Val (A4V, legacy numbering; p.Ala5Val in HGVS)
  description: The p.Ala5Val allele (legacy A4V) is associated with rapid progression in reported North American families. A historical study reported mean survival of 1.4 years from onset; this is a cohort estimate rather than an individual prognosis. Most carriers studied shared a founder haplotype. The inferred founder origin and failure to identify a nearby modifier do not exclude distant modifiers or prove that every carrier has the same course.
  evidence:
  - reference: PMID:18055113
    reference_title: 'SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Carriers of the SOD1(A4V) mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3-5 years with other dominant SOD1 mutations).
    explanation: Quantifies the survival difference that makes this allele a clinically distinct stratum.
  - reference: PMID:18055113
    reference_title: 'SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It therefore appears likely that the aggressive nature of the SOD1(A4V) mutation is not a result of a modifying factor within the region around the SOD1 gene.
    explanation: The authors considered a closely linked modifier unlikely within the region studied; this does not exclude modifiers elsewhere or establish purely allele-intrinsic severity.
- name: D90A homozygous
  display_name: SOD1 p.Asp90Ala homozygous (D90A/D91A, recessive Scandinavian form)
  description: Homozygosity for p.Asp91Ala (legacy D90A) defines a well-described recessive Scandinavian form, often with slowly progressive leg-onset disease. Sensory and urinary manifestations and widespread pathology were documented in a selected nine-person autopsy series. The same variant can be associated with dominant ALS outside this recessive context, and ataxia-first presentations have occurred in both heterozygous and homozygous carriers. Normal or near-normal dismutase activity in this variant argues against a universal enzymatic-loss explanation. Transgenic coexpression and aggregate-strain experiments are retained as models, not as proof of the human recessive mechanism.
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement
    explanation: Defines the recessive inheritance and the extra-motor clinical features of this stratum.
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns.
    explanation: Neuropathological confirmation that the lesion extends beyond motor pathways in D90A homozygotes.
review_notes: 'The full GeneReviews ALS overview was recovered through the NCBI Bookshelf /sites/books/ route and reviewed alongside all cited primary full texts available in the cache. General ALS guidance is explicitly distinguished from SOD1-specific observations. Canonical abstract-only records remain abstract-limited; unsuccessful full-text URL retrievals were excluded. Legacy SOD1 amino-acid numbering omits the initiating methionine: A4V/A5V, D90A/D91A and G93A/G94A refer to the respective same substitutions, whereas p.Gly94Ser is a different allele. Cohort and variant-specific observations are not assigned disease-wide frequency bands. This genetically defined entry does not impose an absolute TDP-43-negative rule: the D90A autopsy series documents rare TDP-43-positive structures. Clinical trial status was checked against ClinicalTrials.gov on 2026-09-21. Mechanistic model and treatment interpretation limits are recorded locally and in discussions.'
references:
- reference: PMID:20301623
  title: Amyotrophic Lateral Sclerosis Overview.
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
  title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:38470068
  title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
- reference: PMID:8446170
  title: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.
- reference: PMID:17469116
  title: Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.
- reference: PMID:18055113
  title: 'SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia.'
- reference: PMID:36385230
  title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
- reference: PMID:42265995
  title: Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.
- reference: PMID:7647793
  title: Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.
- reference: PMID:41511639
  title: 'Clinical trajectories and genetic profiles of SOD1-related amyotrophic lateral sclerosis: insights from a single-center cohort in India.'
- reference: PMID:41661214
  title: Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.
- reference: PMID:9029070
  title: Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.
- reference: PMID:8209258
  title: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
- reference: PMID:42614182
  title: 'Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.'
- reference: PMID:32640130
  title: Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
- reference: PMID:18519638
  title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
- reference: PMID:16741123
  title: Onset and progression in inherited ALS determined by motor neurons and microglia.
- reference: PMID:18246065
  title: Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis.
- reference: PMID:35478453
  title: P2X7 receptor activation mediates superoxide dismutase 1 (SOD1) release from murine NSC-34 motor neurons.
- reference: PMID:40450581
  title: Diverse effects of coexpression of human SOD1 variants on motor neuron disease.
- reference: PMID:41702846
  title: Efficient induction of motor neuron disease in transgenic G93A SOD1 mice by prion-like seeding.
- reference: PMID:40328546
  title: 'Advances and research priorities in the respiratory management of ALS: Historical perspectives and new technologies.'
- reference: PMID:42698373
  title: Protein Biomarkers in Risk and Prognosis of Amyotrophic Lateral Sclerosis.
- reference: PMID:36129998
  title: Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
- reference: PMID:35585374
  title: 'Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.'
- reference: PMID:42335888
  title: An emergent disease-associated motor neuron state precedes cell death in ALS.
- reference: PMID:42618698
  title: 'Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.'
- reference: PMID:42625715
  title: 'Amyotrophic lateral sclerosis and degenerative cervical myelopathy: phenotype-based diagnostic pitfalls, investigative mismatch, and practical clinical reasoning.'
- reference: PMID:42406382
  title: Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors.
- reference: url:https://www.biogencdn.com/us/pdfs/qalsody-prescribing-information.pdf
  title: https://www.biogencdn.com/us/pdfs/qalsody-prescribing-information.pdf
- reference: url:https://www.radicavahcp.com/pdfs/radicava-prescribing-information.pdf
  title: https://www.radicavahcp.com/pdfs/radicava-prescribing-information.pdf
- reference: PMID:8673102
  title: Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.
- reference: PMID:42503607
  title: 'Introducing Borsantrazole: A Trifunctional Boron-Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice.'
- reference: clinicaltrials:NCT02623699
  title: A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects With Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
- reference: clinicaltrials:NCT04856982
  title: A Phase 3 Randomized, Placebo-Controlled Trial With a Longitudinal Natural History Run-In and Open-Label Extension to Evaluate BIIB067 Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation
- reference: clinicaltrials:NCT03070119
  title: An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 Administered to Previously Treated Adults With Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
- reference: GEO:GSE271030
  title: RNA Expression Profiling in Lymphoblastoid Cell Lines from Mutated and Non-Mutated Amyotrophic Lateral Sclerosis Patients
- reference: PMID:41670738
  title: Treating SOD1-ALS with tofersen results in nonprogressive chronic ALS-a case series from Iceland.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Most SOD1-associated ALS is autosomal dominant, with variant-dependent and age-dependent penetrance. An affected heterozygous parent can transmit the variant to half of offspring, but variant transmission is not a prediction of whether or when ALS will develop. Two reported juvenile p.Asp125Gly cases inherited the variant from asymptomatic fathers; those observations do not establish lifetime nonpenetrance.
  evidence:
  - reference: PMID:8446170
    reference_title: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We identified 11 different SOD1 missense mutations in 13 different FALS families.
    explanation: The original association identifies pathogenic SOD1 variants in familial ALS; it does not provide an allele-specific penetrance estimate.
  - reference: PMID:42265995
    reference_title: Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: whole-exome sequencing revealed the pathogenic variant p.Asp125Gly in the SOD1 gene inherited from asymptomatic fathers
    explanation: The fathers were asymptomatic when described; their ages and subsequent lifetime outcomes are not established by the cached abstract.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: ALS has a 50% chance of inheriting the ALS-related
    explanation: Within the autosomal dominant offspring subsection, this fragment gives the transmission probability; it does not quantify penetrance.
- name: Autosomal recessive (Asp90Ala)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: The p.Asp91Ala allele (legacy D90A) segregates recessively in described Swedish and Finnish families, although heterozygous disease occurs in other genetic backgrounds. Homozygous SOD1 variants were also found in six of 37 probands in a selected Indian SOD1-ALS cohort; homozygosity alone does not establish the same variant or inheritance mechanism as Scandinavian D90A.
  evidence:
  - reference: PMID:7647793
    reference_title: Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report homozygosity for an exon 4 mutation, Asp90Ala in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland.
    explanation: Establishes recessive (homozygous) inheritance for the Asp90Ala allele in Scandinavian ALS families.
  - reference: PMID:41511639
    reference_title: 'Clinical trajectories and genetic profiles of SOD1-related amyotrophic lateral sclerosis: insights from a single-center cohort in India.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Remarkably, a high frequency of homozygous variants (6 patients) were observed in the cohort, which were associated with earlier disease onset.
    explanation: The selected Indian cohort reports six homozygous genotypes and an association with earlier onset, without establishing a general causal effect of homozygosity.
genetic:
- name: SOD1
  gene_term:
    preferred_term: SOD1
    term:
      id: hgnc:11179
      label: SOD1
  relationship_type: CAUSATIVE
  notes: SOD1 encodes Cu/Zn superoxide dismutase. More than 200 ALS-associated variants are reported, with variant-dependent penetrance and progression. A5V (legacy A4V) is associated with rapid progression in described families, whereas some other variants have slower courses. These associations do not determine an individual prognosis. p.Asp91Ala can occur in recessive or dominant contexts; homozygosity for a different allele does not establish the Scandinavian D90A inheritance mechanism.
  frequency: The SOD1 share of ALS varies by ancestry, familial ascertainment and cohort; the selected Indian cohort reported 24.2% of familial ALS and 4.8% of all sequenced ALS.
  case_fractions:
  - population: Familial ALS probands, single-center Indian cohort (NIMHANS)
    case_fraction_percent: 24.2
    notes: 37 SOD1-ALS probands from 33 families among 765 individuals undergoing whole-exome sequencing; the 24.2% figure is the share of familial ALS, while SOD1-ALS was 4.8% of the whole sequenced cohort.
    evidence:
    - reference: PMID:41511639
      reference_title: 'Clinical trajectories and genetic profiles of SOD1-related amyotrophic lateral sclerosis: insights from a single-center cohort in India.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among 765 individuals who underwent WES, 37 probands (4.8%) from 33 families were identified with SOD1-ALS, representing a substantial 24.2% of familial ALS (fALS) cases.
      explanation: Quantifies the SOD1 share of familial ALS in a contemporary large cohort.
  evidence:
  - reference: PMID:8446170
    reference_title: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified 11 different SOD1 missense mutations in 13 different FALS families.
    explanation: The original report establishing SOD1 as the ALS1 disease gene.
  - reference: PMID:41661214
    reference_title: Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Over 200 ALS-associated SOD1 variants induce varying disease progression rates
    explanation: Sources the variant count and the fact that allele identity modulates progression rate.
    quote_role: BACKGROUND
  - reference: PMID:9029070
    reference_title: Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The presence of one mutation, A4V, correlated with shorter survival. G37R, G41D, and G93C mutations predicted longer survival.
    explanation: The historical cohort associates particular variants with survival differences; the result is neither a universal ranking nor an individual prediction.
pathophysiology:
- name: Pathogenic SOD1 Variation
  biological_scale: MOLECULAR
  description: ALS1 is associated with pathogenic SOD1 coding variants, usually heterozygous but sometimes biallelic. Missense and truncating alleles can have toxic properties. Effects on stability, aggregation and dismutase activity differ by allele; normal activity in D90A and disease in high-expressing G93A mice argue against a universal simple enzyme-loss mechanism. Biallelic loss-of-function SOD1 syndromes are a distinct genetic context.
  evidence:
  - reference: PMID:8446170
    reference_title: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We identified 11 different SOD1 missense mutations in 13 different FALS families.
    explanation: The initial linkage and mutation study establishes the genetic association.
