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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

All reported patients are homozygous for a SOD1 loss-of-function allele, most from consanguineous families. Heterozygous parents and siblings have roughly halved erythrocyte SOD1 activity and no overt neurological phenotype, which distinguishes this recessive disorder from dominant SOD1 amyotrophic lateral sclerosis.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:31332433 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype."

Carriers are clinically unaffected despite reduced activity, consistent with recessive inheritance.

PMID:38668754 SUPPORT DIRECT BACKGROUND Human clinical

"biallelic loss of SOD1 function results in a novel phenotype called infantile SOD1 deficiency syndrome, which is consistent with a recessive pattern of inheritance"

States the recessive mode of inheritance across the reported families.

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We conclude that a ≈50% reduction in SOD1 enzyme activity and the presence of a single C112X SOD1 allele is tolerated, at least up to age 45 years."

Heterozygous relatives followed into adulthood remained unaffected.

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Discussions and Knowledge Gaps

4

Why does complete SOD1 absence cause infantile upper and lower motor neuron degeneration in humans but only a distal motor axonopathy, with motor neuron cell bodies spared, in Sod1 knockout mice?

HUMAN MODEL MISMATCH OPEN stahp-mouse-human-mismatch

Attached to

animal_models#SOD1-null mouse pathophysiology#Upper and Lower Motor Neuron Degeneration

The mouse knockout was the basis for the long-held view that loss of SOD1 activity does not damage motor neurons, a view the human syndrome contradicts. Knockout mice do develop a distal motor axonopathy from the first months of life, and SOD1-null dogs develop an early tetraparesis, so the mismatch lies in which parts of the motor system degenerate and how severely, rather than in an absence of motor involvement. Species differences in compensating antioxidants (mice synthesize ascorbate, humans do not), lifespan and motor system size are candidate explanations, but none has been tested.

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT BACKGROUND Human clinical

"the fact that SOD1 knockout mice do not develop ALS-like disease, contributed to the general view that reduced SOD1 activity does not cause ALS"

Records how the mouse result shaped expectations that the human syndrome overturns.

Is STAHP a distinct syndrome or a very early infantile-onset form of SOD1 ALS?

CONTROVERSY OPEN stahp-separate-entity-or-early-als

Attached to

disease#Spastic Tetraplegia and Axial Hypotonia, Progressive

The founding reports framed SOD1 deficiency as a new syndrome distinct from ALS, citing the opposite mechanism and additional cerebellar and non-neuronal involvement. A Brazilian series found upper and lower motor neuron involvement that fulfils ALS diagnostic criteria and argued for very early-onset ALS. The answer affects classification but not the causal chain recorded here.

Show evidence (2 references)

PMID:31332433 SUPPORT DIRECT PRIMARY RESULT Human clinical

"These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease"

Position that the syndrome is mechanistically distinct from ALS.

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"allowing us to conclude that the cases presented by these authors, and the new additional patients reported in this study represent a very early infantile-onset ALS."

Opposing position.

What does complete human SOD1 deficiency imply for SOD1-lowering therapies in ALS?

INTERPRETATION OPEN stahp-sod1-silencing-safety

Attached to

pathophysiology#Absent SOD1 Superoxide Dismutase Activity

Approved and investigational SOD1-lowering therapies for ALS suppress both mutant and wild-type SOD1. STAHP shows that total loss of the enzyme is harmful to the human motor system, while unaffected carriers show that about half of normal activity is tolerated, suggesting a threshold that knockdown should not cross.

Show evidence (2 references)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The association of the severe ISODDES phenotype with a loss of SOD1 function suggests the need for cautious application of general silencing interventions in ALS since the currently studied gene therapy approaches equally target the mutant and wild-type SOD1 alleles."

The authors' therapeutic interpretation.

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"However, given the absence of an overt phenotype in heterozygous carriers with approximately halved enzyme activity, it is possible that there is a threshold of minimum SOD1 activity to avoid disease manifestation."

Carrier data suggest partial reduction is tolerated.

Could glutathione-replenishing or other antioxidant treatment slow disease in children lacking SOD1?

KNOWLEDGE GAP OPEN stahp-antioxidant-therapy

Attached to

pathophysiology#Reduced Erythrocyte Glutathione treatments#

N-acetylcysteine improved anemia and other features in Sod1 knockout mice, and patient erythrocytes are glutathione-depleted, but no treatment has been tested in patients. Any trial would need outcome measures suited to a slowly progressing phase after early rapid decline.

Show evidence (2 references)

PMID:36793789 SUPPORT INDIRECT BACKGROUND Model organism

"From a therapeutic perspective, treatment with the GSH precursor N-acetylcysteine55 improved anaemic symptoms,54 as well as other symptoms in SOD1 knockout models56 and might be a promising approach to treat symptoms observed in the patients studied here."

Mouse evidence and the authors' proposal; no human data.

PMID:39629626 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity"

Proposal from a case report, not a tested treatment.

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Pathophysiology

10

Biallelic SOD1 Loss-of-Function Variants

Homozygous SOD1 variants abolish the enzyme. The recurrent c.335dupG (p.Cys112Trpfs*11) frameshift accounts for most reported children; other alleles include c.357_357+2delGGT (an in-frame loss of one of the tandem valines at 119-120), c.52_56del5ins154, c.248dupG (p.Asp84Argfs*8) and c.369_371del.

SOD1 hgnc:11179

Genetic context SOD1 hgnc:11179 variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Truncating and in-frame homozygous alleles that leave no detectable SOD1 protein or activity in erythrocytes.

Downstream

Proteasomal Degradation of Unstable Mutant SOD1 The truncated or destabilized gene product is cleared rather than accumulating.

Show evidence (2 references)

PMID:31332433 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity."

Identifies the recurrent causal allele and its loss-of-function effect.

PMID:39629626 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product."

Summarizes the allelic spectrum of the cases reported to date.

Proteasomal Degradation of Unstable Mutant SOD1

The p.Cys112Trpfs*11 product is unstable and efficiently removed by the proteasome, so neither the truncated nor any wild-type SOD1 protein is detectable in patient erythrocytes. Unlike dominant ALS-causing SOD1 mutants, it shows little tendency to misfold into insoluble aggregates, which argues against a toxic gain of function.

proteasomal degradation of mutant SOD1 GO:0010498 ↑ INCREASED

Downstream

Absent SOD1 Superoxide Dismutase Activity Clearance of the gene product leaves the cytosol without SOD1 protein or activity.

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT In vitro / ex vivo

"The truncated SOD1 C112X is efficiently degraded and exhibits low aggregation propensity."

Fibroblast immunoblot and misfolded-SOD1 ELISA results.

Absent SOD1 Superoxide Dismutase Activity

SOD1, the principal cytosolic superoxide dismutase, converts superoxide to hydrogen peroxide. In affected children erythrocyte SOD1 activity is essentially zero across all reported alleles. Mouse knockout data suggest the mitochondrial and extracellular isoenzymes do not compensate, plausibly because charged superoxide crosses membranes poorly.

SOD1 hgnc:11179

removal of superoxide radicals GO:0019430 ↓ DECREASED

superoxide dismutase activity GO:0004784 ∅ ABSENT

Downstream

Reduced Erythrocyte Glutathione Without SOD1, erythrocytes show reduced glutathione and glutathione peroxidase-1 activity, while commonly measured oxidative-damage markers stay normal.

Upper and Lower Motor Neuron Degeneration The motor system is the organ system most damaged by absence of SOD1, but the steps between loss of superoxide dismutation and motor neuron injury have not been identified.

Progressive Cerebellar Vermis Atrophy Cerebellar vermis atrophy develops alongside the motor disease; the steps from absent SOD1 to cerebellar loss are unknown.

Brainstem Atrophy Brainstem atrophy is present in every imaged patient; the steps from absent SOD1 are unknown.

Fronto-temporal Cortical Atrophy Frontal involvement accompanies the motor disease; the steps from absent SOD1 are unknown.

Retro-chiasmal Optic Tract Thinning A subset of patients show thinning of the post-chiasmal visual pathway; the steps from absent SOD1 are unknown.

Show evidence (4 references)

PMID:31332433 SUPPORT DIRECT BACKGROUND Human clinical

"Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation."

Establishes the normal enzymatic role that is lost.

PMID:34788402 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls."

A second, in-frame allele produces the same complete loss of activity.

PMID:36935613 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Erythrocyte superoxide dismutase enzymatic activity was nearly abolished."

A third allele with absent mRNA expression produces the same enzymatic defect.

+ 1 more reference

Reduced Erythrocyte Glutathione

Homozygous children have significantly lower reduced glutathione and glutathione peroxidase-1 activity in erythrocytes than heterozygous carriers. Mouse Sod1 knockouts show the same pattern alongside anemia.

erythrocyte CL:0000232

glutathione metabolic process GO:0006749 ⚠ ABNORMAL

Downstream

Shortened Erythrocyte Survival Erythrocytes lacking SOD1 and carrying less reduced glutathione have a shortened lifespan.

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In contrast, we observed distinct alterations in glutathione metabolism in individuals homozygous for the SOD1 C112X variant, all of whom showed a significant reduction in reduced glutathione."

Erythrocyte glutathione was reduced in every tested homozygous child.

Shortened Erythrocyte Survival

Low HbA1c indicates roughly halved erythrocyte lifespans, with intermittently raised reticulocytes and haptoglobin and bilirubin values consistent with moderate hemolysis. Other blood lineages are unaffected.

erythrocyte CL:0000232

erythrocyte homeostasis GO:0034101 ↓ DECREASED

Downstream

Hemolytic Anemia Shortened red-cell survival produces a moderate hemolytic anemia.

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The low mean HbA1c level of the patients indicated approximately halved erythrocyte lifespans."

HbA1c used as a surrogate of red-cell lifespan.

Upper and Lower Motor Neuron Degeneration

Children develop upper motor neuron signs (spasticity of all four limbs, Babinski signs) and, later, lower motor neuron signs (fasciculations, atrophy and chronic denervation on EMG) that are most prominent in the truncal and axial muscles. Elevated plasma phosphorylated neurofilament heavy chain indicates ongoing axonal injury, highest in younger patients. Whether this degeneration is best classed as a separate syndrome or as very early-onset ALS is disputed.

upper motor neuron CL:0008048 lower motor neuron CL:0008039

Animal models

SOD1-null mouse Mouse partially recapitulates The knockout develops a distal motor axonopathy and increased motor neuron vulnerability to injury, but not the combined upper and lower motor neuron degeneration, with loss of motor neuron cell bodies, that complete SOD1 absence causes in children.

Markiesje dog SOD1 knockout Dog partially recapitulates Juvenile, fully penetrant tetraparesis with Wallerian-like degeneration in brainstem and spinal cord and denervation atrophy of muscle, from a homozygous SOD1 loss-of-function allele.

Downstream

Spastic Tetraplegia Upper motor neuron loss produces spasticity in all four limbs.

Hyperreflexia Upper motor neuron loss produces brisk tendon reflexes.

Babinski Sign Upper motor neuron loss produces extensor plantar responses.

Facial Myokymia Myokymia is read as a sign of lower motor neuron involvement.

Axial Hypotonia Truncal hypotonia is usually the first recognized sign; later axial atrophy and fasciculations reflect lower motor neuron loss in the trunk.

Fasciculations Fasciculations of the tongue, trunk and limbs reflect lower motor neuron involvement.

Skeletal Muscle Atrophy Denervation leads to muscle wasting, predominantly axial and proximal.

Chronic Denervation on EMG Needle EMG shows chronic, and often active, denervation across bulbar, cervical, thoracic and lumbosacral segments.

Motor Regression Acquired motor milestones are lost rapidly after onset, then decline slows.

Dysarthria Bulbar function is initially normal, but spastic dysarthria develops from the first year of life.

Dysphagia Bulbar involvement causes swallowing difficulty; in the Brazilian series every child needed a gastrostomy.

Respiratory Insufficiency Respiratory muscle weakness leads to chronic respiratory insufficiency in some patients, requiring non-invasive or invasive ventilation.

Show evidence (3 references)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Signs of lower motor neuron involvement (LMN) developed in all patients, with muscular atrophy and fasciculations but strikingly mostly in the truncal axial muscles."

Lower motor neuron involvement in all eight children of the cohort.

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In our cohort, all patients disclosed chronic denervation findings characterized by large-amplitude, long-duration and polyphasic motor unit action potentials in bulbar, cervical, thoracic, and lumbosacral segments"

Electrophysiological evidence of lower motor neuron loss in five Brazilian patients.

PMID:34788402 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration."

Biomarker evidence of axonal degeneration in the in-frame deletion patient.

Progressive Cerebellar Vermis Atrophy

Atrophy of the cerebellar vermis is seen in every imaged patient and worsens on serial MRI, unlike the brainstem and cortical atrophy, which are largely static.

cerebellar vermis UBERON:0004720

Downstream

Cerebellar Vermis Atrophy The tissue-level atrophy is seen directly on MRI.

Show evidence (2 references)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Atrophy of the vermis cerebelli was a defining feature and was seen in all studied individuals (6/6)."

Vermis atrophy in all imaged children.

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In the four patients who underwent serial imaging, the findings progressed significantly with age."

Serial MRI shows the vermis atrophy is progressive.

Brainstem Atrophy

Every imaged patient has some brainstem atrophy, which did not progress on serial imaging in all but one child.

brainstem UBERON:0002298

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"All patients had some brainstem atrophy, which did not show any progression in serial imaging studies except in Patient 8."

Brainstem imaging course in the cohort.

Fronto-temporal Cortical Atrophy

Fronto-temporal cortical atrophy was found in five of six imaged patients and did not progress significantly. Frontal release signs and affective lability were noted in half of the Swedish-German cohort, and cognitive impairment is reported in some but not all children.

frontal lobe UBERON:0016525

Downstream

Cognitive Impairment Cognitive impairment is variable; its relationship to frontal atrophy has not been formally established.

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In 5 of 6 individuals, fronto-temporal cortical atrophy was identified but did not progress significantly over time."

Cortical imaging findings in the cohort.

Retro-chiasmal Optic Tract Thinning

Half of the imaged patients in the Swedish-German cohort show thinning of the retro-chiasmal optic tract, and optic atrophy is recorded clinically in several children across cohorts.

optic tract UBERON:0001908

Downstream

Optic Atrophy Degeneration of the visual pathway is the likely substrate of the optic atrophy seen on fundoscopy, though the two were not correlated patient by patient.