  - reference: PMID:7647793
    reference_title: Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The erythrocyte CuZn-SOD activity is essentially normal. Our findings suggest that this CuZn-SOD mutation causes ALS by a gain of function rather than by loss
    explanation: Human genetic evidence that ALS occurs with preserved dismutase activity, establishing gain of function in patients rather than only in transgenic models.
    quote_role: PRIMARY_RESULT
  genes:
  - preferred_term: SOD1
    term:
      id: hgnc:11179
      label: SOD1
  downstream:
  - target: SOD1 Protein Supply
    causal_link_type: DIRECT
    description: A coding variant changes the sequence of expressed SOD1; this edge denotes variant protein production, not an increase in total abundance.
    evidence:
    - reference: PMID:8446170
      reference_title: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2
      explanation: Establishes the gene, its product, and its normal catalytic function as the starting point of the mechanism.
      quote_role: PRIMARY_RESULT
  - target: Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Human genetic association and disease caused by tested transgenes support pathogenic SOD1 as an upstream cause, while the relative mediation by the mapped molecular routes remains unresolved.
    evidence:
    - reference: PMID:8209258
      reference_title: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Expression of high levels of human SOD containing a substitution of glycine to alanine at position 93--a change that has little effect on enzyme activity--caused motor neuron disease in transgenic mice.
      explanation: A variant with preserved catalytic activity is sufficient to cause motor neuron disease, completing the gain-of-function argument.
      quote_role: PRIMARY_RESULT
  - target: Extra-Motor CNS Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The D90A genotype is associated with this broader pathological phenotype; the cellular toxic intermediates are unresolved.
    evidence: &id009
    - reference: PMID:36385230
      reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns.
      explanation: Direct pathology establishes involvement outside the motor pathways.
  - target: Functional Abnormality of the Bladder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Urinary manifestations occur in a selected D90A cohort; the causal autonomic pathway is not resolved by the available pathology.
    evidence:
    - reference: PMID:36385230
      reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: may also include sensory, autonomic, and urinary bladder involvement
      explanation: Reports bladder involvement as a recognised feature of the D90A homozygous phenotype.
  - target: Gait Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Ataxia-first presentations are associated with p.Asp91Ala in the selected case series; the underlying cerebellar or sensory mechanism is not established.
    evidence:
    - reference: PMID:42614182
      reference_title: 'Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All patients presented with progressive gait ataxia as their initial and predominant symptom, with upper and lower motor neuron signs emerging months to years later and ultimately meeting criteria for ALS.
      explanation: Case series documenting ataxia-onset SOD1-ALS in Asp91Ala carriers.
- name: SOD1 Protein Supply
  biological_scale: MOLECULAR
  description: Transcription and translation supply SOD1 protein, including variant protein in ALS1. This upstream substrate is a treatment target; lowering it does not by itself establish removal of existing aggregates or identify the toxic molecular species.
  evidence:
  - reference: PMID:32640130
    reference_title: Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis.
    explanation: The intervention targets protein production, not correction of the DNA variant.
  genes:
  - preferred_term: SOD1
    term:
      id: hgnc:11179
      label: SOD1
  downstream:
  - target: Cytoplasmic SOD1 Aggregate Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Expressed variant SOD1 can enter abnormal conformational and aggregation pathways. The intervening folding, maturation and nucleation steps are allele dependent and are not resolved by tissue colocalization.
    evidence:
    - reference: PMID:17469116
      reference_title: Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43.
      explanation: Human postmortem series establishing that ALS1 inclusions are ubiquitin-positive and TDP-43-negative.
      quote_role: PRIMARY_RESULT
  - target: Mutant SOD1 Association with Derlin-1
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Tested mutant proteins gain association with Derlin-1. Whether exposed mutant surfaces bind directly or require chaperones remains unresolved.
    evidence: &id001
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Here we show that SOD1mut specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD.
      explanation: The cellular studies identify the Derlin-1-associated route in tested mutants.
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: we cannot rule out the possibility that chaperon proteins in the reticulocyte lysate mediate the interaction between SOD1mut and Derlin-1.
      explanation: The authors explicitly limit a direct-binding interpretation.
  - target: Microglial Mutant SOD1 Contribution
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mutant protein expression in this glial lineage contributes to disease progression in conditional mouse experiments; the downstream toxic molecular species is unresolved.
    evidence: &id003
    - reference: PMID:16741123
      reference_title: Onset and progression in inherited ALS determined by motor neurons and microglia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression.
      explanation: The lineage perturbation establishes a later progression contribution in this mouse model.
  - target: Astrocytic Mutant SOD1 Contribution
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mutant protein expression in this glial lineage contributes to disease progression in conditional mouse experiments; the downstream toxic molecular species is unresolved.
    evidence: &id004
    - reference: PMID:18246065
      reference_title: Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: diminished mutant expression in astrocytes did not affect onset, but delayed microglial activation and sharply slowed later disease progression
      explanation: The abstract supports an astrocyte contribution, with source detail limited to the cached abstract.
  - target: P2X7-Associated SOD1 Release
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Expressed SOD1 supplies released material under the ATP challenge; this includes wild-type as well as tested mutant protein, and does not establish spontaneous human neuron-to-neuron spread.
    evidence: &id005
    - reference: PMID:35478453
      reference_title: P2X7 receptor activation mediates superoxide dismutase 1 (SOD1) release from murine NSC-34 motor neurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: ATP induced the rapid release of aggregated SOD1G93A from NSC-34 cells transiently transfected with SOD1G93A, a process blocked by AZ10606120 and revealing a role for P2X7 in this process.
      explanation: The experiment measures ATP-triggered release and antagonist sensitivity.
- name: Cytoplasmic SOD1 Aggregate Formation
  biological_scale: CELLULAR
  description: Abnormal SOD1 conformers accumulate in neurons and glia in experimental systems and human SOD1 ALS tissue. The specific harmful species and the contribution of visible inclusions versus soluble species remain unresolved. Most SOD1 pathology differs from the predominant TDP-43 proteinopathy of other ALS, although rare TDP-43-positive structures were observed in the D90A series. Neither universal dimer destabilization nor uniform TDP-43 absence is assumed.
  evidence:
  - reference: PMID:17469116
    reference_title: Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43.
    explanation: Human postmortem series establishing that ALS1 inclusions are ubiquitin-positive and TDP-43-negative.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem.
    explanation: The selected D90A autopsy series documents misfolded-SOD1 pathology.
  - reference: PMID:40450581
    reference_title: Diverse effects of coexpression of human SOD1 variants on motor neuron disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Even though the current results suggest that hSOD1 aggregation is the primary cause of disease, the identities of the principal harmful species are still unknown.
    explanation: The coexpression study explicitly leaves the harmful aggregate species unresolved.
  conforms_to: loss_of_proteostasis#Misfolded-Protein Aggregation
  cell_types:
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  downstream:
  - target: Seeded SOD1 Inclusion Pathology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Aggregate-bearing donor tissue carries seeding activity in selected transgenic hosts. The experiment uses unpurified homogenate rather than a molecularly defined seed.
    evidence: &id006
    - reference: PMID:41702846
      reference_title: Efficient induction of motor neuron disease in transgenic G93A SOD1 mice by prion-like seeding.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: injected intrathecally with seeding homogenates containing misfolded G93A or G85R SOD1 developed accelerated motor neuron disease efficiently
      explanation: The recipient experiment demonstrates acceleration in susceptible transgenic lines.
    - reference: PMID:41702846
      reference_title: Efficient induction of motor neuron disease in transgenic G93A SOD1 mice by prion-like seeding.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: The general appearance of the pathological inclusions by ubiquitin immunostaining was similar among all of the paralysed animals
      explanation: Histology supports inclusion pathology in the affected recipients.
- name: Mutant SOD1 Association with Derlin-1
  biological_scale: MOLECULAR
  description: Tested SOD1 mutants associate with Derlin-1 in transfected cells and mouse tissue. Recombinant-protein experiments support interaction, but reticulocyte-lysate chaperones could mediate it. This is an association with an ERAD component, without demonstrated sequestration or disassembly of the whole ERAD complex.
  evidence: *id001
  downstream:
  - target: Impaired ER-Associated Protein Degradation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The interaction is implicated by perturbation studies, while substrate presentation or transfer rather than complex disassembly is proposed as the inhibited step.
    evidence:
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: SOD1mut did not inhibit association of Derlin-1 with VIMP, p97, Derlin family proteins, and HRD1
      explanation: The measured component associations exclude a blanket complex-disassembly claim.
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Derlin-1(CT4) inhibited SOD1mut-induced activation of IRE1, PERK, and ASK1
      explanation: Disrupting the mutant-associated route suppresses downstream stress signaling.
- name: Impaired ER-Associated Protein Degradation
  biological_scale: CELLULAR
  description: Overexpression of tested mutant SOD1 retards degradation of luminal NHK and transmembrane CD3delta ERAD reporters. Reduced reporter ubiquitination and retention on a Derlin-1/VIMP-containing complex suggest impaired substrate transfer. The exact blocked step is unresolved; core component association and measured cytosolic proteasomal degradation were preserved under the tested conditions.
  evidence:
  - reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In contrast, overexpression of SOD1mut decreased the degradation of NHK to a half-life of >8 h
    explanation: The pulse-chase assay measures delayed ERAD reporter turnover.
  - reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Cycloheximide chase experiments showed that the degradation of CD3δ was also retarded by overexpression of SOD1mut
    explanation: A second ERAD substrate corroborates impaired degradation.
  biological_processes:
  - preferred_term: ERAD pathway
    term:
      id: GO:0036503
      label: ERAD pathway
    modifier: DECREASED
  downstream:
  - target: Endoplasmic Reticulum Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Defective ERAD is proposed to accumulate improperly processed luminal substrates and activate the stress response. Reporter turnover and stress activation support this route, without isolating every retained endogenous substrate.
    evidence:
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: triggered ER stress through dysfunction of ERAD.
      explanation: The study interprets ERAD dysfunction as upstream of the observed stress response.
- name: Endoplasmic Reticulum Stress
  biological_scale: CELLULAR
  description: 'The tested mutant-SOD1 cell systems activate ER stress responses, including IRE1/PERK changes and XBP1 splicing. These stress readouts are distinct from motor neuron death: NSC34 cells showed signaling without detectable mutant-induced death under the reported conditions.'
  evidence:
  - reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Derlin-1 siRNA exhibited no effect on the basal level of activation of IRE1
    explanation: Derlin-1 depletion did not simply induce or abolish every ER stress response.
  - reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: SOD1mut-induced activation of IRE1 and ASK1 was clearly inhibited by Derlin-1 depletion
    explanation: The depletion experiment supports the mutant-associated stress pathway.
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  downstream:
  - target: IRE1-TRAF2-ASK1 Complex Formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: ER stress-associated IRE1 activation recruits the TRAF2/ASK1 complex in the tested cell system.
    evidence: &id002
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut
      explanation: The experiment resolves the dependence of the measured association on TRAF2 and mutant SOD1.
- name: IRE1-TRAF2-ASK1 Complex Formation
  biological_scale: MOLECULAR
  description: In mutant-SOD1-expressing NSC34 cells, coimmunoprecipitation supports recruitment of ASK1 to IRE1 in the presence of TRAF2. This records the signaling assembly separately from kinase activation.
  evidence: *id002
  downstream:
  - target: ASK1 Kinase Activation
    causal_link_type: DIRECT
    description: IRE1/TRAF2-associated assembly is the experimentally supported route to ASK1 activation; complex formation and kinase activity were assayed separately.
    evidence:
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: suggesting that SOD1mut induces formation of an IRE1–TRAF2–ASK1 complex on the ER membrane and thus activates ASK1 by triggering ER stress-induced IRE1 activation.
      explanation: The authors infer kinase activation through the measured signaling assembly.
- name: ASK1 Kinase Activation
  biological_scale: MOLECULAR
  description: Mutant SOD1 activates ASK1 in a kinase assay. Genetic ASK1 deletion and a Derlin-1-derived competing peptide partially protect embryonic spinal-cord neurons; ASK1 deletion also mitigates neuron loss and delays terminal disease in transgenic mice. Downstream p38 and caspase routes are candidates rather than directly established effectors in this study.
  evidence:
  - reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1
    explanation: The kinase assay distinguishes activation from mere complex association.
  downstream:
  - target: Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: ASK1 contributes to neuronal injury through incompletely resolved downstream death pathways. Protection is partial and does not prevent onset in the tested mice.
    evidence:
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Moreover, deletion of ASK1 mitigated the motor neuron loss and extended the life span of SOD1mut transgenic mice.
      explanation: Genetic perturbation supports a contribution to degeneration and progression.
- name: Microglial Mutant SOD1 Contribution
  biological_scale: CELLULAR
  description: Lineage-restricted lowering in a deletable-transgene mouse implicates microglial mutant SOD1 in later disease progression. It does not establish a specific human microglial toxic mediator or an invariant onset/progression division across SOD1 genotypes.
  evidence: *id003
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  downstream:
  - target: Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Lineage-restricted reduction slows model progression, supporting a non-cell-autonomous contribution; specific human toxic mediators remain unknown.
    evidence: *id003
- name: Astrocytic Mutant SOD1 Contribution
  biological_scale: CELLULAR
  description: Reducing astrocytic mutant SOD1 in a conditional mouse delays microglial activation and later disease progression without changing onset in that experiment. The mediator linking astrocytes to neuronal injury remains unresolved.
  evidence: *id004
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  downstream:
  - target: Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Lineage-restricted reduction slows model progression, supporting a non-cell-autonomous contribution; specific human toxic mediators remain unknown.
    evidence: *id004
- name: P2X7-Associated SOD1 Release
  biological_scale: CELLULAR
  description: High extracellular ATP induces rapid release of SOD1-containing particulate material from transfected murine NSC34 hybrid cells; AZ10606120 inhibits this response. This pharmacological experiment supports a P2X7-associated release process, with overexpression, millimolar ATP and non-primary neuronal lineage limits.
  evidence: *id005
- name: Seeded SOD1 Inclusion Pathology
  biological_scale: CELLULAR
  description: Spinal-cord homogenates from paralysed transgenic donors accelerate paralysis and inclusion pathology in susceptible low-copy G93A or G85R:YFP mice. Homogenate inoculation supports experimentally transmissible disease activity without proving purified-SOD1 sufficiency, a particular cell-to-cell transport mechanism or necessity for human ALS spread.
  evidence: *id006
  downstream:
  - target: Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Homogenate inoculation accelerates the disease endpoint in susceptible mice, with pathological inclusions. This does not isolate the lethal aggregate species or prove the same route in patients.
    evidence: *id006
- name: Motor Neuron Degeneration
  biological_scale: TISSUE
  description: Loss and dysfunction of upper and lower motor neurons produce the clinical motor syndrome. Human D90A autopsy tissue directly documents severe ventral-horn neuron loss and corticospinal degeneration. Multiple experimentally supported toxic routes may contribute, but no single aggregate species or stress pathway explains every patient.
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon microscopic investigation, all nine patients had severe loss of motor neurons in the ventral horn to the point of rarefaction of the tissue and the appearance of cavities.
    explanation: Direct human pathology supports lower motor neuron loss in the selected D90A series.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Motor symptoms occur as the result of degeneration of both upper and lower motor neurons.
    explanation: The clinical overview links motor-system pathology to the syndrome.
  conforms_to: loss_of_proteostasis#Proteotoxic Cell Dysfunction and Neurodegeneration
  cell_types:
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  - preferred_term: Betz upper motor neuron
    term:
      id: CL:4023052
      label: Betz upper motor neuron
  downstream:
  - target: Upper Motor Neuron Dysfunction
    causal_link_type: DIRECT
    description: Degeneration of upper motor pathways reduces descending motor control.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
      reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Motor symptoms occur as the result of degeneration of both upper and lower motor neurons.
      explanation: General ALS clinicopathology supports the branch.
  - target: Progressive Muscle Denervation
    causal_link_type: DIRECT
    description: Loss of lower motor neurons removes motor innervation to their muscle fibers.
    evidence: &id008
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
      reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: LMNs, located in the brain stem and spinal cord, innervate striated muscle. LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations.
      explanation: General ALS physiology connects lower motor neurons to their muscle manifestations.
- name: Upper Motor Neuron Dysfunction
  biological_scale: TISSUE
  description: Damage to corticospinal and corticobulbar motor control contributes to pyramidal signs and some bulbar manifestations. Upper and lower motor involvement vary by genotype and stage.
  evidence: &id007
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: UMN signs in ALS include hyperreflexia, extensor plantar response, and increased muscle tone.
    explanation: General ALS physiology identifies the consequences of upper motor neuron dysfunction.
  downstream:
  - target: Spasticity
    causal_link_type: DIRECT
    description: Impaired upper motor control produces this pyramidal sign; its presence varies by stage and phenotype.
    evidence: *id007
  - target: Hyperreflexia
    causal_link_type: DIRECT
    description: Impaired upper motor control produces this pyramidal sign; its presence varies by stage and phenotype.
    evidence: *id007
  - target: Extensor Plantar Response
    causal_link_type: DIRECT
    description: Impaired upper motor control produces this pyramidal sign; its presence varies by stage and phenotype.
    evidence: *id007
- name: Progressive Muscle Denervation
  biological_scale: TISSUE
  description: Loss of lower motor neuron output progressively denervates skeletal muscle. Weakness, wasting, cramps and fasciculations can result; the distribution varies among limb, bulbar and respiratory muscles. Fasciculations are not treated as proof that compensatory reinnervation itself causes the syndrome.
  evidence: *id008
  downstream:
  - target: Progressive Muscle Weakness
    causal_link_type: DIRECT
    description: Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.
    evidence: *id008
  - target: Lower Limb Muscle Weakness
    causal_link_type: DIRECT
    description: Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.
    evidence: *id008
  - target: Skeletal Muscle Atrophy
    causal_link_type: DIRECT
    description: Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.
    evidence: *id008
  - target: Fasciculations
    causal_link_type: DIRECT
    description: Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.
    evidence: *id008
  - target: Muscle Cramps
    causal_link_type: DIRECT
    description: Reduced lower motor neuron innervation contributes to this manifestation; clinical distribution is variable.
    evidence: *id008
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Denervation affecting the relevant bulbar or respiratory muscles contributes to impaired function; bulbar symptoms may also involve upper motor pathways.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
      reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Early manifestations may vary, with affected individuals most often presenting with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia).
      explanation: The overview connects regional motor involvement to clinical manifestations.
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Denervation affecting the relevant bulbar or respiratory muscles contributes to impaired function; bulbar symptoms may also involve upper motor pathways.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
      reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Early manifestations may vary, with affected individuals most often presenting with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia).
      explanation: The overview connects regional motor involvement to clinical manifestations.
  - target: Dysphonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Denervation affecting the relevant bulbar or respiratory muscles contributes to impaired function; bulbar symptoms may also involve upper motor pathways.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
      reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Early manifestations may vary, with affected individuals most often presenting with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia).
      explanation: The overview connects regional motor involvement to clinical manifestations.
  - target: Respiratory Insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Denervation affecting the relevant bulbar or respiratory muscles contributes to impaired function; bulbar symptoms may also involve upper motor pathways.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
      reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Early manifestations may vary, with affected individuals most often presenting with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia).
      explanation: The overview connects regional motor involvement to clinical manifestations.
- name: Extra-Motor CNS Degeneration
  biological_scale: TISSUE
  description: In the selected D90A homozygous series, degeneration includes dorsal columns and circumscribed cortical areas. SOD1 inclusions coexist with these lesions, without an experiment establishing that visible inclusions cause them. These findings are genotype- and cohort-scoped.
  evidence: *id009
  downstream:
  - target: Somatic Sensory Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Dorsal-column injury is anatomically consistent with the vibration-sense deficits in the same series, although no intervention isolates the responsible lesion.
    evidence: *id009
phenotypes:
- name: Progressive Muscle Weakness
  category: Neurological
  description: Progressive weakness spreads from the initial region to other limb, bulbar or respiratory regions; rate and sequence vary by SOD1 variant and individual.
  phenotype_term:
    preferred_term: Progressive muscle weakness
    term:
      id: HP:0003323
      label: Progressive muscle weakness
    clinical_course: PROGRESSIVE
  sequelae:
  - target: Respiratory Insufficiency
    description: Progressive involvement of respiratory muscles can cause ventilatory insufficiency.
  evidence:
  - reference: PMID:42265995
    reference_title: Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: rapid progression over months to involve all body regions
    explanation: Documents the generalisation this node describes. The cited cases are juvenile p.Asp125Gly, where progression is unusually rapid, so the quote establishes the pattern of spread rather than its typical rate.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination
    explanation: The full ALS overview supports clinical progression as a general ALS feature, applied here with SOD1-specific variation.