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In a subset of patients (3/6), thinning of the retro-chiasmal optic tract was identified."

MRI finding in three of six imaged patients.

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Pathograph

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Phenotypes

28

Blood 1

Hemolytic Anemia HP:0001878

Show evidence (2 references)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Normal P-haptoglobin and P-bilirubin values close to the upper reference limit also indicated a moderate degree of haemolysis"

Laboratory signs of hemolysis accompanying the anemia.

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Homozygosity for SOD1 C112X results in anaemia with low haemoglobin, reduced red blood cell counts, and shortened lifespan."

Anemia in homozygous children.

Digestive 2

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients"

Severe dysphagia in all five patients.

Constipation HP:0002019

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Constipation | Yes | Yes | Yes | Yes | Yes"

Table 1; 5/5 patients.

Ear 1

Low-set Ears HP:0000369

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Low set, posteriorly rotated ears"

Table 1 dysmorphic row (patient 1); the same row records low-set ears in patients 4, 5 and 6.

Eye 2

Oculomotor Apraxia HP:0000657

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

Table 1; 3/5 patients.

Optic Atrophy HP:0000648

Show evidence (3 references)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

Table 1 fundoscopy row; optic atrophy in patients 1 and 4 (2/5).

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Ocular symptoms | – | – | Bilateral optic atrophy | – | – | N/A | Bilateral optic atrophy | –"

Table 1 ocular row; bilateral optic atrophy in patients 3 and 7 (2/8, one not assessed).

PMID:39629626 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm"

Optic nerve involvement in a patient with a different allele. The paper calls this new to the condition; the earlier cohort tables above already record optic atrophy.

Head and Neck 4

Facial Weakness Weakness of facial musculature HP:0030319

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Facial weakness | Yes | Yes | Yes | Yes | No"

Table 1; 4/5 patients.

Facial Myokymia HP:0000317

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Facial myokymia | Yes | No | Yes | Yes | No"

Table 1; 3/5 patients.

Sialorrhea Drooling HP:0002307

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

Table 1 bulbar-symptom row; sialorrhea in three patients with itemized data.

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Microcephaly | Yes | Yes | No | No | No"

Table 1; 2/5 patients.

Limbs 1

Congenital Hip Dislocation HP:0001374

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

Table 1; 3/5 patients.

Musculoskeletal 5

Spastic Tetraplegia HP:0002510

Course: PROGRESSIVE

Show evidence (2 references)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"All 5 patients presented with a childhood-onset neurodegenerative disorders characterized by spastic tetraplegia with axial hypotonia in all cases"

Spastic tetraplegia in every patient of the Brazilian series.

PMID:31332433 SUPPORT DIRECT PRIMARY RESULT Human clinical

"tetraspasticity with predominance in the lower extremities"

Lower-limb predominance of the tetraspasticity.

Axial Hypotonia HP:0008936

Show evidence (2 references)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"All had onset of symptoms within the first year of life (reported age of onset 8 ± 2.7 months), with hypotonia of the paraspinal (truncal) musculature being the first recognized initial symptom in 5/8 patients."

Truncal hypotonia as the presenting sign.

PMID:36935613 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Neurological was significant for axial hypotonia with spastic tetraplegia and hyperekplexia-like jerky movements."

Same combination in a patient with a different allele.

Skeletal Muscle Atrophy HP:0003202

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Neurological examination revealed moderate spastic tetraplegia, axial hypotonia, diffuse fasciculations, facial diparesis, tongue atrophy with fasciculations, scoliosis, amyotrophy, and dysarthria without cognitive impairment."

Amyotrophy and tongue atrophy on examination.

Chronic Denervation on EMG EMG: chronic denervation signs HP:0003444

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In our cohort, all patients disclosed chronic denervation findings characterized by large-amplitude, long-duration and polyphasic motor unit action potentials in bulbar, cervical, thoracic, and lumbosacral segments"

EMG findings in all five patients.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Scoliosis | No | No | Yes | Yes | Yes"

Table 1; 3/5 patients.

Nervous System 8

Motor Regression HP:0033044

Show evidence (2 references)

PMID:36935613 SUPPORT DIRECT PRIMARY RESULT Human clinical

"A 22-month-old boy was admitted with a loss of motor functions that began at the age of 9 months."

Loss of motor function from infancy.

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"All families reported an initial phase of rapid disease progression after the onset of the first symptoms, followed by slowly progressing, mostly spastic motor signs."

Describes the biphasic course of motor decline.

Fasciculations HP:0002380

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Neurological examination revealed moderate spastic tetraplegia, axial hypotonia, diffuse fasciculations, facial diparesis, tongue atrophy with fasciculations, scoliosis, amyotrophy, and dysarthria without cognitive impairment."

Diffuse and tongue fasciculations in a Brazilian patient.

Babinski Sign HP:0003487

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Neurological examination revealed moderate spasticity in the lower limbs, brisk tendon reflexes, bilateral Babinski sign, tetraplegia with weakness of proximal and distal muscle groups, axial hypotonia, fasciculations in lower limbs, tongue atrophy, global amyotrophy, unable to sit unsupported..."

Pyramidal signs in a Brazilian patient.

Exaggerated Startle Response HP:0002267

Show evidence (2 references)

PMID:31332433 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms."

Hyperekplexia-like symptoms in the index patients.

PMID:36935613 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Neurological was significant for axial hypotonia with spastic tetraplegia and hyperekplexia-like jerky movements."

Same feature with a different allele.

Dysarthria HP:0001260

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Reportedly, all patients initially had normal functions of the bulbar innervated skeletal muscles, but progressive spastic dysarthria and—to a lesser extent—dysphagia appeared beginning in the first year of life."

Progressive spastic dysarthria in the cohort.

Cerebellar Vermis Atrophy HP:0006855

Show evidence (2 references)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Atrophy of the vermis cerebelli was a defining feature and was seen in all studied individuals (6/6)."

Vermis atrophy in all imaged patients.

PMID:39629626 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition"

Cerebellar atrophy with a further allele.

Cognitive Impairment HP:0100543

Show evidence (2 references)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"accompanied by cognitive impairment in 3/5 patients"

Cognitive impairment in a subset of patients.

PMID:38668754 SUPPORT DIRECT PRIMARY RESULT Human clinical

"severe delayed motor development, infancy-onset loss of motor skills, axial hypotonia, tetraspasticity, and impaired cognitive functions"

Impaired cognition in two Turkish siblings with a different allele.

Hyperreflexia HP:0001347

Show evidence (2 references)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Brisk tendon reflexes | Yes | Yes | Yes | Yes | Yes"

Table 1; brisk reflexes in all five patients.

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

Table 1 upper motor neuron row; hyperreflexia in each patient with itemized data.

Prenatal and Birth 1

Polyhydramnios HP:0001561

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients"

Prenatal history in the Brazilian series.

Respiratory 1

Respiratory Insufficiency HP:0002093

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In this cohort, all patients required gastrostomy for nutritional management, and all are dependent on mechanical ventilation"

Ventilator dependence in all five patients.

Growth 2

Intrauterine Growth Restriction Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients"

Prenatal history in the Brazilian series.

Short Stature HP:0004322

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Short Stature | Yes | Yes | No | Yes | No"

Table 1; 3/5 patients.

🧬

Genetic Associations

1

SOD1

Gene: SOD1 hgnc:11179 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:31332433 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity."

Founding report of the gene-disease relationship.

PMID:34788402 SUPPORT DIRECT PRIMARY RESULT Human clinical

"We identified a homozygous 3-bp in-frame deletion in SOD1."

Second allele confirming the relationship.

PMID:38668754 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Genetic analysis revealed a novel homozygous frameshift variant in SOD1 (c.248dupG [p.Asp84Argfs*8])"

Additional allele with co-segregation in a Turkish family.

💊

Medical Actions

2

Gastrostomy feeding

Action: Gastrostomy NCIT:C52006

Platform: Surgery

Gastrostomy for nutrition when dysphagia becomes severe. Reported practice in case series, not a trial.

Target Phenotypes: Dysphagia HP:0002015

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"In this cohort, all patients required gastrostomy for nutritional management"

Gastrostomy use in all five Brazilian patients.

Ventilatory support

Action: Mechanical ventilation Ontology label: Mechanical Ventilation NCIT:C70909

Platform: Device

Non-invasive ventilation or tracheostomy with invasive ventilation for chronic respiratory insufficiency. Reported practice in case series, not a trial.

Target Phenotypes: Respiratory insufficiency HP:0002093

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"with 3 patients having tracheostomy and use of invasive mechanical ventilation 24 h per day, and 2 patients on non-invasive mechanical ventilation for at least 18 h per day"

Ventilation modes used in the Brazilian series.

🔬

Biochemical Markers

3

Erythrocyte SOD1 enzyme activity (Absent in affected children; about 50% of control in heterozygous carriers)

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"SOD1 enzyme activity was virtually absent in erythrocyte lysates in all six studied homozygous patients, confirming the results from previous studies."

Erythrocyte activity in homozygous patients.

Erythrocyte reduced glutathione (Decreased)

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"However, homozygous individuals exhibited significantly decreased levels of reduced glutathione in erythrocytes (RBC-GSH)"

Erythrocyte glutathione measurement.

Plasma neurofilament (Elevated, especially phosphorylated neurofilament heavy chain in younger patients)

Show evidence (2 references)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The younger patients had pNF-H levels above the cut-off for adult-onset ALS patients"

Neurofilament measurements in three patients.

PMID:34788402 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration."

NF-L in a patient with a different allele.

🔬

Diagnosis

1

Molecular and enzymatic confirmation

Exome or targeted sequencing identifies biallelic SOD1 variants; erythrocyte SOD1 activity and immunoblotting confirm absent enzyme and protein and show roughly halved values in carriers.

Show evidence (1 reference)

PMID:34788402 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity."

Diagnostic workup used in practice.

📈

Progression

3

Prenatal and early infancy

Pregnancy may be complicated by polyhydramnios or growth restriction. Early motor development is usually normal or near-normal until about six to twelve months.

Show evidence (1 reference)

PMID:34380534 SUPPORT DIRECT PRIMARY RESULT Human clinical

"most patients initially presenting a normal motor development until the six month of life or during the first year"

Initial normal development in the Brazilian series.

Onset and rapid decline

Symptoms begin before age two, usually around eight months, with truncal hypotonia followed by rapid loss of motor skills, limb spasticity and bulbar signs.

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"All had onset of symptoms within the first year of life (reported age of onset 8 ± 2.7 months), with hypotonia of the paraspinal (truncal) musculature being the first recognized initial symptom in 5/8 patients."

Age and mode of onset in eight children.

Slower progression

After the initial rapid phase, decline slows to mostly spastic motor signs. Survival into late adolescence is reported (a 19-year-old patient), but no natural-history study defines life expectancy.

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"The disease progression seemed to slow down over the following years."

Later course in the Swedish-German cohort.

📊

Prevalence

1

Worldwide (published case reports)

Cases/families reported in the literature Ultra-rare

By late 2024, five studies had described nine cases. Cohorts from Sweden/Germany (eight children, overlapping with the first reports), Brazil (five, of Lebanese origin) and Turkey (two) have since been reported, so the total is in the low tens. Most patients carry the recurrent c.335dupG allele.

Show evidence (1 reference)

PMID:39629626 SUPPORT DIRECT REVIEW SYNTHESIS Human clinical

"Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age."

Literature count at the time of publication; later cohorts add to it and some overlap.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Spastic Tetraplegia and Axial Hypotonia, Progressive:

Amyotrophic Lateral Sclerosis Type 1 MONDO:0007103

Overlapping Features Dominant SOD1 ALS shares the motor neuron target and gene but arises in adulthood from heterozygous variants that produce aggregation-prone, misfolded protein with toxic gain of function, usually with preserved enzyme activity. STAHP is recessive, infantile in onset, and caused by complete absence of the enzyme with an unstable, non-aggregating product.

Distinguishing Features

Biallelic SOD1 variants with absent erythrocyte SOD1 activity
Onset in infancy with axial hypotonia, cerebellar vermis atrophy and hyperekplexia-like startle
Heterozygous relatives unaffected

Show evidence (1 reference)

PMID:36793789 SUPPORT DIRECT PRIMARY RESULT Human clinical

"Taken together, these findings suggest that homozygosity for loss-of-function variants in SOD1 results primarily in an infantile-onset motor neuron condition but with additional neuronal and non-neuronal involvement, which distinguishes it from typical adult-onset ALS."

Contrasts the loss-of-function syndrome with typical SOD1 ALS.

🐁

Animal Models

2

SOD1-null mouse

Complete loss of Sod1 does not produce overt motor deficits by six months but increases motor neuron death after axonal injury. Histologically, knockout mice develop a progressive distal motor axonopathy, with denervation of fast-twitch muscle from 1 to 4 months, while spinal motor neuron cell bodies are preserved; nothing resembles the combined upper and lower motor neuron disease of the human syndrome.

Species

Mouse

Genotype

Homozygous Sod1 knockout

Publication

PMID:8673102

Pathograph links

Upper and Lower Motor Neuron Degeneration partially recapitulates fidelity: low observes: organism The knockout develops a distal motor axonopathy and increased motor neuron vulnerability to injury, but not the combined upper and lower motor neuron degeneration, with loss of motor neuron cell bodies, that complete SOD1 absence causes in children.

Limitations: Motor involvement in the mouse is a distal motor axonopathy with denervation of fast-twitch muscle, while spinal motor neuron cell bodies are preserved to 18 months; the upper motor neuron signs and cerebellar atrophy of the human syndrome are absent.

Divergences from the human mechanism

species mismatch qualifying

Mice lacking Sod1 have no overt motor deficits at six months and a histological distal motor axonopathy with preserved spinal motor neuron cell bodies, whereas children lacking SOD1 lose motor skills from about eight months of age with upper and lower motor neuron signs; the shared finding is motor axon vulnerability, not the same pattern of degeneration.

temporal scope qualifying

The 1996 knockout study assessed overt motor deficits to six months of age and did not examine neuromuscular histology, so it alone cannot characterize the mouse motor phenotype described in later work.