- name: Lower Limb Muscle Weakness
  category: Neurological
  description: Lower-limb onset was reported in 67.6% of the selected 37-proband Indian SOD1-ALS cohort and is characteristic of the described D90A homozygous series. Other onset patterns occur; this percentage is not a disease-wide frequency.
  phenotype_term:
    preferred_term: Lower limb muscle weakness
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  evidence:
  - reference: PMID:41511639
    reference_title: 'Clinical trajectories and genetic profiles of SOD1-related amyotrophic lateral sclerosis: insights from a single-center cohort in India.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most patients presented with a lower limb onset (67.6%) and a lower motor neuron phenotype.
    explanation: Quantifies lower-limb onset as the predominant presentation in this cohort.
  - reference: PMID:42265995
    reference_title: Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: lower limb onset of weakness, lower motor neuron examination findings, and rapid progression over months to involve all body regions
    explanation: Independent report of the same onset pattern in juvenile-onset SOD1-ALS, showing it is not confined to one cohort or one allele.
- name: Skeletal Muscle Atrophy
  category: Neurological
  description: Wasting of denervated limb and bulbar musculature.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations.
    explanation: The ALS overview identifies this lower motor neuron manifestation; no SOD1-specific frequency is inferred.
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'the two patients with the most severe motor neuron cell loss and muscle wasting (patients #8–9)'
    explanation: Direct human observations corroborate muscle wasting in the D90A cohort.
- name: Fasciculations
  category: Neurological
  description: Fasciculations are a lower motor neuron sign; widespread fasciculations were directly observed in a p.Gly94Ser case. Disease-wide frequency is not established.
  phenotype_term:
    preferred_term: Fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations.
    explanation: The ALS overview identifies this lower motor neuron manifestation; no SOD1-specific frequency is inferred.
  - reference: PMID:41670738
    reference_title: Treating SOD1-ALS with tofersen results in nonprogressive chronic ALS-a case series from Iceland.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The patient had difficulty standing on the tiptoes, and widespread fasciculations were present.
    explanation: Direct patient examination supports fasciculations in SOD1 ALS.
- name: Spasticity
  category: Neurological
  description: Upper motor neuron sign reflecting corticospinal tract degeneration.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upper motor neuron signs (primarily brisk deep-tendon reflexes, Hoffmann’s sign, Babinski’s sign, and spasticity) preceded lower motor neuron signs when a new region (leg, arm, trunk, or bulbar) became involved.
    explanation: The D90A series directly observes the pyramidal signs; the temporal order is cohort-specific.
- name: Hyperreflexia
  category: Neurological
  description: Brisk tendon reflexes can reflect upper motor neuron involvement; they need not be present in every affected muscle or disease stage.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upper motor neuron signs (primarily brisk deep-tendon reflexes, Hoffmann’s sign, Babinski’s sign, and spasticity) preceded lower motor neuron signs when a new region (leg, arm, trunk, or bulbar) became involved.
    explanation: The D90A series directly observes the pyramidal signs; the temporal order is cohort-specific.
- name: Dysarthria
  category: Neurological
  description: Bulbar involvement producing slurred, effortful speech.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Dysarthria preceded dysphagia and dysphonia.
    explanation: The selected human D90A series directly documents progressive bulbar symptoms.
- name: Dysphagia
  category: Neurological
  description: Bulbar weakness impairing swallowing, with consequent aspiration risk and weight loss.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Dysarthria preceded dysphagia and dysphonia.
    explanation: The selected human D90A series directly documents progressive bulbar symptoms.
- name: Respiratory Insufficiency
  category: Respiratory
  description: Respiratory muscle involvement can cause ventilatory insufficiency as disease progresses. Pneumonia and other complications also contribute to mortality, so respiratory failure is not the sole terminal event.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:40328546
    reference_title: 'Advances and research priorities in the respiratory management of ALS: Historical perspectives and new technologies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Respiratory involvement has been identified as a cardinal feature of amyotrophic lateral sclerosis (ALS) since its earliest descriptions in the 19th century.
    explanation: Establishes respiratory involvement as a cardinal ALS feature; the terminal mechanism in this entry is denervation of the respiratory muscles.
    quote_role: REVIEW_SYNTHESIS
- name: Somatic Sensory Dysfunction
  category: Neurological
  subtype: D90A homozygous
  description: Sensory abnormalities are documented in selected SOD1 phenotypes. In nine D90A homozygotes, vibration sense was impaired in all and tactile sensation in two; the same autopsy cohort had dorsal-column degeneration. These findings do not imply sensory involvement in every SOD1 carrier.
  phenotype_term:
    preferred_term: Somatic sensory dysfunction
    term:
      id: HP:0003474
      label: Somatic sensory dysfunction
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns.
    explanation: Neuropathological substrate for the sensory involvement in this stratum.
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Loss of sense of vibration, first at the ankles and later also in the hands, was observed early in all patients.
    explanation: Clinical sensory examination complements the anatomical pathology in this selected series.
- name: Functional Abnormality of the Bladder
  category: Genitourinary
  subtype: D90A homozygous
  description: Urinary bladder involvement reported as part of the stereotyped D90A homozygous phenotype, outside the motor system.
  phenotype_term:
    preferred_term: Functional abnormality of the bladder
    term:
      id: HP:0000009
      label: Functional abnormality of the bladder
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: may also include sensory, autonomic, and urinary bladder involvement
    explanation: Reports bladder involvement as a recognised feature of the D90A homozygous phenotype.
- name: Gait Ataxia
  category: Neurological
  description: Progressive gait ataxia preceded motor neuron signs in a selected four-index-case p.Asp91Ala series containing two heterozygotes and two homozygotes. The reported diagnostic delays were 3–9 years. Cerebellar atrophy was visible in only one index case, and the cellular cause of ataxia remains unresolved.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: PMID:42614182
    reference_title: 'Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients presented with progressive gait ataxia as their initial and predominant symptom, with upper and lower motor neuron signs emerging months to years later and ultimately meeting criteria for ALS.
    explanation: Case series documenting ataxia-onset SOD1-ALS in Asp91Ala carriers.
  - reference: PMID:42614182
    reference_title: 'Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diagnostic latencies from ataxia onset to recognition of ALS ranged from 3 to 9 years.
    explanation: Quantifies the diagnostic delay that makes this presentation clinically consequential.
- name: Muscle Cramps
  category: Neurological
  phenotype_term:
    preferred_term: Muscle cramps
    term:
      id: HP:0003394
      label: Muscle spasm
  description: Severe leg cramps were reported in the selected nine-person D90A homozygous series; frequency across ALS1 is not established.
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: All patients described the onset of motor dysfunction as a sense of stiffness and complained of severe muscular cramps in the legs, unsteadiness or clumsiness, and general fatigue.
    explanation: Direct clinical observations support cramps in this selected genotype-specific cohort.
- name: Extensor Plantar Response
  category: Neurological
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  description: An extensor plantar response is one observed upper motor neuron sign in SOD1 ALS.
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upper motor neuron signs (primarily brisk deep-tendon reflexes, Hoffmann’s sign, Babinski’s sign, and spasticity) preceded lower motor neuron signs when a new region (leg, arm, trunk, or bulbar) became involved.
    explanation: The D90A cohort directly documents Babinski signs; timing is scoped to this series.
- name: Dysphonia
  category: Neurological
  phenotype_term:
    preferred_term: Dysphonia
    term:
      id: HP:0001618
      label: Dysphonia
  description: Voice impairment was reported with progressive bulbar involvement in the D90A series.
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Dysarthria preceded dysphagia and dysphonia.
    explanation: Directly supports voice impairment in the reported cohort.
- name: Emotional Lability
  category: Neurological
  phenotype_term:
    preferred_term: Emotional lability
    term:
      id: HP:0000712
      label: Emotional lability
  description: Five of nine D90A homozygotes developed prominent emotional lability later in the disease; this is distinct from a diagnosis of frontotemporal dementia.
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: None of the patients showed overt signs of FTD, but five had prominent emotional lability in the later stages of the disease.
    explanation: Documents a selected-cohort count without converting it to general ALS1 frequency.
biochemical:
- name: Neurofilament light chain
  presence: INCREASED
  biomarker_term:
    preferred_term: neurofilament light chain
    term:
      id: hgnc:7739
      label: NEFL
  notes: NfL in blood or CSF is a nonspecific marker of neuroaxonal injury. SOD1-tofersen trials document reduced plasma NfL with treatment. Presymptomatic rises have informed the selected ATLAS trial population, but no universal clinical treatment threshold or guaranteed phenoconversion time follows. General-ALS proteomic associations are not SOD1-specific validation.
  readouts:
  - target: Motor Neuron Degeneration
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Higher NfL can reflect neuroaxonal injury and has prognostic and pharmacodynamic use. It is not disease-specific and does not by itself establish neuronal rescue or determine when an individual carrier will develop ALS.
    evidence:
    - reference: PMID:42698373
      reference_title: Protein Biomarkers in Risk and Prognosis of Amyotrophic Lateral Sclerosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: NEFL was the most robust biomarker in plasma and CSF
      explanation: Ranks NfL first among 363 profiled proteins across case status, risk, survival and functional decline. The cohort is ALS broadly (198 patients), not SOD1-specific.
    - reference: PMID:36129998
      reference_title: Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo.
      explanation: The SOD1-specific NfL result, and the biomarker change that carried the accelerated approval.
  evidence:
  - reference: PMID:35585374
    reference_title: 'Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease
    explanation: The ATLAS design paper summarizes prior presymptomatic natural-history observations, chiefly in rapidly progressing variants; this is not a universal carrier prediction rule.
    quote_role: BACKGROUND
- name: Disease-associated motor neuron transcriptional signature
  notes: A DM-like molecular state is observed in stage-stratified SOD1 G93A mice and human postmortem ALS including SOD1 donors. Cross-sectional tissue, rare surviving nuclei and inferred pseudotime do not establish a causal state-to-death sequence or a prospective survival prediction. Neuronal fragments provide a distinct assay, not additional independent patients.
  evidence:
  - reference: PMID:42335888
    reference_title: An emergent disease-associated motor neuron state precedes cell death in ALS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Using models that accounted for sample identity, we found a statistically significant increase in average DM score in pan-ALS versus control (Figure 7E) and in SOD1 versus control (Figure S11C).
    explanation: Sample-aware human analysis supports the signature in the SOD1 subgroup.