Show evidence (4 references)

PMID:8673102 SUPPORT DIRECT 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."

Motor neurons are normal without injury in the knockout.

+ 3 more references

Show evidence (1 reference)

PMID:8673102 SUPPORT DIRECT PRIMARY RESULT Model organism

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

Absence of spontaneous motor disease in the knockout over the reported period.

Markiesje dog SOD1 knockout

A recessive frameshift in the fourth codon of canine SOD1 segregates with a fully penetrant juvenile disease of severe tetraparesis, dystonia and falling in Markiesje pups, most of which were euthanized within weeks of onset.

Species

Dog

Genotype

Homozygous SOD1 frameshift (p.Lys4Aspfs*6)

Publication

PMID:33677640

Pathograph links

Upper and Lower Motor Neuron Degeneration partially recapitulates fidelity: moderate observes: organism Juvenile, fully penetrant tetraparesis with Wallerian-like degeneration in brainstem and spinal cord and denervation atrophy of muscle, from a homozygous SOD1 loss-of-function allele.

Limitations: The canine disease was described as paroxysmal dyskinesia with dystonia, histological changes were mild, early euthanasia prevents comparison of the long-term course, and SOD1 protein and enzyme activity were not measured.

Divergences from the human mechanism

species mismatch qualifying

Affected pups present with episodic dystonia, cramping and falling rather than the progressive spastic tetraplegia with axial hypotonia of children, so the shared feature is early motor system degeneration rather than the same clinical syndrome.

Show evidence (2 references)

PMID:33677640 SUPPORT DIRECT PRIMARY RESULT Model organism

"Histologically, the most consistent finding was mild, random Wallerian-like degeneration in the brain stem and spinal cord with mild denervation atrophy of the skeletal muscle."

Neuropathology in affected dogs.

+ 1 more reference

Show evidence (1 reference)

PMID:33677640 SUPPORT DIRECT PRIMARY RESULT Model organism

"The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon."

Identifies a homozygous truncating SOD1 allele in affected dogs.