  - reference: PMID:42335888
    reference_title: An emergent disease-associated motor neuron state precedes cell death in ALS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: only 150 bona fide alpha motor neurons (excluding cluster 11) passed quality control across all conditions
    explanation: The low number of surviving nuclei limits the human comparison.
diagnosis:
- name: Clinical and electrodiagnostic diagnosis of ALS
  diagnosis_term:
    preferred_term: electromyography
    term:
      id: NCIT:C38056
      label: Electromyography
  description: Diagnosis integrates progressive motor impairment, clinical upper/lower motor neuron findings, electromyography when appropriate, and exclusion of alternative causes. Gold Coast criteria permit UMN and LMN involvement in one region or LMN involvement in at least two. In five general suspected-ALS cohorts (3007 participants), pooled sensitivity was 0.96 and specificity 0.68, with very low certainty for specificity; these are not SOD1-specific test characteristics.
  evidence:
  - reference: PMID:42618698
    reference_title: 'Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'GCC demonstrated higher sensitivity than rEEC and Awaji criteria: 0.96 (95% confidence interval [CI] 0.93-0.98) versus 0.87 (95% CI 0.78-0.92) and 0.87 (95% CI 0.78-0.93), respectively.'
    explanation: Individual-participant meta-analysis quantifying the sensitivity advantage of the Gold Coast criteria.
    quote_role: PRIMARY_RESULT
  - reference: PMID:42618698
    reference_title: 'Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Specificity was imprecise and heterogeneous, supporting use with mimic exclusion and longitudinal reassessment.
    explanation: Supports this node's claim as stated, which already says the criteria buy sensitivity at the cost of specificity and are therefore applied with mimic exclusion and longitudinal reassessment. It is a caveat the claim absorbs, not a contradiction of it, so it is graded SUPPORT rather than REFUTE.
    quote_role: PRIMARY_RESULT
  - reference: PMID:42618698
    reference_title: 'Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Upper and lower motor neuron dysfunction in at least one body region, with both present in the same region when only one region is involved; or lower motor neuron dysfunction in at least two body regions
    explanation: The reproduced Gold Coast definition specifies the regional motor-neuron requirement.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The diagnosis of ALS requires characteristic clinical features and specific findings on electrodiagnostic testing, as well as exclusion of other health conditions with related manifestations
    explanation: The full GeneReviews diagnostic section supports clinical/electrodiagnostic assessment and exclusion of mimics; the newer Gold Coast evidence is described separately.
- name: Exclusion of structural and treatable mimics
  diagnosis_term:
    preferred_term: cervical spine magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: Investigations should exclude structural and treatable mimics based on the clinical presentation. Cervical myelopathy may resemble or coexist with ALS; an MRI lesion must account for the distribution and progression of findings. EMG/NCS distribution, clinical examination and follow-up are complementary. The narrative review does not establish a frequency ranking of mimics.
  evidence:
  - reference: PMID:42625715
    reference_title: 'Amyotrophic lateral sclerosis and degenerative cervical myelopathy: phenotype-based diagnostic pitfalls, investigative mismatch, and practical clinical reasoning.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MRI is indispensable but not self-interpreting, EMG/NCS is most useful when interpreted by distribution rather than positivity alone
    explanation: The narrative review supports distribution-based interpretation and exclusion of a clinically relevant structural mimic; it is not a new diagnostic-accuracy cohort.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:42625715
    reference_title: 'Amyotrophic lateral sclerosis and degenerative cervical myelopathy: phenotype-based diagnostic pitfalls, investigative mismatch, and practical clinical reasoning.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: both may present with upper-limb weakness, hand wasting, hyperreflexia, gait disturbance, and cervical MRI abnormalities
    explanation: The narrative review supports distribution-based interpretation and exclusion of a clinically relevant structural mimic; it is not a new diagnostic-accuracy cohort.
    quote_role: REVIEW_SYNTHESIS
- name: SOD1 genetic testing
  diagnosis_term:
    preferred_term: SOD1 genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: Molecular testing identifies an ALS-causing SOD1 variant in a person with a compatible motor neuron syndrome. Testing may be part of an ALS multigene panel, with variant classification and inheritance interpreted in context. A variant of uncertain significance alone does not establish ALS1. A pathogenic result informs counseling and eligibility for SOD1-directed therapy; presymptomatic testing is a separate counseling decision.
  evidence:
  - reference: PMID:41661214
    reference_title: Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.
    explanation: The therapeutic indication makes identification of the causal SOD1 variant clinically relevant; it does not make every detected variant diagnostic.
    quote_role: BACKGROUND
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: A three-generation family history should be obtained, with attention paid to relatives with neurologic signs and symptoms, particularly cognitive impairment,
    explanation: The overview supports a structured family history alongside molecular evaluation.
treatments:
- name: Tofersen
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  description: Tofersen is an intrathecal antisense oligonucleotide that promotes RNase H-mediated degradation of SOD1 mRNA and reduces SOD1 protein production. EAN guidance recommends it for progressive ALS caused by pathogenic SOD1 variants, with discussion of treatment burden and serious adverse events. US accelerated approval was based on reduced plasma NfL. In the 108-participant randomized VALOR phase, the 28-week primary clinical endpoint in the prespecified faster-progression subgroup (60 of 108 participants) was not met despite reduced CSF SOD1 and plasma NfL. The extension retained the original randomized early/delayed groups, but everyone could receive active drug after week 28; later comparisons therefore lack an untreated control. At week 148, earlier initiation was associated with numerically less decline, with imprecise survival estimates. Four uncontrolled Icelandic p.Gly94Ser cases provide additional clinical observations, not proof of universal stabilization. Myelitis/radiculitis, raised intracranial pressure with papilledema, and aseptic meningitis require specific safety discussion and evaluation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tofersen
      term:
        id: NCIT:C166584
        label: Tofersen
  target_mechanisms:
  - target: SOD1 Protein Supply
    treatment_effect: INHIBITS
    description: Reducing SOD1 mRNA lowers protein supply; this does not directly correct the variant or prove clearance of existing aggregates.
    evidence:
    - reference: PMID:36129998
      reference_title: Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo.
      explanation: Demonstrates target engagement via a CSF surrogate, together with a fall in a neuroaxonal injury marker.
    - reference: PMID:42406382
      reference_title: Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84%
      explanation: The abstract reports cross-sectional tissue reductions in three recently treated autopsy donors, not a within-person serial measurement or clearance of inclusions.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: In patients with progressive ALS caused by pathogenic mutations in superoxide dismutase 1 (SOD1), offer tofersen as first‐line treatment.
    explanation: The guideline supports treatment for progressive pathogenic-variant SOD1 ALS.
  - reference: PMID:32640130
    reference_title: Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks.
    explanation: First-in-human demonstration that intrathecal tofersen lowers CSF SOD1 in ALS1.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36129998
    reference_title: Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events.
    explanation: The randomized phase found biomarker reductions without significant benefit on the primary clinical endpoint at 28 weeks; this limits efficacy claims without refuting target engagement or the treatment indication.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36129998
    reference_title: Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort
    explanation: The original randomized groups differed by treatment initiation time; after crossover there was no untreated control, and these analyses were not adjusted for multiplicity.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41661214
    reference_title: Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function
    explanation: The long-term analysis retains initial randomized assignment but has attrition and no untreated comparator beyond 28 weeks; numerical differences do not establish a precise survival benefit.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Discuss with the patient that this treatment may be associated with serious adverse events.
    explanation: The recommendation explicitly requires discussion of serious adverse events.
  - reference: url:https://www.biogencdn.com/us/pdfs/qalsody-prescribing-information.pdf
    reference_title: https://www.biogencdn.com/us/pdfs/qalsody-prescribing-information.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Serious adverse reactions of myelitis and radiculitis have been reported in patients treated with QALSODY.
    explanation: The label directly supports the inflammatory neurological safety warning.
  oligonucleotide_details:
    target_gene:
      preferred_term: SOD1
      term:
        id: hgnc:11179
        label: SOD1
    target_transcript: SOD1 mRNA
    conjugation: UNCONJUGATED
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    oligonucleotide_chemistry: TWO_PRIME_O_METHOXYETHYL
- name: Riluzole
  therapeutic_modality: SMALL_MOLECULE
  description: Riluzole is recommended as general ALS therapy from diagnosis, including SOD1-associated disease. Its modest survival evidence comes from broader ALS populations and does not establish a separate SOD1-specific effect. Tolerability and adverse effects should guide dose adjustment or discontinuation.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Offer lifelong riluzole to all people with ALS at diagnosis.
    explanation: General ALS guidance supports use in ALS1 without implying a genotype-specific efficacy estimate.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: riluzole
      term:
        id: CHEBI:8863
        label: Riluzole
- name: Edaravone
  therapeutic_modality: SMALL_MOLECULE
  description: Edaravone is an ALS therapy available in intravenous and oral formulations in the US. Its pivotal efficacy trial selected early-stage Japanese patients with preserved function and respiration; these trial criteria are not the full US labeled indication. EAN 2024 guidance recommends against routine use outside clinical trials, so clinical use depends on jurisdiction, evidence assessment and shared decisions. A distinct SOD1-specific benefit has not been established, and its therapeutic mechanism in patients remains unknown despite antioxidant activity.
  evidence:
  - reference: url:https://www.radicavahcp.com/pdfs/radicava-prescribing-information.pdf
    reference_title: https://www.radicavahcp.com/pdfs/radicava-prescribing-information.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: RADICAVA and RADICAVA ORS are indicated for the treatment of amyotrophic lateral sclerosis (ALS).
    explanation: The US label does not restrict the indication to the pivotal trial subgroup.
  - reference: url:https://www.radicavahcp.com/pdfs/radicava-prescribing-information.pdf
    reference_title: https://www.radicavahcp.com/pdfs/radicava-prescribing-information.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The mechanism by which RADICAVA and RADICAVA ORS exert their therapeutic effect in patients with ALS is unknown.
    explanation: The label limits claims about the human therapeutic mechanism.
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Based on the available evidence, the panel currently does not recommend the use of intravenous or oral edaravone outside the context of a clinical trial.
    explanation: The European guideline recommendation differs from US availability; this is not a claim that the drug is unapproved everywhere.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: edaravone
      term:
        id: CHEBI:31530
        label: edaravone
- name: Multidisciplinary ALS Care
  description: Coordinated specialist ALS care, generally reviewed every 3–6 months according to progression, integrates respiratory, nutritional, mobility, communication and psychosocial needs. This is general ALS guidance applied to ALS1.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Provide coordinated care for people with ALS using a clinic‐based, specialist ALS MDT approach.
    explanation: The guideline supports coordinated ALS care rather than a SOD1-specific intervention trial.
- name: Noninvasive Ventilation
  description: Offer noninvasive ventilation when symptoms, signs or investigations support respiratory insufficiency, with efforts to accommodate bulbar dysfunction. Discuss invasive ventilation in advance according to preferences and clinical circumstances. Diaphragmatic pacing is not recommended.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: NIV should be offered to all patients with ALS with either symptoms, signs, or laboratory investigations supportive of respiratory insufficiency.
    explanation: Ventilatory support compensates for respiratory impairment; it does not reverse motor neuron degeneration.