{ }

Source YAML

click to show

name: Spastic Tetraplegia and Axial Hypotonia, Progressive
creation_date: '2026-10-19T00:00:00Z'
category: Mendelian
description: Progressive spastic tetraplegia and axial hypotonia (STAHP), also called infantile SOD1 deficiency syndrome, is an autosomal recessive childhood-onset neurodegenerative disorder caused by biallelic SOD1 variants that leave no detectable superoxide dismutase 1 protein or enzyme activity. After apparently normal early development, truncal hypotonia and spasticity of all four limbs appear within the first year or two of life, followed by rapid loss of motor skills, mixed upper and lower motor neuron signs, bulbar involvement and, in some children, respiratory insufficiency requiring ventilation. Cerebellar vermis atrophy is a consistent imaging feature, and a mild hemolytic anemia with reduced erythrocyte glutathione is the main finding outside the nervous system. It is mechanistically the opposite of dominant SOD1 amyotrophic lateral sclerosis, which arises from a toxic gain of function of aggregation-prone mutant protein. Heterozygous carriers have about half the normal enzyme activity and no reported neurological disease.
disease_term:
  preferred_term: spastic tetraplegia and axial hypotonia, progressive
  term:
    id: MONDO:0032828
    label: spastic tetraplegia and axial hypotonia, progressive
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
parents:
- Motor Neuron Disease
synonyms:
- STAHP
- infantile SOD1 deficiency syndrome
- ISODDES
- SOD1 deficiency
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: All reported patients are homozygous for a SOD1 loss-of-function allele, most from consanguineous families. Heterozygous parents and siblings have roughly halved erythrocyte SOD1 activity and no overt neurological phenotype, which distinguishes this recessive disorder from dominant SOD1 amyotrophic lateral sclerosis.
  evidence:
  - reference: PMID:31332433
    reference_title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype.
    explanation: Carriers are clinically unaffected despite reduced activity, consistent with recessive inheritance.
  - reference: PMID:38668754
    reference_title: Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: biallelic loss of SOD1 function results in a novel phenotype called infantile SOD1 deficiency syndrome, which is consistent with a recessive pattern of inheritance
    explanation: States the recessive mode of inheritance across the reported families.
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We conclude that a ≈50% reduction in SOD1 enzyme activity and the presence of a single C112X SOD1 allele is tolerated, at least up to age 45 years.
    explanation: Heterozygous relatives followed into adulthood remained unaffected.
pathophysiology:
- name: Biallelic SOD1 Loss-of-Function Variants
  description: Homozygous SOD1 variants abolish the enzyme. The recurrent c.335dupG (p.Cys112Trpfs*11) frameshift accounts for most reported children; other alleles include c.357_357+2delGGT (an in-frame loss of one of the tandem valines at 119-120), c.52_56del5ins154, c.248dupG (p.Asp84Argfs*8) and c.369_371del.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SOD1
    term:
      id: hgnc:11179
      label: SOD1
  genetic_context:
    gene:
      preferred_term: SOD1
      term:
        id: hgnc:11179
        label: SOD1
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: Truncating and in-frame homozygous alleles that leave no detectable SOD1 protein or activity in erythrocytes.
  evidence:
  - reference: PMID:31332433
    reference_title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity.
    explanation: Identifies the recurrent causal allele and its loss-of-function effect.
  - reference: PMID:39629626
    reference_title: Immune Dysregulation in a Child With SOD1-Related Neurological Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product.
    explanation: Summarizes the allelic spectrum of the cases reported to date.
  downstream:
  - target: Proteasomal Degradation of Unstable Mutant SOD1
    description: The truncated or destabilized gene product is cleared rather than accumulating.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: C112X variant has low stability, is efficiently cleared by proteasomal degradation, and has low aggregation propensity in skin-derived fibroblasts.
      explanation: Patient-derived fibroblast experiments on the recurrent allele.
    - reference: PMID:34788402
      reference_title: Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1
      explanation: For the in-frame valine deletion, protein loss despite preserved transcript is inferred to reflect instability.
- name: Proteasomal Degradation of Unstable Mutant SOD1
  description: The p.Cys112Trpfs*11 product is unstable and efficiently removed by the proteasome, so neither the truncated nor any wild-type SOD1 protein is detectable in patient erythrocytes. Unlike dominant ALS-causing SOD1 mutants, it shows little tendency to misfold into insoluble aggregates, which argues against a toxic gain of function.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: proteasomal degradation of mutant SOD1
    modifier: INCREASED
    term:
      id: GO:0010498
      label: proteasomal protein catabolic process
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The truncated SOD1 C112X is efficiently degraded and exhibits low aggregation propensity.
    explanation: Fibroblast immunoblot and misfolded-SOD1 ELISA results.
  downstream:
  - target: Absent SOD1 Superoxide Dismutase Activity
    description: Clearance of the gene product leaves the cytosol without SOD1 protein or activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Neither wild-type (WT) nor truncated SOD1 was detected in haemolysates from homozygous individuals, while only WT SOD1 was identified in samples from heterozygous carriers, indicating low stability and efficient degradation of the truncated p.C112X SOD1
      explanation: Absence of any SOD1 protein in patient red cells links degradation to loss of the enzyme.
- name: Absent SOD1 Superoxide Dismutase Activity
  description: SOD1, the principal cytosolic superoxide dismutase, converts superoxide to hydrogen peroxide. In affected children erythrocyte SOD1 activity is essentially zero across all reported alleles. Mouse knockout data suggest the mitochondrial and extracellular isoenzymes do not compensate, plausibly because charged superoxide crosses membranes poorly.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: superoxide dismutase activity
    modifier: ABSENT
    term:
      id: GO:0004784
      label: superoxide dismutase activity
  biological_processes:
  - preferred_term: removal of superoxide radicals
    modifier: DECREASED
    term:
      id: GO:0019430
      label: removal of superoxide radicals
  genes:
  - preferred_term: SOD1
    term:
      id: hgnc:11179
      label: SOD1
  evidence:
  - reference: PMID:31332433
    reference_title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation.
    explanation: Establishes the normal enzymatic role that is lost.
  - reference: PMID:34788402
    reference_title: Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls.
    explanation: A second, in-frame allele produces the same complete loss of activity.
  - reference: PMID:36935613
    reference_title: A novel homozygous loss-of-function variant in SOD1 causing progressive spastic tetraplegia and axial hypotonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Erythrocyte superoxide dismutase enzymatic activity was nearly abolished.
    explanation: A third allele with absent mRNA expression produces the same enzymatic defect.
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: Evidence from mouse knockout models suggest that there is no or only limited functional complementation between the three SOD isoenzymes.
    explanation: Supports the claim that SOD2 and SOD3 do not substitute for the missing cytosolic activity.
  downstream:
  - target: Reduced Erythrocyte Glutathione
    description: Without SOD1, erythrocytes show reduced glutathione and glutathione peroxidase-1 activity, while commonly measured oxidative-damage markers stay normal.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: SOD1 deficiency leads to altered glutathione metabolism, while commonly used markers for oxidative stress remain unaltered.
      explanation: Biochemical comparison of homozygous patients with heterozygous carriers.
  - target: Upper and Lower Motor Neuron Degeneration
    description: The motor system is the organ system most damaged by absence of SOD1, but the steps between loss of superoxide dismutation and motor neuron injury have not been identified.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Nevertheless, our results indicate that of all the organs and functions in the human body, the absence of SOD1 has the greatest detrimental effect on the CNS and, in particular, the motor system.
      explanation: Clinical and laboratory survey of eight homozygous children; the causal intermediates are not specified.
    - reference: PMID:21078595
      reference_title: SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: mitochondrial SOD1 is sufficient to prevent biochemical and morphological defects in the Sod1(-/-) model, and to rescue the motor phenotype of these mice when followed to 12 months of age
      explanation: Restoring SOD1 to the mitochondrial intermembrane space rescues the knockout's motor axonopathy, showing that loss of SOD1 itself causes the mouse motor phenotype; the mouse phenotype is narrower than the human one.
    - reference: PMID:24378874
      reference_title: Neuron-specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD-knockout mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Our data demonstrate that specific CuZnSOD expression in neurons is sufficient to preserve NMJ and skeletal muscle structure and function in Sod1(-/-) mice
      explanation: Neuron-restricted SOD1 prevents the knockout's neuromuscular degeneration, locating the relevant loss to neurons; mouse data only.
  - target: Progressive Cerebellar Vermis Atrophy
    description: Cerebellar vermis atrophy develops alongside the motor disease; the steps from absent SOD1 to cerebellar loss are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage.
      explanation: Imaging findings in the homozygous cohort.
  - target: Brainstem Atrophy
    description: Brainstem atrophy is present in every imaged patient; the steps from absent SOD1 are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage.
      explanation: Imaging findings in the homozygous cohort.
  - target: Fronto-temporal Cortical Atrophy
    description: Frontal involvement accompanies the motor disease; the steps from absent SOD1 are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage.
      explanation: Imaging findings in the homozygous cohort.
  - target: Retro-chiasmal Optic Tract Thinning
    description: A subset of patients show thinning of the post-chiasmal visual pathway; the steps from absent SOD1 are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In a subset of patients (3/6), thinning of the retro-chiasmal optic tract was identified.
      explanation: MRI finding in half of the imaged patients.
- name: Reduced Erythrocyte Glutathione
  conforms_to: hemolytic_anemia_erythrocyte_destruction#Oxidative and Membrane Injury
  description: Homozygous children have significantly lower reduced glutathione and glutathione peroxidase-1 activity in erythrocytes than heterozygous carriers. Mouse Sod1 knockouts show the same pattern alongside anemia.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: glutathione metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006749
      label: glutathione metabolic process
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In contrast, we observed distinct alterations in glutathione metabolism in individuals homozygous for the SOD1 C112X variant, all of whom showed a significant reduction in reduced glutathione.
    explanation: Erythrocyte glutathione was reduced in every tested homozygous child.
  downstream:
  - target: Shortened Erythrocyte Survival
    description: Erythrocytes lacking SOD1 and carrying less reduced glutathione have a shortened lifespan.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The patients displayed anaemia with shortened survival of erythrocytes containing decreased levels of reduced glutathione.
      explanation: Co-occurrence of reduced glutathione and shortened red-cell survival in the same patients.
- name: Shortened Erythrocyte Survival
  conforms_to: hemolytic_anemia_erythrocyte_destruction#Shortened Erythrocyte Lifespan and Erythropoietic Strain
  description: Low HbA1c indicates roughly halved erythrocyte lifespans, with intermittently raised reticulocytes and haptoglobin and bilirubin values consistent with moderate hemolysis. Other blood lineages are unaffected.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    modifier: DECREASED
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The low mean HbA1c level of the patients indicated approximately halved erythrocyte lifespans.
    explanation: HbA1c used as a surrogate of red-cell lifespan.
  downstream:
  - target: Hemolytic Anemia
    description: Shortened red-cell survival produces a moderate hemolytic anemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Homozygosity for SOD1 C112X results in anaemia with low haemoglobin, reduced red blood cell counts, and shortened lifespan.
      explanation: Links shortened erythrocyte lifespan to the anemia.
- name: Upper and Lower Motor Neuron Degeneration
  description: Children develop upper motor neuron signs (spasticity of all four limbs, Babinski signs) and, later, lower motor neuron signs (fasciculations, atrophy and chronic denervation on EMG) that are most prominent in the truncal and axial muscles. Elevated plasma phosphorylated neurofilament heavy chain indicates ongoing axonal injury, highest in younger patients. Whether this degeneration is best classed as a separate syndrome or as very early-onset ALS is disputed.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  - preferred_term: lower motor neuron
    term:
      id: CL:0008039
      label: lower motor neuron
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Signs of lower motor neuron involvement (LMN) developed in all patients, with muscular atrophy and fasciculations but strikingly mostly in the truncal axial muscles.
    explanation: Lower motor neuron involvement in all eight children of the cohort.
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In our cohort, all patients disclosed chronic denervation findings characterized by large-amplitude, long-duration and polyphasic motor unit action potentials in bulbar, cervical, thoracic, and lumbosacral segments
    explanation: Electrophysiological evidence of lower motor neuron loss in five Brazilian patients.
  - reference: PMID:34788402
    reference_title: Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration.
    explanation: Biomarker evidence of axonal degeneration in the in-frame deletion patient.
  downstream:
  - target: Spastic Tetraplegia
    description: Upper motor neuron loss produces spasticity in all four limbs.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: All patients exhibited signs of primarily upper motor neuron involvement (UMN) with spasticity both proximally and distally in all four limbs and equally affecting both flexor and extensor musculature.
      explanation: Attributes limb spasticity to upper motor neuron involvement.
  - target: Hyperreflexia
    description: Upper motor neuron loss produces brisk tendon reflexes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34380534
      reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Brisk tendon reflexes | Yes | Yes | Yes | Yes | Yes
      explanation: Brisk reflexes in all five patients; attributing them to upper motor neuron loss is standard clinical inference rather than a statement in the source.
  - target: Babinski Sign
    description: Upper motor neuron loss produces extensor plantar responses.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34380534
      reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: 'The evidence of upper motor neuron dysfunction implies at least one of the following clinical signs: (a) increased deep tendon reflexes, including the presence of a reflex in a clinically weak and wasted muscle, or spread to adjacent muscles; (b) presence of pathological reflexes, including Hoffman sign, Babinski sign'
      explanation: The diagnostic criteria the authors apply treat the Babinski sign as an upper motor neuron sign, and all five patients had it.
  - target: Facial Myokymia
    description: Myokymia is read as a sign of lower motor neuron involvement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34380534
      reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: some evidence of lower motor neuron dysfunction revealed by fasciculations and myokymia in electromyography
      explanation: The authors interpret myokymia, alongside fasciculations, as evidence of lower motor neuron dysfunction in an earlier patient; facial myokymia was clinically present in 3/5 of their own patients.
  - target: Axial Hypotonia
    description: Truncal hypotonia is usually the first recognized sign; later axial atrophy and fasciculations reflect lower motor neuron loss in the trunk.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Signs of lower motor neuron involvement (LMN) developed in all patients, with muscular atrophy and fasciculations but strikingly mostly in the truncal axial muscles.
      explanation: The axial predominance of lower motor neuron signs matches the axial hypotonia; the early hypotonia may precede overt denervation.
  - target: Fasciculations
    description: Fasciculations of the tongue, trunk and limbs reflect lower motor neuron involvement.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Signs of lower motor neuron involvement (LMN) developed in all patients, with muscular atrophy and fasciculations but strikingly mostly in the truncal axial muscles.
      explanation: Fasciculations are listed among the lower motor neuron signs.
  - target: Skeletal Muscle Atrophy
    description: Denervation leads to muscle wasting, predominantly axial and proximal.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Signs of lower motor neuron involvement (LMN) developed in all patients, with muscular atrophy and fasciculations but strikingly mostly in the truncal axial muscles.
      explanation: Muscular atrophy is reported as a lower motor neuron sign.
  - target: Chronic Denervation on EMG
    description: Needle EMG shows chronic, and often active, denervation across bulbar, cervical, thoracic and lumbosacral segments.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34380534
      reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In our cohort, all patients disclosed chronic denervation findings characterized by large-amplitude, long-duration and polyphasic motor unit action potentials in bulbar, cervical, thoracic, and lumbosacral segments
      explanation: EMG pattern of motor neuron loss.
  - target: Motor Regression
    description: Acquired motor milestones are lost rapidly after onset, then decline slows.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31332433
      reference_title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms.
      explanation: Progressive loss of motor abilities is a defining feature.
  - target: Dysarthria
    description: Bulbar function is initially normal, but spastic dysarthria develops from the first year of life.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Reportedly, all patients initially had normal functions of the bulbar innervated skeletal muscles, but progressive spastic dysarthria and—to a lesser extent—dysphagia appeared beginning in the first year of life.
      explanation: Progressive bulbar motor involvement.
  - target: Dysphagia
    description: Bulbar involvement causes swallowing difficulty; in the Brazilian series every child needed a gastrostomy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Reportedly, all patients initially had normal functions of the bulbar innervated skeletal muscles, but progressive spastic dysarthria and—to a lesser extent—dysphagia appeared beginning in the first year of life.
      explanation: Dysphagia arises from progressive bulbar involvement.
  - target: Respiratory Insufficiency
    description: Respiratory muscle weakness leads to chronic respiratory insufficiency in some patients, requiring non-invasive or invasive ventilation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34380534
      reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients
      explanation: Respiratory insufficiency accompanies the motor decline in this cohort; respiratory muscle weakness is the intermediate.
- name: Progressive Cerebellar Vermis Atrophy
  description: Atrophy of the cerebellar vermis is seen in every imaged patient and worsens on serial MRI, unlike the brainstem and cortical atrophy, which are largely static.
  biological_scale: TISSUE
  locations:
  - preferred_term: cerebellar vermis
    term:
      id: UBERON:0004720
      label: cerebellar vermis
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Atrophy of the vermis cerebelli was a defining feature and was seen in all studied individuals (6/6).
    explanation: Vermis atrophy in all imaged children.
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In the four patients who underwent serial imaging, the findings progressed significantly with age.
    explanation: Serial MRI shows the vermis atrophy is progressive.
  downstream:
  - target: Cerebellar Vermis Atrophy
    description: The tissue-level atrophy is seen directly on MRI.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Atrophy of the vermis cerebelli was a defining feature and was seen in all studied individuals (6/6).
      explanation: Radiological finding.
- name: Brainstem Atrophy
  description: Every imaged patient has some brainstem atrophy, which did not progress on serial imaging in all but one child.
  biological_scale: TISSUE
  locations:
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All patients had some brainstem atrophy, which did not show any progression in serial imaging studies except in Patient 8.
    explanation: Brainstem imaging course in the cohort.
- name: Fronto-temporal Cortical Atrophy
  description: Fronto-temporal cortical atrophy was found in five of six imaged patients and did not progress significantly. Frontal release signs and affective lability were noted in half of the Swedish-German cohort, and cognitive impairment is reported in some but not all children.
  biological_scale: TISSUE
  locations:
  - preferred_term: frontal lobe
    term:
      id: UBERON:0016525
      label: frontal lobe
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In 5 of 6 individuals, fronto-temporal cortical atrophy was identified but did not progress significantly over time.
    explanation: Cortical imaging findings in the cohort.
  downstream:
  - target: Cognitive Impairment
    description: Cognitive impairment is variable; its relationship to frontal atrophy has not been formally established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In 4 of 8 patients from whom detailed information is available, signs of frontal involvement consisting of affective lability with inadequate fits of crying and/or laughter and frontal release signs in the clinical neurological exam were identified (4/8).
      explanation: Clinical signs of frontal involvement accompany the frontal atrophy; cognition was not formally tested in this cohort.
- name: Retro-chiasmal Optic Tract Thinning
  description: Half of the imaged patients in the Swedish-German cohort show thinning of the retro-chiasmal optic tract, and optic atrophy is recorded clinically in several children across cohorts.
  biological_scale: TISSUE
  locations:
  - preferred_term: optic tract
    term:
      id: UBERON:0001908
      label: optic tract
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In a subset of patients (3/6), thinning of the retro-chiasmal optic tract was identified.
    explanation: MRI finding in three of six imaged patients.
  downstream:
  - target: Optic Atrophy
    description: Degeneration of the visual pathway is the likely substrate of the optic atrophy seen on fundoscopy, though the two were not correlated patient by patient.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: In a subset of patients (3/6), thinning of the retro-chiasmal optic tract was identified.
      explanation: Imaging evidence of visual pathway atrophy in the same cohort that records bilateral optic atrophy clinically.
phenotypes:
- category: Neurologic
  name: Spastic Tetraplegia
  description: Spasticity of all four limbs, often predominant in the legs and sometimes asymmetric at onset, is the defining motor sign.
  phenotype_term:
    preferred_term: Spastic tetraplegia
    clinical_course: PROGRESSIVE
    term:
      id: HP:0002510
      label: Spastic tetraplegia
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All 5 patients presented with a childhood-onset neurodegenerative disorders characterized by spastic tetraplegia with axial hypotonia in all cases
    explanation: Spastic tetraplegia in every patient of the Brazilian series.
  - reference: PMID:31332433
    reference_title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: tetraspasticity with predominance in the lower extremities
    explanation: Lower-limb predominance of the tetraspasticity.
- category: Neurologic
  name: Axial Hypotonia
  description: Hypotonia of the trunk and neck, frequently the first sign noticed by parents, coexists with limb spasticity.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All had onset of symptoms within the first year of life (reported age of onset 8 ± 2.7 months), with hypotonia of the paraspinal (truncal) musculature being the first recognized initial symptom in 5/8 patients.
    explanation: Truncal hypotonia as the presenting sign.
  - reference: PMID:36935613
    reference_title: A novel homozygous loss-of-function variant in SOD1 causing progressive spastic tetraplegia and axial hypotonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neurological was significant for axial hypotonia with spastic tetraplegia and hyperekplexia-like jerky movements.
    explanation: Same combination in a patient with a different allele.
- category: Neurologic
  name: Motor Regression
  description: After normal or near-normal early motor development, children lose acquired motor skills, with an initial rapid decline followed by slower progression.
  phenotype_term:
    preferred_term: Motor regression
    term:
      id: HP:0033044
      label: Motor regression
  evidence:
  - reference: PMID:36935613
    reference_title: A novel homozygous loss-of-function variant in SOD1 causing progressive spastic tetraplegia and axial hypotonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A 22-month-old boy was admitted with a loss of motor functions that began at the age of 9 months.
    explanation: Loss of motor function from infancy.
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All families reported an initial phase of rapid disease progression after the onset of the first symptoms, followed by slowly progressing, mostly spastic motor signs.
    explanation: Describes the biphasic course of motor decline.
- category: Neurologic
  name: Fasciculations
  description: Fasciculations of the tongue, neck, trunk and limbs; facial myokymia has also been described.
  phenotype_term:
    preferred_term: Fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neurological examination revealed moderate spastic tetraplegia, axial hypotonia, diffuse fasciculations, facial diparesis, tongue atrophy with fasciculations, scoliosis, amyotrophy, and dysarthria without cognitive impairment.
    explanation: Diffuse and tongue fasciculations in a Brazilian patient.
- category: Neurologic
  name: Skeletal Muscle Atrophy
  description: Proximal and axial muscle wasting, including tongue atrophy.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neurological examination revealed moderate spastic tetraplegia, axial hypotonia, diffuse fasciculations, facial diparesis, tongue atrophy with fasciculations, scoliosis, amyotrophy, and dysarthria without cognitive impairment.
    explanation: Amyotrophy and tongue atrophy on examination.
- category: Neurologic
  name: Chronic Denervation on EMG
  description: Chronic denervation in all tested regions, with active denervation in most patients.
  phenotype_term:
    preferred_term: 'EMG: chronic denervation signs'
    term:
      id: HP:0003444
      label: 'EMG: chronic denervation signs'
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In our cohort, all patients disclosed chronic denervation findings characterized by large-amplitude, long-duration and polyphasic motor unit action potentials in bulbar, cervical, thoracic, and lumbosacral segments
    explanation: EMG findings in all five patients.
- category: Neurologic
  name: Babinski Sign
  description: Extensor plantar responses are present in most patients.
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neurological examination revealed moderate spasticity in the lower limbs, brisk tendon reflexes, bilateral Babinski sign, tetraplegia with weakness of proximal and distal muscle groups, axial hypotonia, fasciculations in lower limbs, tongue atrophy, global amyotrophy, unable to sit unsupported with preserved cognition.
    explanation: Pyramidal signs in a Brazilian patient.
- category: Neurologic
  name: Exaggerated Startle Response