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Do not use diaphragmatic pacing for the treatment of ALS.
    explanation: The guideline distinguishes ventilatory support from ineffective diaphragm pacing.
  target_mechanisms:
  - target: Respiratory Insufficiency
    treatment_effect: BYPASSES
    description: Ventilatory support compensates for respiratory impairment; it does not reverse motor neuron degeneration.
    evidence:
    - reference: PMID:38470068
      reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: NIV should be offered to all patients with ALS with either symptoms, signs, or laboratory investigations supportive of respiratory insufficiency.
      explanation: Ventilatory support compensates for respiratory impairment; it does not reverse motor neuron degeneration.
- name: Nutritional Support and Gastrostomy
  description: Assess swallowing, nutrition and feeding effort and discuss gastrostomy early, revisiting the decision as disease progresses. In respiratory insufficiency, introduce NIV and perform gastrostomy with the patient established on NIV. Tube feeding supports nutritional delivery without restoring bulbar motor function.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Discuss gastrostomy at an early stage, and at regular intervals as ALS progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking, and risk of choking.
    explanation: Gastrostomy can bypass impaired oral swallowing to provide nutrition, with timing individualized.
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: If there is respiratory insufficiency, perform the gastrostomy with the patient established on NIV.
    explanation: Respiratory support is part of safe gastrostomy planning in people with respiratory impairment.
  target_mechanisms:
  - target: Dysphagia
    treatment_effect: BYPASSES
    description: Gastrostomy can bypass impaired oral swallowing to provide nutrition, with timing individualized.
    evidence:
    - reference: PMID:38470068
      reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Discuss gastrostomy at an early stage, and at regular intervals as ALS progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking, and risk of choking.
      explanation: Gastrostomy can bypass impaired oral swallowing to provide nutrition, with timing individualized.
- name: Cough Augmentation
  description: Manual assisted cough or breath stacking can assist ineffective cough, with mechanical cough assistance considered when needed. This is a general ALS supportive intervention.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Offer cough augmentation techniques, such as manual assisted cough, to people with ALS who cannot cough effectively.
    explanation: The guideline recommends augmenting an ineffective cough.
- name: Communication Support
  description: Speech-language assessment and augmentative or alternative communication equipment should be provided promptly, with adaptation as abilities change. Communication aids compensate for impaired speech rather than restoring the underlying motor neurons.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life.
    explanation: Communication equipment bypasses impaired speech production to support communication.
  target_mechanisms:
  - target: Dysarthria
    treatment_effect: BYPASSES
    description: Communication equipment bypasses impaired speech production to support communication.
    evidence:
    - reference: PMID:38470068
      reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life.
      explanation: Communication equipment bypasses impaired speech production to support communication.
- name: Rehabilitation and Mobility Support
  description: Exercise, positioning and assistive or orthotic support are individualized to function, fatigue and preferences. Goals include joint mobility, comfort and participation; a SOD1-specific disease-modifying effect is not established.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Choose a programme that is appropriate to the person's level of function and tailored to their needs, abilities, and preferences.
    explanation: The guideline supports individualized physical rehabilitation rather than fixed-intensity exercise.
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: If a person needs orthoses to help with muscle problems, they should be referred to orthotics services without delay, and the orthoses should be provided without delay.
    explanation: Orthoses support function when muscle weakness causes a need.
- name: Spasticity Management
  description: Physical therapy and, where appropriate, baclofen, tizanidine, gabapentin or other guideline-listed agents can relieve stiffness and spasticity. Choice depends on comorbidity, tolerability and functional consequences.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Consider cannabinoids, baclofen, tizanidine, or gabapentin to treat muscle stiffness, spasticity, or increased tone.
    explanation: These symptomatic treatments reduce spasticity without reversing the causal motor neuron disease.
  target_mechanisms:
  - target: Spasticity
    treatment_effect: INHIBITS
    description: These symptomatic treatments reduce spasticity without reversing the causal motor neuron disease.
    evidence:
    - reference: PMID:38470068
      reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Consider cannabinoids, baclofen, tizanidine, or gabapentin to treat muscle stiffness, spasticity, or increased tone.
      explanation: These symptomatic treatments reduce spasticity without reversing the causal motor neuron disease.
- name: Muscle Cramp Management
  description: Symptomatic treatment of troublesome cramps may include agents such as mexiletine or baclofen, selected with attention to comorbidities and adverse effects. Cardiac risk requires particular consideration for relevant drugs.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Consider sodium blockers (ranolazine, quinine sulfate, mexiletine, carbamazepine), gabapentine, pregabalin, and baclofen for the management of cramps as symptomatic treatment.
    explanation: The general ALS guideline supports symptomatic cramp treatment.
  target_mechanisms:
  - target: Muscle Cramps
    treatment_effect: INHIBITS
    description: The general ALS guideline supports symptomatic cramp treatment.
    evidence:
    - reference: PMID:38470068
      reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Consider sodium blockers (ranolazine, quinine sulfate, mexiletine, carbamazepine), gabapentine, pregabalin, and baclofen for the management of cramps as symptomatic treatment.
      explanation: The general ALS guideline supports symptomatic cramp treatment.
- name: Emotional Lability Management
  description: Emotional lability should be distinguished from depression or frontotemporal cognitive/behavioral symptoms. SSRIs, tricyclic antidepressants or dextromethorphan/quinidine may be considered according to comorbidity and tolerability.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Consider selective serotonin reuptake inhibitor (SSRI) antidepressants, tricyclic antidepressants, or DMQ for treating emotional lability in people with ALS.
    explanation: General ALS recommendations support symptom reduction for emotional lability.
  target_mechanisms:
  - target: Emotional Lability
    treatment_effect: INHIBITS
    description: General ALS recommendations support symptom reduction for emotional lability.
    evidence:
    - reference: PMID:38470068
      reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Consider selective serotonin reuptake inhibitor (SSRI) antidepressants, tricyclic antidepressants, or DMQ for treating emotional lability in people with ALS.
      explanation: General ALS recommendations support symptom reduction for emotional lability.
- name: Saliva and Secretion Management
  description: If troublesome sialorrhea develops, consider anticholinergic treatment with attention to adverse effects and coexisting bulbar problems; refractory severe symptoms may warrant specialist botulinum toxin. This care indication does not establish a disease-wide frequency of sialorrhea in SOD1 ALS.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Consider anticholinergics (e.g., amitriptyline, atropine, glycopyrrolate, oxybutynin, scopolamine) as first‐line treatment.
    explanation: The recommendation applies to the guideline section on symptomatic sialorrhea management.
- name: Psychological and Palliative Support
  description: Offer psychological support, caregiver support and individualized advance care planning throughout the disease course. Discuss ventilation, feeding and end-of-life preferences at a time and in a manner appropriate to the individual.
  evidence:
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Offer the person and their family/carers information about sources of emotional and psychological support, including support groups and online forums, and respite care.
    explanation: The guideline supports psychosocial care for patients and carers.
  - reference: PMID:38470068
    reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Be prepared to discuss end‐of‐life issues whenever people wish to do so
    explanation: The guideline supports ongoing access to preference-sensitive end-of-life discussion.
- name: Genetic Counseling and Predictive Testing
  therapeutic_modality: BEHAVIORAL
  description: Genetic counseling addresses variant-specific inheritance, age-dependent penetrance, reproductive options, implications for relatives and the psychosocial consequences of predictive testing. Testing an unaffected relative requires informed counseling; a positive result does not predict an individual onset date. ATLAS is evaluating biomarker-triggered presymptomatic therapy in a selected carrier group, rather than establishing routine presymptomatic treatment.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35585374
    reference_title: 'Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: During screening for enrollment in Part A of the study, genetic counseling sessions are required before a DNA sample is collected for testing and at the time that the results are communicated.
    explanation: The ATLAS protocol illustrates pre- and post-test counseling rather than a demonstrated preventive treatment benefit.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
    reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Potential consequences of such testing (including, but not limited to, socioeconomic changes, the need for long-term follow up and evaluation arrangements for individuals with a positive test result)
    explanation: The counseling section explicitly includes these possible consequences of predictive testing.
animal_models:
- name: SOD1 G93A transgenic mouse
  species: Mouse
  genotype: High-expression human SOD1 G93A transgene
  publication: PMID:8209258
  description: High-level expression of the G93A variant, which has little effect on enzyme activity, causes progressive paralysis and spinal motor neuron loss.
  evidence:
  - &id010
    reference: PMID:8209258
    reference_title: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age.
    explanation: The original report documents spinal motor neuron loss and paralysis.
  modeled_mechanisms:
  - target: Motor Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    description: Reproduces progressive motor neuron loss with a defined mutant SOD1 transgene.
    limitations: Supraphysiological transgene dosage differs from endogenous human alleles. Prior poor response of high-copy lines to homogenate seeding has no definitive explanation and does not refute their motor degeneration.
    evidence:
    - *id010
- name: SOD1-null mouse
  species: Mouse
  genotype: Homozygous Sod1 knockout
  publication: PMID:8673102
  description: Complete SOD1 deficiency did not produce overt motor deficits by six months, but increased motor neuron vulnerability after axonal injury. This tests simple absence of the enzyme rather than every possible loss-of-function contribution to ALS.
  evidence:
  - &id011
    reference: PMID:8673102
    reference_title: Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: These animals develop normally and show no overt motor deficits by 6 months in age.
    explanation: The negative result is limited to the described development and observation period.
  - reference: PMID:8673102
    reference_title: Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.
    explanation: The injury result demonstrates a physiological protective role.
  modeled_mechanisms:
  - target: Motor Neuron Degeneration
    relationship: FAILS_TO_RECAPITULATE
    model_scale: ORGANISM
    description: Does not reproduce spontaneous ALS-like motor degeneration by the reported six-month assessment.
    limitations: The observation period and injury dependence preclude an absolute lifetime or stress-independent negative claim. ALS1 includes several inheritance contexts, not only heterozygous missense alleles.
    evidence:
    - *id011
- name: Microglial and motor-neuron conditional SOD1 reduction
  species: Mouse
  genotype: Deletable mutant human SOD1 transgene with lineage-restricted excision
  publication: PMID:16741123
  description: Lineage-directed reduction separates motor-neuron contributions to onset/early progression from a microglial contribution to later progression in the tested transgenic model.
  evidence:
  - &id012
    reference: PMID:16741123
    reference_title: Onset and progression in inherited ALS determined by motor neurons and microglia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression.
    explanation: The conditional model distinguishes the microglial progression contribution.
  modeled_mechanisms:
  - target: Microglial Mutant SOD1 Contribution
    relationship: PERTURBS
    model_scale: ORGANISM
    description: Microglial reduction slows later progression.
    limitations: The cached source is abstract-only; exact Cre specificity and quantitative excision details are not imported. The phase division is not assumed universal in human ALS.
    evidence:
    - *id012
- name: Astrocyte conditional SOD1 reduction
  species: Mouse
  genotype: Deletable mutant human SOD1 transgene with astrocytic reduction
  publication: PMID:18246065
  description: Reduced astrocytic mutant expression delays microglial activation and later disease progression in the reported mouse study.
  evidence:
  - &id013
    reference: PMID:18246065
    reference_title: Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: diminished mutant expression in astrocytes did not affect onset, but delayed microglial activation and sharply slowed later disease progression
    explanation: Astrocytic reduction modifies the measured progression and activation outcomes.
  modeled_mechanisms:
  - target: Astrocytic Mutant SOD1 Contribution
    relationship: PERTURBS
    model_scale: ORGANISM
    description: Perturbs an astrocytic contribution to disease progression.
    limitations: The cached abstract does not resolve the secreted or contact-dependent mediator. Delayed microglial activation alone does not prove that microglia completely mediate the benefit.
    evidence:
    - *id013
- name: ASK1-deficient SOD1 G93A mice
  species: Mouse
  genotype: SOD1 G93A transgene crossed with Ask1-null mice
  publication: PMID:18519638
  description: In male low-copy G1L mice, ASK1 deletion extends survival and partly preserves spinal motor neurons without delaying motor onset; a high-copy comparison also shows a survival extension without onset change.
  evidence:
  - &id014
    reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: the mean survival of SOD1G93A/ASK1−/− mice was 38.4 ± 2.7 wk (±SEM) and significantly longer than the 34.9 ± 1.6 wk survival of control SOD1G93A mice
    explanation: ASK1 deletion delays the terminal endpoint in the male low-copy model.
  - reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: ASK1 deficiency also extended the survival of SOD1G93A(high) mice but not the time of onset
    explanation: The onset/progression distinction is preserved in the reported additional model.
  modeled_mechanisms:
  - target: ASK1 Kinase Activation
    relationship: PERTURBS
    model_scale: ORGANISM
    description: Genetic removal tests the contribution of ASK1 to model progression.
    limitations: Protection is partial, sex and transgene context are restricted, and a constitutive knockout is not a clinical drug intervention. The study does not establish aggregate-independent protection.
    evidence:
    - *id014
  - target: Motor Neuron Degeneration
    relationship: PERTURBS
    model_scale: ORGANISM
    description: ASK1 deficiency mitigates the loss of spinal motor neurons.
    limitations: The result does not identify every downstream death effector or imply prevention of ALS onset.
    evidence:
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: These findings indicated that the absence of ASK1 mitigates motor neuron death in ALS mice.
      explanation: Direct histology complements the survival endpoint.
- name: Low-copy SOD1 homogenate-seeding recipients
  species: Mouse
  genotype: VLE G93A on B6SJL and homozygous G85R:YFP Line 230 on FVB/NJ
  publication: PMID:41702846
  description: Adult intrathecal inoculation uses 4 microliters containing 2 microliters of 10% spinal-cord homogenate and lidocaine. Donors, recipient genotypes, ages and passage histories vary across comparisons. Paralysis leading to humane euthanasia is the primary endpoint.
  evidence:
  - &id015
    reference: PMID:41702846
    reference_title: Efficient induction of motor neuron disease in transgenic G93A SOD1 mice by prion-like seeding.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: injected intrathecally with seeding homogenates containing misfolded G93A or G85R SOD1 developed accelerated motor neuron disease efficiently
    explanation: The study tests disease induction in susceptible transgenic recipients.
  - reference: PMID:41702846
    reference_title: Efficient induction of motor neuron disease in transgenic G93A SOD1 mice by prion-like seeding.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: The primary humane endpoint for all injections was overt paralysis of at least one hindlimb.
    explanation: Defines the operational endpoint rather than spontaneous death.
  modeled_mechanisms:
  - target: Seeded SOD1 Inclusion Pathology
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    description: Homogenate inoculation accelerates inclusion-associated disease in susceptible hosts.
    limitations: Inocula are not purified or seed-titer normalized. Age, route, batch and passage vary together; long incubation overlaps spontaneous disease in some older animals. Conditional incubation analyses exclude asymptomatic animals. An internal six-versus-five denominator discrepancy prevents a universal seeding-rate estimate.
    evidence:
    - *id015
  - target: Motor Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    description: The inoculated mice reach an accelerated motor disease endpoint.
    limitations: The experiment does not prove necessity of cell-to-cell propagation in human ALS or isolate which aggregate species kills neurons.
    evidence:
    - *id015
- name: SOD1 G85R with wild-type or D90A coexpression
  species: Mouse
  genotype: G85R/WT or G85R/D90A double transgenes on C57BL/6J
  publication: PMID:40450581
  description: Both double-transgenic lines have earlier onset and shorter endpoint survival than G85R alone. Wild-type coexpression aggravates the phenotype more than D90A; D90A also prolongs onset-to-endpoint duration. Insoluble pools contain both expressed proteins and show strain-A epitope profiles.
  evidence:
  - &id016
    reference: PMID:40450581
    reference_title: Diverse effects of coexpression of human SOD1 variants on motor neuron disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: In both cases, the lifespans of the combined Tg mice were shortened, but the effect of coexpression of hSOD1WT was far greater than that of hSOD1D90A
    explanation: Both coexpression combinations aggravate the endpoint relative to G85R alone; D90A is less aggravating, not protective.
  modeled_mechanisms:
  - target: Cytoplasmic SOD1 Aggregate Formation
    relationship: PERTURBS
    model_scale: ORGANISM
    description: Coexpression modifies aggregate accumulation and disease kinetics.
    limitations: WT expression is about 2.5-fold higher than D90A, confounding a purely sequence-based comparison. Coaccumulation does not directly demonstrate hybrid-fibril nucleation. No WT/D90A human heterozygous genotype was tested, so human recessivity remains a proposed explanation.
    evidence:
    - *id016
    - reference: PMID:40450581
      reference_title: Diverse effects of coexpression of human SOD1 variants on motor neuron disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Although not shown here directly, we suggest that the mechanism involves direct combination of hSOD1WT or hSOD1D90A with hSOD1G85R to accelerate the nucleation and growth of aggregate fibrils.
      explanation: The authors explicitly distinguish inferred coassembly from a measured molecular event.
- name: Borsantrazole-treated SOD1 G37R mice
  species: Mouse
  genotype: High-copy SOD1 G37R line 42
  publication: PMID:42503607
  description: Presymptomatic daily intraperitoneal borsantrazole, 10 mg/kg from day 90, was compared with vehicle in 12 mice per group, six of each sex. The study reports delayed onset, less weight loss and a longer humane-endpoint survival. Borsantrazole remains an experimental compound.
  evidence:
  - &id017
    reference: PMID:42503607
    reference_title: 'Introducing Borsantrazole: A Trifunctional Boron-Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: the mean age of survival differed significantly between the vehicle‐treated (177.9 days) and the BSZ‐treated group (193 days).
    explanation: The primary model reports a 15.1-day difference in mean terminal age.
  modeled_mechanisms:
  - target: Motor Neuron Degeneration
    relationship: PERTURBS
    model_scale: ORGANISM
    description: The intervention modifies disease-related motor and terminal outcomes in one transgenic model.
    limitations: There is no human efficacy result or in vivo edaravone comparator. Small sex subgroups do not establish a treatment-by-sex interaction. End-stage male spinal proteomics is exploratory and does not prove antioxidant, NRF2 or autophagy mediation; limited mouse safety assays do not establish clinical safety.
    evidence:
    - *id017
- name: SOD1 G93A motor-neuron multiomic atlas
  species: Mouse
  genotype: High-copy SOD1 G93A transgene
  publication: PMID:42335888
  description: Single-nucleus and spatial analyses identify a disease-associated alpha-motor-neuron transcriptional state across separately sampled disease stages. Human postmortem data include 12 SOD1 ALS donors and support related signature changes.
  evidence:
  - &id018
    reference: PMID:42335888
    reference_title: An emergent disease-associated motor neuron state precedes cell death in ALS.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: mid-stage (~P100), end-stage (~P125), and age-matched, non-transgenic control mice
    explanation: Defines a cross-sectional stage series rather than repeated sampling of the same neurons.
  modeled_mechanisms:
  - target: Motor Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    description: Profiles molecular states associated with vulnerable motor neurons during model progression.
    limitations: Pseudotime and cross-stage sampling do not trace individual neurons to death. The DM program includes potentially protective responses and is not an established causal intermediate or survival predictor. Human analysis retains only 150 bona fide alpha nuclei across all conditions, with neuronal fragments as a separate assay.
    evidence:
    - *id018
clinical_trials:
- name: NCT02623699
  phase: PHASE_III
  status: COMPLETED
  description: The phase III VALOR component of a multipart tofersen study randomized 108 symptomatic adults. The primary 28-week clinical endpoint in the 60-participant faster-progression subgroup was not met, while CSF SOD1 and plasma NfL fell. Its linked extension is recorded separately as NCT03070119.
  evidence:
  - reference: clinicaltrials:NCT02623699
    reference_title: A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects With Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The primary objective of Part C of this study is to evaluate the clinical efficacy of tofersen administered to adults with ALS and a confirmed SOD1 mutation.
    explanation: Registry record establishing the trial that supports SOD1-directed therapy in this entry.
- name: NCT04856982
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: ATLAS evaluates tofersen initiated before clinical onset in selected adult SOD1-variant carriers with elevated neurofilament. The registry remained active, not recruiting, on 2026-09-21. Preventive efficacy is unresolved; the published protocol is not an outcome report.
  evidence:
  - reference: clinicaltrials:NCT04856982
    reference_title: A Phase 3 Randomized, Placebo-Controlled Trial With a Longitudinal Natural History Run-In and Open-Label Extension to Evaluate BIIB067 Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The primary objective of this study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF).
    explanation: Registry record for the presymptomatic-initiation trial referenced in the genetic counseling treatment entry.
- name: NCT03070119
  phase: PHASE_III
  status: COMPLETED
  description: Open-label extension of prior tofersen studies. The long-term VALOR comparison retained initial randomized early/delayed assignment, although both groups could receive active drug after crossover. The registry covers a broader extension population than the 95 VALOR participants entering its extension.
  evidence:
  - reference: clinicaltrials:NCT03070119
    reference_title: An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 Administered to Previously Treated Adults With Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 (tofersen) in participants with amyotrophic lateral sclerosis (ALS) and confirmed superoxide dismutase 1 (SOD1) mutation.
    explanation: The registry identifies the extension scope.
discussions:
- discussion_id: sod1_model_dose_and_human_response
  kind: HUMAN_MODEL_MISMATCH
  prompt: How does transgene dosage affect translation of SOD1 model interventions to human ALS?
  attaches_to:
  - animal_models#SOD1 G93A transgenic mouse
  - animal_models#Low-copy SOD1 homogenate-seeding recipients
  rationale: Human pathogenic alleles and high-copy transgenic models differ in expression, genotype and disease timing. Seeding susceptibility varies across model and inoculation conditions, but no isolated transgene-dose experiment explains every difference. This uncertainty does not establish why VALOR missed its 28-week clinical endpoint; timing, power, progression heterogeneity and other factors remain possible.