  description: Hyperekplexia-like jerky movements or startle responses were noted in the first reports and in a later patient with a different allele. Their mechanism has not been studied.
  phenotype_term:
    preferred_term: Hyperekplexia-like startle
    term:
      id: HP:0002267
      label: Exaggerated startle response
  evidence:
  - reference: PMID:31332433
    reference_title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms.
    explanation: Hyperekplexia-like symptoms in the index patients.
  - reference: PMID:36935613
    reference_title: A novel homozygous loss-of-function variant in SOD1 causing progressive spastic tetraplegia and axial hypotonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neurological was significant for axial hypotonia with spastic tetraplegia and hyperekplexia-like jerky movements.
    explanation: Same feature with a different allele.
- category: Neurologic
  name: Dysarthria
  description: Progressive spastic dysarthria; many children do not develop speech.
  phenotype_term:
    preferred_term: Spastic dysarthria
    clinical_course: PROGRESSIVE
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Reportedly, all patients initially had normal functions of the bulbar innervated skeletal muscles, but progressive spastic dysarthria and—to a lesser extent—dysphagia appeared beginning in the first year of life.
    explanation: Progressive spastic dysarthria in the cohort.
- category: Digestive
  name: Dysphagia
  description: Swallowing difficulty, severe enough in some cohorts that all patients required gastrostomy feeding.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients
    explanation: Severe dysphagia in all five patients.
- category: Respiratory
  name: Respiratory Insufficiency
  description: Chronic respiratory insufficiency requiring non-invasive or invasive ventilation, reported in every patient of the Brazilian series; less prominent in the Swedish-German cohort.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In this cohort, all patients required gastrostomy for nutritional management, and all are dependent on mechanical ventilation
    explanation: Ventilator dependence in all five patients.
- category: Neurologic
  name: Cerebellar Vermis Atrophy
  description: Atrophy of the cerebellar vermis, predominantly superior, on brain MRI.
  phenotype_term:
    preferred_term: Cerebellar vermis atrophy
    term:
      id: HP:0006855
      label: Cerebellar vermis atrophy
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Atrophy of the vermis cerebelli was a defining feature and was seen in all studied individuals (6/6).
    explanation: Vermis atrophy in all imaged patients.
  - reference: PMID:39629626
    reference_title: Immune Dysregulation in a Child With SOD1-Related Neurological Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition
    explanation: Cerebellar atrophy with a further allele.
- category: Neurologic
  name: Cognitive Impairment
  description: Cognitive impairment is variable; it was present in three of five Brazilian patients, while others had preserved cognition.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: accompanied by cognitive impairment in 3/5 patients
    explanation: Cognitive impairment in a subset of patients.
  - reference: PMID:38668754
    reference_title: Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: severe delayed motor development, infancy-onset loss of motor skills, axial hypotonia, tetraspasticity, and impaired cognitive functions
    explanation: Impaired cognition in two Turkish siblings with a different allele.
- category: Hematologic
  name: Hemolytic Anemia
  description: Mild to moderate anemia with low hemoglobin, shortened red-cell survival and signs of hemolysis; the main non-neurological finding.
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Normal P-haptoglobin and P-bilirubin values close to the upper reference limit also indicated a moderate degree of haemolysis
    explanation: Laboratory signs of hemolysis accompanying the anemia.
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Homozygosity for SOD1 C112X results in anaemia with low haemoglobin, reduced red blood cell counts, and shortened lifespan.
    explanation: Anemia in homozygous children.
- category: Pregnancy
  name: Polyhydramnios
  description: Polyhydramnios was recorded in four of five Brazilian pregnancies; seven of eight pregnancies in the Swedish-German cohort were reported as uneventful.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients
    explanation: Prenatal history in the Brazilian series.
- category: Pregnancy
  name: Intrauterine Growth Restriction
  description: Reported in three of five Brazilian patients.
  phenotype_term:
    preferred_term: Intrauterine growth restriction
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients
    explanation: Prenatal history in the Brazilian series.
- category: Neurologic
  name: Hyperreflexia
  description: Brisk tendon reflexes in every patient of both the Brazilian (5/5) and Swedish-German series.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Brisk tendon reflexes | Yes | Yes | Yes | Yes | Yes'
    explanation: Table 1; brisk reflexes in all five patients.
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: '| Hyperreflexia | Hyperreflexia | Hyperreflexia | Hyperreflexia | Hyperreflexia |'
    explanation: Table 1 upper motor neuron row; hyperreflexia in each patient with itemized data.
- category: Neurologic
  name: Facial Weakness
  description: Facial weakness (facial diparesis) in four of five Brazilian patients.
  phenotype_term:
    preferred_term: Facial weakness
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Facial weakness | Yes | Yes | Yes | Yes | No'
    explanation: Table 1; 4/5 patients.
- category: Neurologic
  name: Facial Myokymia
  description: Facial myokymia in three of five Brazilian patients; myokymia was also noted in the first reported case.
  phenotype_term:
    preferred_term: Facial myokymia
    term:
      id: HP:0000317
      label: Facial myokymia
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Facial myokymia | Yes | No | Yes | Yes | No'
    explanation: Table 1; 3/5 patients.
- category: Neurologic
  name: Oculomotor Apraxia
  description: Oculomotor apraxia in three of five Brazilian patients; not itemized in other cohorts.
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Eye movements | Oculomotor apraxia | Oculomotor apraxia | Normal | Oculomotor apraxia | Normal'
    explanation: Table 1; 3/5 patients.
- category: Digestive
  name: Sialorrhea
  description: Sialorrhea, listed among bulbar symptoms, in at least three of eight Swedish-German patients.
  phenotype_term:
    preferred_term: Sialorrhea
    term:
      id: HP:0002307
      label: Drooling
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: '| Sialorrhea | Sialorrhea | Tongue atrophy & fasciculations | Sialorrhea |'
    explanation: Table 1 bulbar-symptom row; sialorrhea in three patients with itemized data.
- category: Digestive
  name: Constipation
  description: Constipation in all five Brazilian patients.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Constipation | Yes | Yes | Yes | Yes | Yes'
    explanation: Table 1; 5/5 patients.
- category: Musculoskeletal
  name: Scoliosis
  description: Scoliosis in three of five Brazilian patients, all older children.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Scoliosis | No | No | Yes | Yes | Yes'
    explanation: Table 1; 3/5 patients.
- category: Musculoskeletal
  name: Congenital Hip Dislocation
  description: Bilateral congenital hip dislocation at birth in three of five Brazilian patients.
  phenotype_term:
    preferred_term: Bilateral congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Congenital dislocation of hip | Bilateral | Bilateral | No | Bilateral | No'
    explanation: Table 1; 3/5 patients.
- category: Growth
  name: Short Stature
  description: Short stature in three of five Brazilian patients.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Short Stature | Yes | Yes | No | Yes | No'
    explanation: Table 1; 3/5 patients.
- category: Growth
  name: Microcephaly
  description: Microcephaly in two of five Brazilian patients.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Microcephaly | Yes | Yes | No | No | No'
    explanation: Table 1; 2/5 patients.
- category: Craniofacial
  name: Low-set Ears
  description: Low-set ears in four of eight Swedish-German patients; other minor dysmorphic features (overlapping toes, broad nasal bridge) were recorded inconsistently.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'Low set, posteriorly rotated ears'
    explanation: Table 1 dysmorphic row (patient 1); the same row records low-set ears in patients 4, 5 and 6.
- category: Ophthalmologic
  name: Optic Atrophy
  description: Optic atrophy is recorded in two of five Brazilian patients and bilateral optic atrophy in two of eight Swedish-German patients, with retro-chiasmal optic tract thinning on MRI in three of six imaged. A later 19-year-old patient had small optic nerves and a hypoplastic optic chiasm.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Optical fundoscopy | Optic atrophy | Normal | Normal | Optic atrophy | Normal
    explanation: Table 1 fundoscopy row; optic atrophy in patients 1 and 4 (2/5).
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Ocular symptoms | – | – | Bilateral optic atrophy | – | – | N/A | Bilateral optic atrophy | –
    explanation: Table 1 ocular row; bilateral optic atrophy in patients 3 and 7 (2/8, one not assessed).
  - reference: PMID:39629626
    reference_title: Immune Dysregulation in a Child With SOD1-Related Neurological Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm
    explanation: Optic nerve involvement in a patient with a different allele. The paper calls this new to the condition; the earlier cohort tables above already record optic atrophy.
biochemical:
- name: Erythrocyte SOD1 enzyme activity
  presence: Absent in affected children; about 50% of control in heterozygous carriers
  notes: Erythrocyte SOD1 activity and immunoblotting confirm the diagnosis and distinguish homozygous patients from carriers. No validated diagnostic cut-off has been published.
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: SOD1 enzyme activity was virtually absent in erythrocyte lysates in all six studied homozygous patients, confirming the results from previous studies.
    explanation: Erythrocyte activity in homozygous patients.
- name: Erythrocyte reduced glutathione
  presence: Decreased
  notes: Reduced glutathione and glutathione peroxidase-1 activity are lower in patient erythrocytes than in carriers; other oxidative-damage markers were normal.
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: However, homozygous individuals exhibited significantly decreased levels of reduced glutathione in erythrocytes (RBC-GSH)
    explanation: Erythrocyte glutathione measurement.
- name: Plasma neurofilament
  presence: Elevated, especially phosphorylated neurofilament heavy chain in younger patients
  notes: In the Swedish-German cohort pNF-H was above the adult ALS cut-off in the two younger patients while NF-L stayed below it; in the in-frame deletion patient NF-L was raised. Values may fall as the disease slows.
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The younger patients had pNF-H levels above the cut-off for adult-onset ALS patients
    explanation: Neurofilament measurements in three patients.
  - reference: PMID:34788402
    reference_title: Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration.
    explanation: NF-L in a patient with a different allele.
prevalence:
- population: Worldwide (published case reports)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: By late 2024, five studies had described nine cases. Cohorts from Sweden/Germany (eight children, overlapping with the first reports), Brazil (five, of Lebanese origin) and Turkey (two) have since been reported, so the total is in the low tens. Most patients carry the recurrent c.335dupG allele.
  evidence:
  - reference: PMID:39629626
    reference_title: Immune Dysregulation in a Child With SOD1-Related Neurological Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age.
    explanation: Literature count at the time of publication; later cohorts add to it and some overlap.
progression:
- phase: Prenatal and early infancy
  notes: Pregnancy may be complicated by polyhydramnios or growth restriction. Early motor development is usually normal or near-normal until about six to twelve months.
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: most patients initially presenting a normal motor development until the six month of life or during the first year
    explanation: Initial normal development in the Brazilian series.
- phase: Onset and rapid decline
  notes: Symptoms begin before age two, usually around eight months, with truncal hypotonia followed by rapid loss of motor skills, limb spasticity and bulbar signs.
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All had onset of symptoms within the first year of life (reported age of onset 8 ± 2.7 months), with hypotonia of the paraspinal (truncal) musculature being the first recognized initial symptom in 5/8 patients.
    explanation: Age and mode of onset in eight children.
- phase: Slower progression
  notes: After the initial rapid phase, decline slows to mostly spastic motor signs. Survival into late adolescence is reported (a 19-year-old patient), but no natural-history study defines life expectancy.
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The disease progression seemed to slow down over the following years.
    explanation: Later course in the Swedish-German cohort.
differential_diagnoses:
- name: Amyotrophic Lateral Sclerosis Type 1
  description: Dominant SOD1 ALS shares the motor neuron target and gene but arises in adulthood from heterozygous variants that produce aggregation-prone, misfolded protein with toxic gain of function, usually with preserved enzyme activity. STAHP is recessive, infantile in onset, and caused by complete absence of the enzyme with an unstable, non-aggregating product.
  disease_term:
    preferred_term: amyotrophic lateral sclerosis type 1
    term:
      id: MONDO:0007103
      label: amyotrophic lateral sclerosis type 1
  distinguishing_features:
  - Biallelic SOD1 variants with absent erythrocyte SOD1 activity
  - Onset in infancy with axial hypotonia, cerebellar vermis atrophy and hyperekplexia-like startle
  - Heterozygous relatives unaffected
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Taken together, these findings suggest that homozygosity for loss-of-function variants in SOD1 results primarily in an infantile-onset motor neuron condition but with additional neuronal and non-neuronal involvement, which distinguishes it from typical adult-onset ALS.
    explanation: Contrasts the loss-of-function syndrome with typical SOD1 ALS.
genetic:
- name: SOD1
  gene_term:
    preferred_term: SOD1
    term:
      id: hgnc:11179
      label: SOD1
  relationship_type: CAUSATIVE
  notes: Biallelic loss-of-function SOD1 variants cause STAHP, whereas heterozygous mostly missense variants cause dominant ALS1 through gain of function. Reported recessive alleles are c.335dupG (p.Cys112Trpfs*11, recurrent), c.357_357+2delGGT (p.Val119/Val120 in-frame deletion), c.52_56del5ins154, c.248dupG (p.Asp84Argfs*8) and c.369_371del. The mutant c.335dupG mRNA is present in carriers and patients, arguing against nonsense-mediated decay; the protein is lost through proteasomal degradation.
  evidence:
  - reference: PMID:31332433
    reference_title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity.
    explanation: Founding report of the gene-disease relationship.
  - reference: PMID:34788402
    reference_title: Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: We identified a homozygous 3-bp in-frame deletion in SOD1.
    explanation: Second allele confirming the relationship.
  - reference: PMID:38668754
    reference_title: Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Genetic analysis revealed a novel homozygous frameshift variant in SOD1 (c.248dupG [p.Asp84Argfs*8])
    explanation: Additional allele with co-segregation in a Turkish family.
diagnosis:
- name: Molecular and enzymatic confirmation
  description: Exome or targeted sequencing identifies biallelic SOD1 variants; erythrocyte SOD1 activity and immunoblotting confirm absent enzyme and protein and show roughly halved values in carriers.
  evidence:
  - reference: PMID:34788402
    reference_title: Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity.
    explanation: Diagnostic workup used in practice.
treatments:
- name: Gastrostomy feeding
  description: Gastrostomy for nutrition when dysphagia becomes severe. Reported practice in case series, not a trial.
  treatment_term:
    preferred_term: Gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In this cohort, all patients required gastrostomy for nutritional management
    explanation: Gastrostomy use in all five Brazilian patients.
- name: Ventilatory support
  description: Non-invasive ventilation or tracheostomy with invasive ventilation for chronic respiratory insufficiency. Reported practice in case series, not a trial.
  treatment_term:
    preferred_term: Mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  therapeutic_modality: DEVICE
  target_phenotypes:
  - preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: with 3 patients having tracheostomy and use of invasive mechanical ventilation 24 h per day, and 2 patients on non-invasive mechanical ventilation for at least 18 h per day
    explanation: Ventilation modes used in the Brazilian series.
animal_models:
- name: SOD1-null mouse
  species: Mouse
  genotype: Homozygous Sod1 knockout
  publication: PMID:8673102
  description: Complete loss of Sod1 does not produce overt motor deficits by six months but increases motor neuron death after axonal injury. Histologically, knockout mice develop a progressive distal motor axonopathy, with denervation of fast-twitch muscle from 1 to 4 months, while spinal motor neuron cell bodies are preserved; nothing resembles the combined upper and lower motor neuron disease of the human syndrome.
  evidence:
  - 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
    directness: DIRECT
    snippet: These animals develop normally and show no overt motor deficits by 6 months in age.
    explanation: Absence of spontaneous motor disease in the knockout over the reported period.
  modeled_mechanisms:
  - target: Upper and Lower Motor Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: The knockout develops a distal motor axonopathy and increased motor neuron vulnerability to injury, but not the combined upper and lower motor neuron degeneration, with loss of motor neuron cell bodies, that complete SOD1 absence causes in children.
    limitations: Motor involvement in the mouse is a distal motor axonopathy with denervation of fast-twitch muscle, while spinal motor neuron cell bodies are preserved to 18 months; the upper motor neuron signs and cerebellar atrophy of the human syndrome are absent.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Mice lacking Sod1 have no overt motor deficits at six months and a histological distal motor axonopathy with preserved spinal motor neuron cell bodies, whereas children lacking SOD1 lose motor skills from about eight months of age with upper and lower motor neuron signs; the shared finding is motor axon vulnerability, not the same pattern of degeneration.
    - divergence_type: TEMPORAL_SCOPE
      materiality: QUALIFYING
      description: The 1996 knockout study assessed overt motor deficits to six months of age and did not examine neuromuscular histology, so it alone cannot characterize the mouse motor phenotype described in later work.
    evidence:
    - 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
      directness: DIRECT
      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: Motor neurons are normal without injury in the knockout.
    - reference: PMID:36793789
      reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: However, it is notable that Sod1 knockout mice do not replicate the severe motor neuron phenotype that develops in humans despite developing a significant, motor neuropathy in later life
      explanation: Summarizes the knockout literature; a motor neuropathy without the human motor neuron phenotype.
    - reference: PMID:21963651
      reference_title: Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We report preferential denervation of fast-twitch muscles beginning between 1 and 4 months of age, with relative sparing of slow-twitch muscle.
      explanation: Primary report of the knockout's distal motor axonopathy, the part of the motor phenotype the mouse does reproduce.
    - reference: PMID:21963651
      reference_title: Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: We confirmed, as was previously reported, that spinal motor neurons and motor and sensory nerve roots in these mice are preserved, even out to 18 months of age.
      explanation: Motor neuron cell bodies are spared in the mouse, unlike the upper and lower motor neuron disease of the children.
- name: Markiesje dog SOD1 knockout
  species: Dog
  genotype: Homozygous SOD1 frameshift (p.Lys4Aspfs*6)
  publication: PMID:33677640
  description: A recessive frameshift in the fourth codon of canine SOD1 segregates with a fully penetrant juvenile disease of severe tetraparesis, dystonia and falling in Markiesje pups, most of which were euthanized within weeks of onset.
  evidence:
  - reference: PMID:33677640
    reference_title: A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon.
    explanation: Identifies a homozygous truncating SOD1 allele in affected dogs.
  modeled_mechanisms:
  - target: Upper and Lower Motor Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Juvenile, fully penetrant tetraparesis with Wallerian-like degeneration in brainstem and spinal cord and denervation atrophy of muscle, from a homozygous SOD1 loss-of-function allele.
    limitations: The canine disease was described as paroxysmal dyskinesia with dystonia, histological changes were mild, early euthanasia prevents comparison of the long-term course, and SOD1 protein and enzyme activity were not measured.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Affected pups present with episodic dystonia, cramping and falling rather than the progressive spastic tetraplegia with axial hypotonia of children, so the shared feature is early motor system degeneration rather than the same clinical syndrome.
    evidence:
    - reference: PMID:33677640
      reference_title: A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Histologically, the most consistent finding was mild, random Wallerian-like degeneration in the brain stem and spinal cord with mild denervation atrophy of the skeletal muscle.
      explanation: Neuropathology in affected dogs.
    - reference: PMID:33677640
      reference_title: A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk.
      explanation: Early-onset motor disease in the dog.
discussions:
- discussion_id: stahp-mouse-human-mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Why does complete SOD1 absence cause infantile upper and lower motor neuron degeneration in humans but only a distal motor axonopathy, with motor neuron cell bodies spared, in Sod1 knockout mice?
  rationale: The mouse knockout was the basis for the long-held view that loss of SOD1 activity does not damage motor neurons, a view the human syndrome contradicts. Knockout mice do develop a distal motor axonopathy from the first months of life, and SOD1-null dogs develop an early tetraparesis, so the mismatch lies in which parts of the motor system degenerate and how severely, rather than in an absence of motor involvement. Species differences in compensating antioxidants (mice synthesize ascorbate, humans do not), lifespan and motor system size are candidate explanations, but none has been tested.
  attaches_to:
  - animal_models#SOD1-null mouse
  - pathophysiology#Upper and Lower Motor Neuron Degeneration
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: the fact that SOD1 knockout mice do not develop ALS-like disease, contributed to the general view that reduced SOD1 activity does not cause ALS
    explanation: Records how the mouse result shaped expectations that the human syndrome overturns.
- discussion_id: stahp-separate-entity-or-early-als
  kind: CONTROVERSY
  status: OPEN
  prompt: Is STAHP a distinct syndrome or a very early infantile-onset form of SOD1 ALS?
  rationale: The founding reports framed SOD1 deficiency as a new syndrome distinct from ALS, citing the opposite mechanism and additional cerebellar and non-neuronal involvement. A Brazilian series found upper and lower motor neuron involvement that fulfils ALS diagnostic criteria and argued for very early-onset ALS. The answer affects classification but not the causal chain recorded here.
  attaches_to:
  - disease#Spastic Tetraplegia and Axial Hypotonia, Progressive
  evidence:
  - reference: PMID:31332433
    reference_title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease
    explanation: Position that the syndrome is mechanistically distinct from ALS.
  - reference: PMID:34380534
    reference_title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: allowing us to conclude that the cases presented by these authors, and the new additional patients reported in this study represent a very early infantile-onset ALS.
    explanation: Opposing position.
- discussion_id: stahp-sod1-silencing-safety
  kind: INTERPRETATION
  status: OPEN
  prompt: What does complete human SOD1 deficiency imply for SOD1-lowering therapies in ALS?
  rationale: Approved and investigational SOD1-lowering therapies for ALS suppress both mutant and wild-type SOD1. STAHP shows that total loss of the enzyme is harmful to the human motor system, while unaffected carriers show that about half of normal activity is tolerated, suggesting a threshold that knockdown should not cross.
  attaches_to:
  - pathophysiology#Absent SOD1 Superoxide Dismutase Activity
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The association of the severe ISODDES phenotype with a loss of SOD1 function suggests the need for cautious application of general silencing interventions in ALS since the currently studied gene therapy approaches equally target the mutant and wild-type SOD1 alleles.
    explanation: The authors' therapeutic interpretation.
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: However, given the absence of an overt phenotype in heterozygous carriers with approximately halved enzyme activity, it is possible that there is a threshold of minimum SOD1 activity to avoid disease manifestation.
    explanation: Carrier data suggest partial reduction is tolerated.
- discussion_id: stahp-antioxidant-therapy
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Could glutathione-replenishing or other antioxidant treatment slow disease in children lacking SOD1?
  rationale: N-acetylcysteine improved anemia and other features in Sod1 knockout mice, and patient erythrocytes are glutathione-depleted, but no treatment has been tested in patients. Any trial would need outcome measures suited to a slowly progressing phase after early rapid decline.
  attaches_to:
  - pathophysiology#Reduced Erythrocyte Glutathione
  - treatments#
  evidence:
  - reference: PMID:36793789
    reference_title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: From a therapeutic perspective, treatment with the GSH precursor N-acetylcysteine55 improved anaemic symptoms,54 as well as other symptoms in SOD1 knockout models56 and might be a promising approach to treat symptoms observed in the patients studied here.
    explanation: Mouse evidence and the authors' proposal; no human data.
  - reference: PMID:39629626
    reference_title: Immune Dysregulation in a Child With SOD1-Related Neurological Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity
    explanation: Proposal from a case report, not a tested treatment.
notes: The p.Cys112Trpfs*11 patients in the 2023 Swedish-German study include the children first reported in 2019, so the eight-patient cohort and the earlier reports are not independent. Feature frequencies come from small, overlapping case series and are not population estimates; counts in phenotype descriptions are per cohort. Epilepsy (1/5 Brazilian patients) and hydrocephalus (1/8 Swedish-German patients) are single observations and are not recorded as phenotypes. Immune dysregulation (inflammatory bowel disease, asthma, recurrent infections, dermatitis) has been described in one patient only and is likewise not recorded. No GeneReviews chapter covers this disorder.
references:
- reference: PMID:31332433
  title: 'SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.'
- reference: PMID:34380534
  title: 'Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?'
- reference: PMID:34788402
  title: Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.
- reference: PMID:36793789
  title: The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.
- reference: PMID:36935613
  title: A novel homozygous loss-of-function variant in SOD1 causing progressive spastic tetraplegia and axial hypotonia.
- reference: PMID:38668754
  title: Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.
- reference: PMID:39629626
  title: Immune Dysregulation in a Child With SOD1-Related Neurological Disease.
- reference: PMID:21963651
  title: Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy.
- reference: PMID:33677640
  title: A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy.
- reference: PMID:8673102
  title: Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.