- discussion_id: human_sod1_toxic_mediation
  kind: KNOWLEDGE_GAP
  prompt: Which abnormal SOD1 species and downstream cellular pathways drive progression in patients?
  attaches_to:
  - pathophysiology#Cytoplasmic SOD1 Aggregate Formation
  - pathophysiology#Mutant SOD1 Association with Derlin-1
  - pathophysiology#Microglial Mutant SOD1 Contribution
  - pathophysiology#Astrocytic Mutant SOD1 Contribution
  rationale: Human tissue demonstrates SOD1 pathology, while experimental perturbations support contributions from ER stress/ASK1 and non-neuronal cells. Visible inclusions, soluble species and associated transcriptional states are not interchangeable causal entities. Relative mediation in human genotypes and the effects of lowering protein supply on pre-existing aggregates remain unresolved.
- discussion_id: dm_state_causal_meaning
  kind: KNOWLEDGE_GAP
  prompt: Does the disease-associated motor-neuron signature contribute to injury, reflect compensation, or contain both?
  attaches_to:
  - biochemical#Disease-associated motor neuron transcriptional signature
  - experimental_models#WTC11 motor-neuron transcription-factor perturbation
  rationale: The mouse stage series and human postmortem data establish association. Some signature regulators may be protective, and forced CREB3/ATF3 expression changes only parts of the program without a death or rescue assay. Neither pseudotime, glial proximity nor computational ligand nomination proves a DM-state-to-death mechanism.
datasets:
- accession: geo:GSE271030
  title: RNA Expression Profiling in Lymphoblastoid Cell Lines from Mutated and Non-Mutated Amyotrophic Lateral Sclerosis Patients
  data_type: BULK_RNA_SEQ
  description: RNA-seq of patient-derived lymphoblastoid cell lines in which SOD1-mutated patients are one of four genotype subgroups (alongside FUS, TARDBP and C9ORF72) compared with sporadic ALS and matched controls. Included because the study stratifies by causal gene and so contains an ALS1 arm; it is not a SOD1-only dataset, and the authors report that expression profiles were genotype-specific, which is what makes the SOD1 arm separable rather than pooled.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:38967638
  notes: Patient-derived lymphoblastoid lines provide a non-neuronal genotype-stratified transcriptomic resource. Expression differences do not by themselves establish motor-neuron causal pathways.
  evidence:
  - reference: GEO:GSE271030
    reference_title: RNA Expression Profiling in Lymphoblastoid Cell Lines from Mutated and Non-Mutated Amyotrophic Lateral Sclerosis Patients
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: a transcriptomic profiling of Sporadic ALS (SALS) and mutated patients (FUS, TARDBP, C9ORF72 and SOD1), and matched controls was realized
    explanation: The repository record states that SOD1-mutated patients are one of the profiled genotype subgroups, which is what makes this dataset relevant to ALS1.
  - reference: GEO:GSE271030
    reference_title: RNA Expression Profiling in Lymphoblastoid Cell Lines from Mutated and Non-Mutated Amyotrophic Lateral Sclerosis Patients
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Gene expression profiles of LCLs were genetic-background specific, indeed only 12 genes were commonly deregulated in all groups.
    explanation: Reports that expression profiles differed by genetic background, with almost no shared deregulated genes. This is what makes the SOD1 arm worth analysing separately rather than pooling it into a generic ALS signature; it is not itself a SOD1-specific result.
- accession: geo:GSE306676
  title: An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS [scRNA-Seq]
  data_type: SINGLE_CELL_RNA_SEQ
  description: Stage-stratified single-nucleus RNA sequencing of spinal motor-neuron populations in SOD1 G93A mice and controls.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:42335888
  notes: Cross-sectional stage samples and inferred molecular trajectories do not constitute same-cell lineage tracing or establish the DM signature as a cause of death.
  evidence:
  - reference: PMID:42335888
    reference_title: An emergent disease-associated motor neuron state precedes cell death in ALS.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: 'Raw and processed sequencing data have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession numbers GEO: GSE306676 for the snRNA-seq data and GEO: GSE306675 for the multiome (paired snATAC/snRNA-seq) data.'
    explanation: The primary publication identifies the deposited assay and accession.
- accession: geo:GSE306675
  title: An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS [multiome]
  data_type: MULTI_OMICS
  description: Paired single-nucleus ATAC and RNA sequencing of SOD1 G93A mouse spinal tissue across disease stages.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:42335888
  notes: Cross-sectional stage samples and inferred molecular trajectories do not constitute same-cell lineage tracing or establish the DM signature as a cause of death.
  evidence:
  - reference: PMID:42335888
    reference_title: An emergent disease-associated motor neuron state precedes cell death in ALS.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: 'Raw and processed sequencing data have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession numbers GEO: GSE306676 for the snRNA-seq data and GEO: GSE306675 for the multiome (paired snATAC/snRNA-seq) data.'
    explanation: The primary publication identifies the deposited assay and accession.
experimental_models:
- name: Mutant SOD1 Derlin-1 and ERAD assays
  experimental_model_type: CELL_LINE
  description: NSC34 and HEK293 systems express tested SOD1 mutants and ERAD components. Interaction assays, NHK/CD3delta turnover, ubiquitination, stress signaling and ASK1 kinase activity interrogate separate steps.
  evidence:
  - &id019
    reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Cycloheximide chase experiments showed that the degradation of CD3δ was also retarded by overexpression of SOD1mut
    explanation: Transfected-cell assays measure slower ERAD substrate turnover.
  modeled_mechanisms:
  - target: Impaired ER-Associated Protein Degradation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    description: Mutant expression retards ERAD reporters.
    limitations: Overexpression and model substrates may not quantify the corresponding endogenous human-neuron burden. Direct binding is not proven in the reticulocyte-lysate assay; measured core-complex associations remain intact.
    evidence:
    - *id019
  - target: ASK1 Kinase Activation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: MOLECULAR
    description: Mutant expression activates an ASK1 kinase readout.
    limitations: NSC34 stress signaling did not itself result in the motor neuron death measured in the separate primary-culture preparation.
    evidence:
    - reference: PMID:18519638
      reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1
      explanation: Direct kinase activity is measured.
- name: Embryonic spinal-cord SOD1 toxicity and rescue cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Mixed E12.5 mouse spinal-cord cultures express G93A or G85R SOD1; the Derlin-1 CT4 peptide or ASK1 deficiency partially preserves SMI32-positive motor neurons.
  evidence:
  - &id020
    reference: PMID:18519638
    reference_title: ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: SOD1mut-induced motor neuron death was significantly attenuated by coexpression of Derlin-1(CT4)
    explanation: The competing peptide partly protects neurons in embryonic spinal cultures.
  modeled_mechanisms:
  - target: Motor Neuron Degeneration
    relationship: PERTURBS
    model_scale: CELLULAR
    description: Tests partial rescue of cultured motor neuron loss.
    limitations: Mixed neurons and glia do not isolate a purely neuron-autonomous effect; lentiviral overexpression and embryonic cells differ from adult human ALS. Rescue is incomplete.
    evidence:
    - *id020
- name: ATP-triggered SOD1 donor and recipient cultures
  experimental_model_type: CELL_LINE
  description: Transfected NSC34 cells exposed to 3–5 mM ATP release particulate material. Recipient NSC34 cells and EOC13 microglia show ER stress reporter activity and TNF release respectively.
  evidence:
  - &id021
    reference: PMID:35478453
    reference_title: P2X7 receptor activation mediates superoxide dismutase 1 (SOD1) release from murine NSC-34 motor neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: ATP induced the rapid release of aggregated SOD1G93A from NSC-34 cells transiently transfected with SOD1G93A, a process blocked by AZ10606120 and revealing a role for P2X7 in this process.
    explanation: The donor-cell assay tests release after an acute ATP challenge.
  modeled_mechanisms:
  - target: P2X7-Associated SOD1 Release
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    description: Antagonist-sensitive release occurs after high ATP exposure.
    limitations: NSC34 is a murine hybrid line, not a primary human motor neuron. A single antagonist without receptor knockout supports pharmacological involvement; low LDH only limits overt lysis under the tested conditions.
    evidence:
    - *id021
  notes: Released 20000-g pellets contain mixed material. EGFP control preparations can also provoke responses, so purified SOD1 necessity and recipient death are not demonstrated. Release includes tested wild-type SOD1. The CELL_LINE classification reflects separate donor and recipient cell-line assays with transfer of released material, rather than an assumption of direct mixed-cell coculture.
- name: WTC11 motor-neuron transcription-factor perturbation
  experimental_model_type: IPSC_DERIVED_MODEL
  description: Lentiviral CREB3 or ATF3 overexpression in WTC11 hNIL motor neurons induces portions of the disease-associated transcriptional signature. RNA is assessed 14 days after transduction.
  evidence:
  - reference: PMID:42335888
    reference_title: An emergent disease-associated motor neuron state precedes cell death in ALS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: CREB3 expression was associated with upregulation of approximately 20% of DM-upregulated genes (precision ~15%), while ATF3 expression was associated with downregulation of approximately 5% of DM-downregulated genes (precision ~34%).
    explanation: Forced transcription-factor expression partially reproduces the associated gene-expression program.
  - reference: PMID:42335888
    reference_title: An emergent disease-associated motor neuron state precedes cell death in ALS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: For each condition, three independent wells were transduced and processed as technical replicates.
    explanation: The replicate unit is a technical well, not an independent patient.
  notes: These are engineered non-patient cells. No SOD1 variant, neuron-death endpoint, functional rescue or validated therapeutic mechanism is tested. The model is left without a degeneration join because changing an associated program does not establish that the program causes cell death.
progression:
- phase: Variable onset and progression
  evidence:
  - reference: PMID:36385230
    reference_title: Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patient age at onset of first symptom ranged from 38 to 60 years (mean 49 years) and duration of symptomatic illness ranged from 5 to 33 years (mean 17 years).
    explanation: The autopsy series defines its own selected genotype-specific course.
  - reference: PMID:42265995
    reference_title: Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: rapid progression over months to involve all body regions
    explanation: Documents the generalisation this node describes. The cited cases are juvenile p.Asp125Gly, where progression is unusually rapid, so the quote establishes the pattern of spread rather than its typical rate.
  notes: SOD1 ALS ranges from rare juvenile rapidly progressive cases to adult-onset disease lasting decades. In the selected nine-person D90A homozygous autopsy series, onset ranged from 38 to 60 years and symptomatic duration from 5 to 33 years. Variant, family, treatment and ascertainment affect course; these are not universal age or survival bounds.

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