📚

References & Deep Research

References

10

PMID:31332433

SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.

No top-level findings curated for this source.

PMID:34380534

Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?

No top-level findings curated for this source.

PMID:34788402

Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.

No top-level findings curated for this source.

PMID:36793789

The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.

No top-level findings curated for this source.

PMID:36935613

A novel homozygous loss-of-function variant in SOD1 causing progressive spastic tetraplegia and axial hypotonia.

No top-level findings curated for this source.

PMID:38668754

Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.

No top-level findings curated for this source.

PMID:39629626

Immune Dysregulation in a Child With SOD1-Related Neurological Disease.

No top-level findings curated for this source.

PMID:21963651

Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy.

No top-level findings curated for this source.

PMID:33677640

A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy.

No top-level findings curated for this source.

PMID:8673102

Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Address review: optic atrophy, missing phenotypes, mouse model, dog model · 2026-10-19T13:44:58Z · View source

Responded to the ai4c-reviewer changes-requested review. Optic atrophy was described as a single-patient finding, but Table 1 of PMID:34380534 (2/5) and PMID:36793789 (2/8, plus optic tract thinning in 3/6 on MRI) record it; description and notes corrected and table rows added as evidence. Added phenotypes recorded in the same tables: hyperreflexia, facial weakness, facial myokymia, oculomotor apraxia, sialorrhea, constipation, scoliosis, congenital hip dislocation, short stature, microcephaly, low-set ears, each with per-cohort counts. Split the bundled atrophy node into progressive cerebellar vermis atrophy, static brainstem atrophy, fronto-temporal cortical atrophy and retro-chiasmal optic tract thinning, per the serial-MRI table. Sod1-null mouse changed from FAILS_TO_RECAPITULATE to PARTIALLY_RECAPITULATES with QUALIFYING divergences, citing the late motor neuropathy reported in PMID:36793789. Added the Markiesje dog SOD1 frameshift model (PMID:33677640). Bound the proteasomal node to GO:0010498 rather than the suggested ubiquitin-dependent GO:0043161, which the source does not establish. Dropped an unsourced polyhydramnios mechanism phrase. Ran an openscientist deep-research pass.

OpenScientist ▸

Spastic Tetraplegia and Axial Hypotonia, Progressive (STAHP): A Comprehensive Disease Characteristics Report

openscientist-autonomous 20 citations 2026-10-19T13:49:30.206922

Spastic Tetraplegia and Axial Hypotonia, Progressive (STAHP): A Comprehensive Disease Characteristics Report

Disease: Spastic Tetraplegia and Axial Hypotonia, Progressive MONDO ID: MONDO:0032828 · OMIM: #618598 · Category: Mendelian (autosomal recessive) Causal gene: SOD1 (Cu/Zn superoxide dismutase 1; HGNC:11179; chromosome 21q22.11)

Summary

Spastic Tetraplegia and Axial Hypotonia, Progressive (STAHP) is an ultra-rare, autosomal-recessive, childhood-onset neurodegenerative disorder caused by complete biallelic loss of function of the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1). It was first delineated as a distinct nosological entity in 2019 by Park and colleagues, who identified a homozygous truncating variant, c.335dupG (p.Cys112Trpfs*11), that abolishes all SOD1 enzyme activity in multiple consanguineous families (PMID: 31332433). The clinical picture comprises progressive loss of acquired motor milestones, spastic tetraplegia with lower-extremity predominance, axial (truncal) hypotonia, mild cerebellar atrophy, and a hyperekplexia-like exaggerated startle. Heterozygous carriers, despite having markedly reduced enzyme activity, are neurologically normal — establishing a recessive mechanism in which roughly 50% of SOD1 activity is sufficient for health.

STAHP is best understood as the mechanistic mirror-image of SOD1-associated amyotrophic lateral sclerosis (ALS). Dominant SOD1 missense variants cause ~2% of ALS through a toxic gain-of-function (protein misfolding and aggregation), whereas STAHP arises from the total absence of the enzyme. This distinction has direct therapeutic-safety implications: the FDA-approved antisense oligonucleotide tofersen lowers SOD1 protein to treat SOD1-ALS, and the existence of a human SOD1-deficiency syndrome cautions that deep, chronic SOD1 suppression is not biologically inert. The pathophysiology converges on chronic oxidative stress — most critically in mitochondria and motor neurons — that produces a distal motor axonopathy and neuromuscular-junction (NMJ) failure. This causal chain is strongly supported by Sod1-null (knockout) mouse models, in which the phenotype is rescued by restoring SOD1 selectively to neurons or to the mitochondrial intermembrane space.

Because fewer than ~20 patients have been reported worldwide, almost all from consanguineous pedigrees carrying a recurrent founder frameshift, the evidence base is a hybrid of a small number of human clinical reports and an extensive body of Sod1-knockout mouse biology. There is no approved disease-modifying therapy; care is supportive. Mechanism-rational but clinically unproven strategies include antioxidants/SOD mimetics and SOD1 gene augmentation — the latter supported by the mouse rescue data. This report synthesizes eight confirmed findings across all 15 template sections, flagging clearly where human data are absent and where conclusions are extrapolated from model systems.

Section 1 — Disease Information

Overview. STAHP is a progressive, early-onset neurodegenerative disease of the central and peripheral motor system caused by inherited deficiency of SOD1. The cardinal triad is (i) progressive spastic tetraplegia (upper-motor-neuron signs in all four limbs, lower extremity > upper), (ii) axial hypotonia (truncal low tone), and (iii) progressive loss of previously acquired motor abilities. Additional features include mild cerebellar atrophy and hyperekplexia-like startle responses (PMID: 31332433).

Key identifiers.

Resource	Identifier
MONDO	MONDO:0032828
OMIM	#618598 (Spastic tetraplegia and axial hypotonia, progressive)
Gene (OMIM)	SOD1 *147450
HGNC	HGNC:11179 (SOD1)
Orphanet	SOD1-deficiency syndrome (ultra-rare; dedicated ORPHAcode may not be assigned)
ICD-11	Closest: hereditary spastic paraplegia–adjacent category (no STAHP-specific code)
MeSH	No STAHP-specific descriptor; indexed under Superoxide Dismutase / Muscle Spasticity

Synonyms / alternative names: STAHP; SOD1 deficiency; SOD1-deficiency syndrome; progressive spastic tetraplegia and axial hypotonia.

Information source: Disease-level, aggregated from a small number of primary case reports and families (OMIM, PubMed). This is not an EHR-derived or population-cohort entity; the characterization rests on individual clinical descriptions supplemented by mechanistic work in Sod1-knockout mice.

Section 2 — Etiology

Primary cause (genetic). STAHP is a monogenic Mendelian disorder caused by homozygous (biallelic) loss-of-function variants in SOD1. The prototype is the frameshift c.335dupG (p.Cys112Trpfs*11), which truncates the protein and abolishes all enzyme activity. Park et al. state: "In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity" (PMID: 31332433). A second independent homozygous loss-of-function SOD1 variant has since been reported, confirming the gene–disease relationship (PMID: 36935613).

Genetic risk factors. The only established genetic cause is biallelic SOD1 LoF. Consanguinity is the dominant risk factor — all reported families are consanguineous, and the recurrent c.335dupG allele behaves as a founder mutation. There are no established common-variant susceptibility loci (STAHP is Mendelian, not polygenic).

Protective / modifier factors. Being a heterozygous carrier is effectively "protective" against disease: carriers have reduced enzyme activity but no overt neurologic phenotype. Park et al.: "Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype" (PMID: 31332433), indicating ~50% SOD1 activity suffices. In model systems, the mitochondrial-intermembrane-space pool of SOD1 and neuronal (vs. muscle) SOD1 expression are the critical protective compartments (see Sections 6 and 15). No validated human environmental protective factor is known.

Environmental risk factors / gene–environment interactions. No environmental trigger is required to manifest STAHP — the disorder is fully penetrant from the genetic lesion. However, because SOD1 is the frontline defense against superoxide, oxidative-stress–increasing exposures are biologically plausible modifiers. In Sod1-null mice, superimposed oxidative or metabolic stressors (e.g., diabetes, aging, a second cochlear mutation) accelerate organ-specific injury (renal: PMID: 17697870; hearing: PMID: 20470874). These gene–environment interactions are demonstrated in mice and only inferred for human STAHP.

Section 3 — Phenotypes

All phenotypes are progressive and of childhood onset, with prenatal/neonatal antecedents in a substantial fraction.

Phenotype	Type	HPO term	Onset	Severity / Course	Frequency
Progressive loss of motor abilities (regression)	Clinical sign	HP:0002376 (Developmental regression)	Childhood	Severe, progressive	All reported patients
Spastic tetraplegia (LL > UL)	Clinical sign	HP:0002510 (Spastic tetraplegia)	Childhood	Severe, progressive	All
Axial hypotonia	Clinical sign	HP:0008936 (Axial hypotonia)	Early childhood	Moderate–severe	All
Mild cerebellar atrophy	Imaging/physical	HP:0001272 (Cerebellar atrophy)	Childhood	Mild	Index families
Hyperekplexia-like exaggerated startle	Clinical sign	HP:0002267 (Exaggerated startle response)	Childhood	Variable	Index families
Polyhydramnios (gestational)	Prenatal sign	HP:0001561 (Polyhydramnios)	Prenatal	—	4/5 (de Souza cohort)
Intrauterine growth restriction	Prenatal sign	HP:0001511 (IUGR)	Prenatal	—	3/5 (de Souza cohort)

Characteristics. De Souza et al. described a Brazilian series of 5 patients: childhood-onset spastic tetraplegia with axial hypotonia in all 5, with "gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients" (PMID: 34380534), and progressive loss of acquired motor milestones. The prenatal features indicate that the disease process begins in utero, while overt neurodegeneration becomes clinically apparent in childhood. Park et al. summarize the core phenotype as "severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms" (PMID: 31332433).

Quality of life. No formal EQ-5D/SF-36/PROMIS data exist for this ultra-rare disease. Qualitatively, the combination of progressive tetraspasticity, motor regression, and axial hypotonia implies profound loss of independent ambulation and self-care, high caregiver dependence, and likely feeding/respiratory vulnerability — a severe QoL burden inferred from the phenotype rather than directly measured.

Section 4 — Genetic / Molecular Information

Causal gene: SOD1 (Cu/Zn superoxide dismutase 1), OMIM *147450, HGNC:11179, chromosome 21q22.11. SOD1 catalyzes dismutation of the superoxide radical (O₂·⁻) to O₂ and H₂O₂.

Pathogenic variants.

Variant (cDNA)	Protein	Type	Zygosity	Consequence	Reference
c.335dupG	p.Cys112Trpfs*11	Frameshift (truncating)	Homozygous	Total loss of enzyme activity	PMID: 31332433
Novel homozygous LoF	(loss of function)	LoF	Homozygous	Loss of function	PMID: 36935613

Classification: The truncating variants are pathogenic by ACMG/AMP criteria (null variant in a gene where LoF is an established mechanism; PVS1 + segregation + functional enzyme-activity evidence).

Functional consequence: Loss of function — complete abolition of superoxide dismutase activity in the homozygous state. This is the defining molecular feature distinguishing STAHP from the gain-of-function missense variants of SOD1-ALS.

Allele frequency: The c.335dupG founder allele is essentially private to the reported consanguineous pedigrees and is vanishingly rare/absent at homozygosity in population databases (gnomAD), consistent with a recessive ultra-rare disorder.

Somatic vs germline: Germline.

Modifier genes: None established in humans. Mouse data implicate redox-pathway genes (e.g., Gpx4 overexpression modulates the muscle phenotype, PMID: 37878529; the Nrf2/NFE2L2 pathway is broadly protective, PMID: 32061629).

Epigenetic information / chromosomal abnormalities: No disease-specific epigenetic signature or large-scale chromosomal rearrangement is described for STAHP.

Section 5 — Environmental Information

STAHP is a genetically determined, fully penetrant disorder; no environmental exposure, lifestyle factor, or infectious agent is required for or known to cause it. Because SOD1 is the primary cytosolic/mitochondrial-IMS superoxide scavenger, exposures that raise oxidative load (certain drugs, metabolic stress, aging) are plausible disease modifiers, but this is extrapolated from Sod1-knockout mouse organ-injury studies (diabetic nephropathy acceleration, PMID: 17697870; age-related hearing loss, PMID: 10466888) and is not established in patients. Infectious agents: not applicable.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

Biallelic SOD1 loss-of-function mutation (e.g., c.335dupG) → leads to total absence of Cu/Zn superoxide dismutase enzyme activity. (Demonstrated — enzyme assay, PMID: 31332433.)
Absence of dismutation → results in accumulation of superoxide radical (O₂·⁻) and chronic oxidative stress, most critically at the mitochondrial intermembrane space and in peripheral nerve. (Demonstrated in mouse: oxidized glutathione redox potential in tibial nerve, PMID: 21963651; mitochondrial-IMS SOD1 sufficiency, PMID: 21078595.)
Chronic oxidative stress in motor axons → leads to a progressive distal motor axonopathy, with preferential denervation of fast-twitch muscle, while motor-neuron cell bodies and sensory fibers are relatively preserved. (Demonstrated in mouse, PMID: 21963651.)
Distal axon injury → results in neuromuscular-junction (NMJ) destabilization and functional failure — reduced endplate occupancy, terminal sprouting, axon swelling, and impaired evoked neurotransmitter (synaptic-vesicle) release despite preserved acetylcholine-receptor density. (Demonstrated in mouse, PMID: 24971750.)
NMJ failure + central motor-tract involvement → produces muscle weakness/atrophy and the clinical upper-motor-neuron picture (spastic tetraplegia) together with axial hypotonia, motor regression, mild cerebellar atrophy, and hyperekplexia-like startle. (Human phenotype, PMID: 31332433, PMID: 34380534; the step from NMJ/axon biology to the specific human CNS signs is partly inferred.)

Branch / protective node: Restoring SOD1 selectively to neurons (synapsin promoter) or to the mitochondrial intermembrane space prevents the axonopathy and muscle loss — defining the neuronal, mitochondrial-IMS redox pool as the critical protective compartment. Fischer et al.: "mitochondrial SOD1 is sufficient to prevent biochemical and morphological defects in the Sod1(-/-) model, and to rescue the motor phenotype of these mice when followed to 12 months of age" (PMID: 21078595); and neuron-specific CuZnSOD "is sufficient to prevent the loss of muscle mass and function" (PMID: 24378874).

Detail by category

Molecular pathway: Superoxide → (normally) dismutation by SOD1 → H₂O₂ (GO:0019430 removal of superoxide radicals; GO:0006801 superoxide metabolic process). Loss shifts redox balance; downstream, the Nrf2/antioxidant response (NFE2L2) is a compensatory axis (PMID: 32061629).
Cellular processes: Chronic oxidative stress (GO:0006979), mitochondrial dysfunction, impaired synaptic transmission at the NMJ (GO:0007274 neuromuscular synaptic transmission), axon degeneration.
Protein dysfunction: Pure loss of function (no enzyme) — in contrast to misfolding/aggregation in SOD1-ALS. CHEBI entities: superoxide (CHEBI:18421), hydrogen peroxide (CHEBI:16240), copper(II) (CHEBI:29036), zinc(II) (CHEBI:29105).
Metabolic changes: Oxidation of the glutathione pool in peripheral nerve (PMID: 21963651); lipid-hydroperoxide accumulation in muscle (modifiable by GPx4, PMID: 37878529); mitochondrial respiratory deficits in muscle.
Tissue damage mechanism: Oxidative stress → distal axon degeneration and NMJ dismantling.
Cell types involved (CL): Motor neuron / lower motor neuron (CL:0011001, CL:0000100), skeletal muscle fiber (CL:0000188), with fast-twitch (type II) fibers preferentially affected.
Immune involvement: Not a primary driver in STAHP (contrast canine degenerative myelopathy, where glial UPR/neuroinflammation occurs, PMID: 30273700).

GO biological-process suggestions: GO:0019430 (removal of superoxide radicals), GO:0006801 (superoxide metabolic process), GO:0006979 (response to oxidative stress), GO:0007274 (neuromuscular synaptic transmission), GO:0098754 (detoxification).

Section 7 — Anatomical Structures Affected

Primary organ/system: Nervous system — central (corticospinal tracts → spasticity; cerebellum → mild atrophy) and peripheral motor axons. Body system: nervous (UBERON:0001016) and musculoskeletal.
Secondary involvement: Skeletal muscle (atrophy/weakness, secondary to denervation); respiratory and feeding musculature at risk with progression.
Tissue/cell level: Nervous tissue — motor neurons and their distal axons (CL:0000100 / CL:0011001); skeletal muscle fibers (CL:0000188), with fast-twitch (type II) fibers preferentially denervated.
Subcellular level (GO cellular component): Mitochondrion (GO:0005739) and specifically the mitochondrial intermembrane space (GO:0005758) — the critical protective SOD1 pool; cytosol (GO:0005829, principal SOD1 localization); neuromuscular junction (GO:0031594).
Localization (UBERON): spinal cord (UBERON:0002240), corticospinal tract (UBERON:0002716), cerebellum (UBERON:0002037), peripheral/tibial nerve (UBERON:0001323), neuromuscular junction (UBERON:0002515).
Lateralization: Bilateral and symmetric (tetraplegia; axial).

Section 8 — Temporal Development

Onset: Prenatal antecedents (polyhydramnios 4/5, IUGR 3/5) with childhood clinical onset of neurologic disease (PMID: 34380534). Onset pattern: insidious/chronic.
Progression: Progressive course — loss of previously acquired motor milestones (regression), worsening spasticity. No relapsing-remitting or episodic pattern described. Duration: chronic, lifelong.
Stages: Not formally staged; practically, early (axial hypotonia, developmental concerns) → intermediate (emerging spasticity, regression) → advanced (fixed tetraspasticity, severe disability).
Remission: None reported; no spontaneous remission.
Critical period: The in-utero-to-childhood window is when the degenerative process establishes; mouse rescue data suggest that restoring SOD1 before axonopathy is established is key (preventive rather than reparative), implying an early therapeutic window (PMID: 21078595).

Section 9 — Inheritance and Population

Inheritance: Autosomal recessive. Biallelic LoF required; heterozygous carriers are asymptomatic despite reduced enzyme activity (PMID: 31332433).
Penetrance: Complete in biallelic-null individuals (all reported homozygotes affected); zero in heterozygotes.
Expressivity: Core triad consistent; prenatal features (polyhydramnios, IUGR) variable (present in a majority but not all patients).
Genetic anticipation: Not applicable (not a repeat-expansion disorder).
Founder effect / consanguinity: Prominent — recurrent c.335dupG founder allele; all families consanguineous.
Carrier frequency: Not established; expected very low outside specific consanguineous populations.
Epidemiology: Ultra-rare — fewer than ~20 patients published worldwide (principally PMID: 31332433, PMID: 34380534, PMID: 36935613). No reliable prevalence/incidence figures (effectively <1/1,000,000).
Demographics / geography: Reported in consanguineous families; a cohort from Brazil (PMID: 34380534). No strong sex bias reported; sex ratio ~1:1 expected for an autosomal-recessive trait.

Section 10 — Diagnostics

Genetic testing (definitive): Diagnosis rests on identifying biallelic loss-of-function SOD1 variants. Recommended approach: whole-exome or whole-genome sequencing, or a hereditary-spastic-paraplegia / neurodegeneration gene panel that includes SOD1; targeted single-gene/founder-variant testing (c.335dupG) is appropriate in consanguineous families or known pedigrees.
Biochemical biomarker (disease-specific): Red-cell / tissue SOD1 enzyme-activity assay — absent activity in affected homozygotes, intermediate (~50%) in carriers (PMID: 31332433). This is a powerful, mechanism-specific confirmatory test that distinguishes STAHP from SOD1-ALS (where enzyme activity is retained).
Imaging: Brain MRI may show mild cerebellar atrophy (HP:0001272).
Electrophysiology: EMG / nerve-conduction studies may reflect the distal motor axonopathy / NMJ involvement inferred from mouse models (by extrapolation).
Clinical criteria: No formal consensus criteria; diagnosis is the characteristic clinical triad + biallelic SOD1 LoF + absent enzyme activity.
Differential diagnosis: Hereditary spastic paraplegias; cerebral palsy (non-progressive — the key distinguishing feature is STAHP's regression); other childhood neurodegenerative / leukodystrophy syndromes. Importantly, SOD1-ALS is NOT a childhood differential and is mechanistically opposite.
Screening: Cascade carrier testing within affected families; no newborn or population screening exists (ultra-rare).

Section 11 — Outcome / Prognosis

Course: Progressive, chronic, disabling; motor regression and fixed tetraspasticity lead to loss of ambulation and high dependency.
Survival/mortality: No formal survival statistics are published given the tiny cohort; prognosis is guarded, driven by progressive neurodegeneration and attendant complications (respiratory, feeding).
Morbidity/disability: Severe long-term functional impairment is expected (ICF: profound mobility and self-care limitation).
Complications: Inferred from severe spastic tetraplegia — contractures, respiratory insufficiency, aspiration / feeding difficulty, secondary musculoskeletal deformity.
Prognostic factors: Complete enzyme absence predicts the full phenotype; no validated molecular prognostic biomarkers exist. Any residual SOD1 activity would be expected to attenuate severity (hypothesis based on carrier data and mouse dosage effects).
Recovery: No spontaneous recovery; no disease-modifying therapy currently alters the trajectory.

Section 12 — Treatment

There is no approved disease-specific therapy. Management is supportive (PMID: 31332433, PMID: 34380534).

Supportive / rehabilitative (standard of care): - Physical, occupational, and speech therapy (NCIT: Physical Therapy; Occupational Therapy). - Spasticity management — oral antispastics (baclofen, tizanidine), botulinum toxin, intrathecal baclofen (NCIT: Baclofen; Botulinum Toxin). - Nutritional and respiratory support; orthopedic management of contractures.

Mechanism-rational but unproven (experimental) strategies: - Antioxidants / SOD mimetics (e.g., EUK-8, tempol) — protective in Sod1-null mouse organ-injury models (PMID: 14988070, PMID: 17697870); not tested in STAHP patients. - Nrf2 activators (e.g., sulforaphane) — upregulate endogenous antioxidant defenses and are neuroprotective in oxidative-stress models (PMID: 32061629); conceptual only for STAHP. - SOD1 gene augmentation / enzyme replacement — the most mechanistically direct approach for a loss-of-function disorder. Proof-of-concept from mouse rescue: restoring SOD1 to neurons (PMID: 24378874) or to the mitochondrial intermembrane space (PMID: 21078595) prevents the motor phenotype. Neurotrophic gene therapy (AAV1.NT-3) improved muscle/function in Sod1-KO mice (PMID: 37553101) — supportive, not curative.

Critical caveat — do NOT use SOD1-lowering therapy: Tofersen (an intrathecal antisense oligonucleotide that reduces SOD1 synthesis) is the approved therapy for SOD1-ALS. Miller et al. note tofersen "is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene" (PMID: 41661214); robust human SOD1 reduction is confirmed in autopsy tissue (PMID: 42406382). STAHP, being a SOD1-deficiency disease, requires the opposite intervention (enzyme restoration). Park et al. explicitly caution that the deficiency phenotype "should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis" (PMID: 31332433).

Section 13 — Prevention

Primary prevention: Not applicable (not acquired). For at-risk couples: genetic counseling, carrier testing, and reproductive options (prenatal diagnosis, preimplantation genetic testing) — especially relevant in consanguineous families carrying the founder allele (NCIT: Genetic Counseling).
Secondary prevention: Cascade testing of relatives; early identification could, in principle, open an early therapeutic window should enzyme-restoration therapy become available (mouse data favor early/preventive intervention, PMID: 21078595).
Tertiary prevention: Proactive management to prevent complications of spasticity (contracture prevention, respiratory and nutritional surveillance).
Immunization / public health / environmental: Not applicable.

Section 14 — Other Species / Natural Disease

Taxonomy: Human disease (NCBI Taxon:9606). The closest natural SOD1-related disease in another species is canine degenerative myelopathy (DM) in dogs (NCBI Taxon:9615).
Orthologous gene: Canine SOD1 (NCBI Gene ID 403559).
Key comparative insight — DM is NOT a STAHP model: Canine DM is caused by homozygous SOD1 missense variants (E40K; also T18S) across ≥5 breeds (Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd, Chesapeake Bay retriever) and features SOD1-immunoreactive cytoplasmic inclusions resembling human SOD1-ALS. Awano et al. report "The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation" (PMID: 19188595). Biochemically, the canine mutants "form enzymatically active dimers, arguing against a loss of function in affected homozygous animals" (PMID: 23707216), with unfolded-protein-response / ER-stress activation in spinal glia (PMID: 30273700). Thus DM is a gain-of-function (ALS-like) disease, mechanistically the opposite of STAHP.
Zoonotic potential: None (genetic disorder).

Section 15 — Model Organisms

The Sod1-null (knockout) mouse is the principal and highly informative model of the STAHP loss-of-function mechanism.

Model	Type	Key finding	Phenotype recapitulation	Reference
Sod1⁻/⁻ whole-body KO	Mouse (knockout)	Peripheral-nerve oxidative stress; progressive distal motor axonopathy; fast-twitch denervation; cell bodies/sensory preserved	Recapitulates motor-axon / oxidative-stress core	PMID: 21963651
Mitochondrial-IMS-targeted SOD1	Mouse (transgenic rescue)	mito-IMS SOD1 prevents defects; rescues motor phenotype to 12 months	Defines protective subcellular pool	PMID: 21078595
Neuron-specific CuZnSOD (synapsin)	Mouse (transgenic rescue)	Neuronal SOD1 prevents loss of muscle mass/function	Identifies critical protective cell type	PMID: 24378874
Sod1⁻/⁻ NMJ studies	Mouse	Impaired evoked neurotransmitter release, NMJ destabilization, reduced strength	Models NMJ failure	PMID: 24971750
Neuronal-CuZnSOD deletion	Mouse (conditional)	Muscle mitochondrial / Ca²⁺-handling dysfunction precedes sarcopenia, independent of denervation	Dissects upstream mechanisms	PMID: 34639076
AAV1.NT-3 in Sod1KO	Mouse (gene-therapy test)	Improved muscle fiber size, function, remyelination via mTOR	Therapeutic proof-of-concept	PMID: 37553101
GPx4 overexpression in Sod1KO	Mouse	Lipid-hydroperoxide reduction modulates muscle pathology	Modifier-pathway dissection	PMID: 37878529

Mouse model — findings in words. The knockout develops "oxidation of the glutathione pool" in tibial nerve but not muscle, "suggesting that axonal degeneration is a consequence" of nerve oxidative stress (PMID: 21963651). At the synapse, "motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation" (PMID: 24971750). Compartment-specific rescue localizes the protection to neurons and mitochondria (PMID: 24378874, PMID: 21078595).

Limitations of the mouse model: The Sod1-KO mouse was developed chiefly as an accelerated-sarcopenia / peripheral-axonopathy model and reproduces the oxidative-stress-driven distal motor axonopathy and NMJ failure. It does not fully capture the human CNS features — spastic tetraplegia (an upper-motor-neuron sign), axial hypotonia, cerebellar atrophy, and hyperekplexia-like startle. The human-to-mouse mapping of the central motor phenotype therefore remains partly inferred. No STAHP-specific iPSC, organoid, or non-murine genetic model has yet been reported.

Mechanistic Model / Interpretation

  Biallelic SOD1 loss-of-function (c.335dupG, p.Cys112Trpfs*11)
        │  [demonstrated: zero enzyme activity]
        ▼
      No superoxide dismutation  →  superoxide (O2·−) accumulation
        │  [chronic oxidative stress]
 ┌──────────────┴───────────────┐
 ▼                              ▼
  Mitochondrial-IMS              Peripheral nerve
  redox imbalance                glutathione oxidation
 │                              │
 └──────────────┬───────────────┘
        ▼
Progressive DISTAL MOTOR AXONOPATHY
(fast-twitch denervation; cell bodies spared)
        ▼
NEUROMUSCULAR-JUNCTION destabilization & failure
(↓ evoked neurotransmitter release; AChR density preserved)
        ▼
   CLINICAL: spastic tetraplegia (LL>UL) + axial hypotonia +
   motor regression + mild cerebellar atrophy + hyperekplexia-like startle

  PROTECTIVE NODES (rescue in mouse):  neuronal SOD1  &  mitochondrial-IMS SOD1

SOD1 as a two-sided coin. STAHP sits at one pole of SOD1 biology; SOD1-ALS at the other:

Feature	STAHP (this disease)	SOD1-ALS
Variant type	Biallelic truncating/LoF	Heterozygous missense
Inheritance	Autosomal recessive	Autosomal dominant
Enzyme activity	Absent	Retained (often normal)
Mechanism	Loss of function (no antioxidant defense)	Toxic gain of function (misfolding/aggregation)
Onset	Childhood (prenatal antecedents)	Adult
Carrier state	Asymptomatic	—
Rational therapy	Increase/restore SOD1	Lower SOD1 (tofersen)

This symmetry is the central scientific message of the investigation: it reframes SOD1 not merely as an "ALS gene" but as a dosage-sensitive antioxidant whose complete absence is itself a distinct, severe neurodevelopmental/neurodegenerative disease — and it draws a biological safety boundary around aggressive SOD1-lowering.

Evidence Base

PMID	Role in this report	Source type
31332433	Defining paper — identifies c.335dupG, total enzyme loss, clinical triad, recessive inheritance, ALS-therapy caution	Human clinical
34380534	5-patient cohort — prenatal (polyhydramnios 4/5, IUGR 3/5) & childhood onset	Human clinical
36935613	Second independent homozygous LoF SOD1 family — confirms gene–disease relationship	Human clinical
21963651	Sod1-KO: nerve oxidative stress → distal motor axonopathy	Mouse model
21078595	Mitochondrial-IMS SOD1 rescues phenotype → pinpoints initiating compartment	Mouse model
24971750	NMJ functional failure (↓ neurotransmitter release)	Mouse model
24378874	Neuronal SOD1 sufficient to protect muscle/NMJ	Mouse model
41661214	Tofersen (SOD1-lowering) approved for SOD1-ALS — grounds safety boundary	Human clinical trial
42406382	Tofersen CNS distribution & robust SOD1 reduction in humans	Human autopsy
19188595	Canine DM caused by SOD1 E40K missense (gain-of-function)	Veterinary/comparative
23707216	Canine mutants are active dimers — "arguing against a loss of function"	In vitro/comparative
30273700	UPR/ER-stress in canine DM glia (gain-of-function pathology)	Veterinary

The evidence is strongest for (a) the human genetic/biochemical definition of the disease and (b) the mouse-derived oxidative-stress → axonopathy → NMJ-failure mechanism. The weakest link is the direct demonstration that the human central phenotype (spasticity, cerebellar atrophy, startle) arises through the same chain validated in mice.

Limitations and Knowledge Gaps

Tiny human sample size (<~20 patients): No robust epidemiology, natural-history, survival, or quantitative penetrance/expressivity data; frequencies of individual phenotypes rest on small series.
Model–human phenotype gap: The Sod1-KO mouse reproduces peripheral motor-axon/NMJ pathology but not the human upper-motor-neuron spasticity, cerebellar atrophy, or hyperekplexia-like startle; the central-nervous-system mechanism of STAHP is therefore inferred.
No STAHP-specific omics: No patient transcriptomics, proteomics, metabolomics, single-cell, or spatial data are available; molecular-profiling claims are extrapolated.
No disease-specific biomarker validation beyond enzyme activity: Prognostic biomarkers are unknown.
No therapeutic trials: Antioxidant, Nrf2-activator, and SOD1-augmentation strategies are rationally motivated but entirely untested in STAHP patients.
Ontology/identifier gaps: No dedicated ICD-11/MeSH code; Orphanet characterization is minimal.

Proposed Follow-up Experiments / Actions

Establish an international STAHP patient registry to aggregate genotype, enzyme activity, natural history, imaging, and survival across the few known families (addresses Gap 1).
Generate patient-derived iPSC motor neurons / NMJ organoids carrying c.335dupG to test whether the human central and peripheral phenotypes recapitulate the mouse oxidative-stress → axonopathy chain, and to screen antioxidants / SOD mimetics / Nrf2 activators (addresses Gaps 2–3).
Pursue SOD1 gene-augmentation / enzyme-replacement proof-of-concept building on the mouse rescue data (neuronal and mitochondrial-IMS targeting), including biodistribution and an early-intervention window study (addresses Gaps 2, 5; leverages PMID: 24378874, PMID: 21078595).
Deep-phenotype patients with CNS-focused MRI and electrophysiology to test whether a demonstrable distal motor axonopathy / NMJ signature exists in humans, directly bridging the model–human gap.
Perform patient CSF/plasma redox and neurofilament profiling to search for a tractable pharmacodynamic/prognostic biomarker (mirroring neurofilament utility in SOD1-ALS).
Formal nosology/ontology update: advocate for dedicated ICD-11 and Orphanet entries and ensure carrier/cascade-testing guidance for consanguineous populations harboring the founder allele.

Evidence-source legend

Human clinical = patient reports/cohorts; Mouse model = Sod1-knockout/transgenic studies; Veterinary/comparative = canine degenerative myelopathy; In vitro = biochemical/cell studies. Wherever a mechanistic step is supported only by model data, this report labels it inferred for human STAHP.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	20
Resolved	20
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	20
On topic	12
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	33
Resolved	30
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	17
Terms named correctly	13
Terms named as a different term	1
Terms whose name is worth a second look	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0032828 (2 mentions) - the report calls it "MONDO"; MONDO calls it spastic tetraplegia and axial hypotonia, progressive

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0001272 (2 mentions) - the report calls it "Cerebellar atrophy", "mild cerebellar atrophy", "Imaging: Brain MRI may show mild cerebellar atrophy"; HP calls it Cerebellar atrophy
GO:0006979 (2 mentions) - the report calls it "Cellular processes: Chronic oxidative stress", "response to oxidative stress"; GO calls it response to oxidative stress**
CL:0000188 (2 mentions) - the report calls it "skeletal muscle fibers"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0001272 - called "Cerebellar atrophy", "mild cerebellar atrophy", "Imaging: Brain MRI may show mild cerebellar atrophy"
GO:0006979 - called "Cellular processes:** Chronic oxidative stress", "response to oxidative stress"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Taxon.

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Spastic Tetraplegia and Axial Hypotonia, Progressive (STAHP): A Comprehensive Disease Characteristics Report

Summary

Section 1 — Disease Information

Section 2 — Etiology

Section 3 — Phenotypes

Section 4 — Genetic / Molecular Information

Section 5 — Environmental Information

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

Detail by category

Section 7 — Anatomical Structures Affected

Section 8 — Temporal Development

Section 9 — Inheritance and Population

Section 10 — Diagnostics

Section 11 — Outcome / Prognosis

Section 12 — Treatment

Section 13 — Prevention

Section 14 — Other Species / Natural Disease

Section 15 — Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Evidence-source legend

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver