I'm pulling the SPTAN1/SPG91 literature from Europe PMC so the report can cite verified PMIDs and abstracts.

Core literature is gathered; I'm checking one more model-organism citation (zebrafish αII-spectrin) and then I'll write the report.

SPG91 (autosomal dominant spastic paraplegia 91, with or without cerebellar ataxia, caused by SPTAN1): research report for the dismech entry

Target: MONDO:0957813 · OMIM #620538 · Gene: SPTAN1 (9q34.11) Prepared: 2026-10-01

How the evidence was checked. I took the PMIDs, titles and abstract quotes in this report from Europe PMC and MedGen records fetched while writing it. I did not look up the ontology CURIEs (HPO, GO, CL, UBERON, NCIT, HGNC). They are leads only. Under the repo's "every CURIE is read from a source" rule, check each one with runoak or just validate-terms before binding it. I have marked them "(verify)".

1. Disease information

Overview. MedGen carries the OMIM definition for SPG91, quoted here in full:

"Autosomal dominant spastic paraplegia-91 with or without cerebellar ataxia (SPG91) is a highly variable neurologic disorder characterized by early-onset gait abnormalities due to spastic paraplegia of the lower limbs, sometimes with cerebellar ataxia. The age at onset is highly variable (congenital to young adult), although most patients have symptom onset in the first decade. Some patients present with a spastic paraplegia-predominant phenotype with significant pyramidal signs, whereas others present with an ataxic-predominant phenotype. In addition, although most patients have a more 'pure' phenotype restricted to gait abnormalities without additional features, others have a more 'complicated' phenotype with additional features such as sensory abnormalities, peripheral neuropathy, optic neuropathy, developmental delay, variably impaired intellectual development, and seizures. Many have normal brain imaging, but cerebellar atrophy may be observed in those with prominent cerebellar ataxia." (MedGen C1846222 → concept 1846222)

Identifiers

Synonyms: SPG91; spastic paraplegia 91; SPTAN1-related hereditary spastic paraplegia; SPTAN1-related spastic ataxia.

Where the data come from: cohort and case-series reports pooled through international consortia (sequencing datasets, the 100,000 Genomes Project, DECIPHER, GeneMatcher), plus disease-level resources (OMIM, MedGen). There are no EHR-derived data.

Allelic disorders of SPTAN1 matter for lumping and splitting, because they are separate MONDO/OMIM entities: - DEE5 / EIEE5. Dominant-negative in-frame variants in the C-terminal α20–α21 region.

"Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay" (title, PMID:20493457) - Autosomal dominant distal hereditary motor neuropathy. Caused by nonsense variants and NMD (PMID:31332438; PMID:33578420). - Proposed autosomal recessive HSP. Biallelic missense variants (PMID:31515523; PMID:34526651). This is distinct from SPG91, which is dominant. - Distal myopathy. Haploinsufficiency through a 9q34 deletion (PMID:40999194).

2. Etiology

• Cause: a heterozygous (monoallelic) germline variant in SPTAN1, the gene for non-erythrocytic αII-spectrin (fodrin). Variants are either inherited dominantly or arise de novo.
• Key evidence:
• Van de Vondel et al., 2022, Mov Disord (PMID:35150594): > "We describe 22 patients from 14 families with five novel SPTAN1 variants… We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case."
• Morsy et al., 2023, Genet Med (PMID:36331550), a case-control burden test: > "Statistically significant enrichment of rare (minor allele frequency < 1 × 10^-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10^-5)."
• Environmental, protective and gene–environment factors: none reported. Not applicable for a monogenic neurodegenerative disorder.
• Modifiers: none identified. Penetrance and expressivity vary within families (see §9), which suggests modifiers that have not been characterised.

3. Phenotypes

Frequencies are approximate. They come from about 25 published SPG91-spectrum patients: - Van de Vondel 2022: 15 patients with p.Arg19Trp HSP and 6 with ataxia. - Morsy 2023: 10 with HSP/HA. - Lan 2025: 2 with p.Arg19Trp, plus a pooled review of the literature.

The cohorts overlap partly. All evidence is HUMAN_CLINICAL.

Onset: congenital to young adult, mostly in the first decade. In the p.Arg19Trp series, onset was typically in childhood or adolescence (Morsy patient 1 at age 8).

Course: slowly progressive. The quality-of-life burden comes from impaired mobility and walking aids. No EQ-5D or SF-36 data have been published.

4. Genetic and molecular information

• Gene: SPTAN1, spectrin alpha, non-erythrocytic 1. HGNC hgnc:11273 (verify), NCBI Gene 6709 (verify), UniProt Q13813 (verify). Located at 9q34.11.
• Protein: αII-spectrin, about 2,472 aa. It has an N-terminal partial repeat (α0) that forms the α/β tetramerization site, 20 spectrin repeats (three-helix bundles), an SH3 domain, a calpain/caspase-cleavage region in repeat α10, and C-terminal EF-hands. The heterodimer nucleation site is in α20–α21.

Variants reported in SPG91

• ACMG classification: check ClinVar for current classifications. p.Arg19Trp is expected to be Pathogenic or Likely Pathogenic given recurrence and segregation. I did not verify ClinVar records here.
• Population frequency: the disease-associated variants are absent or ultra-rare in gnomAD. Morsy's enrichment threshold was MAF < 1×10⁻⁵.
• Variant origin: germline throughout. There is no somatic role.
• Functional consequence: probably dominant-negative or structurally disruptive for the missense and in-frame alleles, not simple loss of function.
• Van de Vondel (PMID:35150594): > "mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat… disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism."
• Morsy (PMID:36331550): > "Variant p.(Arg19Trp) had the most deleterious effect on protein structure. This variant is located within the N-terminal tetramerization domain and results in steric clashes with 2 leucine residues in the beta chain." (full text)
• Lan 2025 (PMID:40397273), computational: p.Arg19Trp is "predicted to perturb the stability of αII/β spectrin heterotetramerization but did not destabilize the tetramerization domain of αII-spectrin."
• Truncating alleles are linked mainly to hereditary motor neuropathy (via NMD, PMID:31332438) or to mild developmental delay (Morsy), not to SPG91.
• For the dismech genetic_context, a reasonable choice is functional_impact_category: DOMINANT_NEGATIVE, with directness: INDIRECT because the support is modelling only, or leave the category unasserted. Neither dominant-negative action nor haploinsufficiency has been shown experimentally for the SPG91 alleles specifically.
• Genotype–phenotype pattern:
• p.Arg19Trp, in the N-terminal tetramerization site, gives HSP.
• Mid-rod and C-terminal in-frame or missense variants give ataxia.
• In-frame variants at the α20–21 nucleation site give DEE5 (PMID:29050398).
• Epigenetic or chromosomal changes: none specific to SPG91. Contiguous 9q34 deletions including SPTAN1 and STXBP1 cause encephalopathy or myopathy, which are separate conditions.
• ClinGen / GenCC: I did not confirm any gene-disease validity curation specifically for SPG91. Run just list-gene-validity and check the ClinGen cache. Leave gene_disease_validity absent unless a CGGV record is found.

5. Environmental information

There are no environmental, lifestyle or infectious factors. Not applicable.

6. Mechanism and pathophysiology

Causal chain

1. A heterozygous SPTAN1 missense or in-frame variant alters αII-spectrin. Examples are p.Arg19Trp at the α0 tetramerization site and mid-rod variants that break the links between spectrin repeats.
2. This leads to destabilised α/β spectrin assembly: heterotetramer formation for Arg19Trp, and repeat folding for rod variants.
3. Evidence is computational or modelling only (PMID:35150594, PMID:40397273, PMID:36331550).
4. Mutant αII-spectrin incorporates into αII/β heterodimers and tetramers and probably acts dominant-negatively. This results in abnormal spectrin aggregation or redistribution.
5. In SPG91 patient fibroblasts, Morsy found "Irregular αII-spectrin aggregation… in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants" (PMID:36331550; IN_VITRO).
6. The dominant-negative mechanism is better shown for DEE5 alleles (PMID:20493457; PMID:29337302). For SPG91 it is inferred.
7. Disruption of the membrane-associated periodic skeleton (MPS) in long axons, built from actin, spectrin and ankyrin. This leads to:
8. Branch A, nodes of Ranvier and AIS: voltage-gated sodium channel and ankyrin-G clustering is lost at nodes, paranodes and the axon initial segment (mouse and zebrafish: PMID:29038240, PMID:29038243, PMID:17331725; DEE5 neurons: PMID:20493457).
9. Branch B, mechanical vulnerability of axons: large-diameter myelinated axons cannot withstand the mechanical forces of limb movement. Huang 2017 (PMID:29038243): αII-spectrin-deficient sensory neurons show "severe ataxia due to preferential degeneration of large-diameter myelinated axons."
10. Branch C, calpain sensitivity: spectrin cleavage is accelerated. In Sptan1 p.R1098Q mice, the human Arg1098 position, this leads to progressive ataxia and neurodegeneration (PMID:33790315). This is model-organism evidence at a residue mutated (R1098C) in a human ataxia patient.
11. Length-dependent axonal degeneration of corticospinal tract axons, the longest CNS axons. This results in upper motor neuron signs: spastic paraplegia, hyperreflexia and Babinski sign. This step is inferred from the HSP pathology paradigm. No SPG91 neuropathology exists.
12. Degeneration of cerebellar neurons, Purkinje cells, or their afferents results in cerebellar ataxia and cerebellar atrophy on MRI. Inferred from MRI and from mouse models (PMID:29038240 widespread neurodegeneration; PMID:33790315).
13. Peripheral sensory and motor axon degeneration results in sensorimotor axonal polyneuropathy (~35% of p.Arg19Trp carriers) and impaired vibration sense.
14. Less often, developmental effects on the cortex (dendrite and AIS development, inhibitory synapses; PMID:29337302) result in ID and seizures in "complicated" cases.

Ontology leads (verify every CURIE)

• GO biological processes:
• actin cytoskeleton organization, GO:0030036
• axon initial segment / node of Ranvier assembly (search l~node of Ranvier, l~axon initial segment)
• axonogenesis, GO:0007409
• clustering of voltage-gated sodium channels, GO:0045162
• neuron projection maintenance, GO:1990535
• axonal degeneration / axon degeneration, GO:0098794 (verify)
• GO molecular functions: structural constituent of cytoskeleton, GO:0005200; actin binding, GO:0003779; calmodulin binding, GO:0005516.
• GO cellular components: spectrin, GO:0008091; cortical cytoskeleton; node of Ranvier, GO:0033268; axon initial segment, GO:0043194; paranode region of axon, GO:0033270.
• CL cell types: upper motor neuron, CL:2000062 (verify); pyramidal neuron, CL:0000598; Purkinje cell, CL:0000121; sensory neuron, CL:0000101; motor neuron, CL:0000100.
• UBERON sites: lateral corticospinal tract / corticospinal tract, UBERON:0002707 (verify); cerebellum, UBERON:0002037; spinal cord, UBERON:0002240; peripheral nerve, UBERON:0001021; optic nerve, UBERON:0000941.
• Biological scale tags: step 1 MOLECULAR; steps 2–3 CELLULAR; steps 4–6 TISSUE; phenotypes ORGANISM.

Related dismech modules

Check just list-modules axon. Likely candidates are a length-dependent axonopathy/HSP corticospinal module and peripheral_axonal_degeneration.

Molecular profiling

No transcriptomic, proteomic, metabolomic, single-cell or CRISPR-screen data are available for SPG91.

7. Anatomical structures affected

• Primary: corticospinal tracts (upper motor neurons); cerebellum (vermis atrophy in ataxic cases).
• Secondary: peripheral nerves (sensorimotor axonal neuropathy); optic nerve (optic neuropathy); cerebral cortex in complicated forms (seizures, ID; subcortical white-matter changes reported once).
• System: nervous system.
• Subcellular: axonal membrane periodic skeleton, nodes of Ranvier, paranodes, axon initial segment.
• Distribution: bilateral and symmetric. Lower limbs are affected before upper limbs.

8. Temporal development

• Onset: congenital to young adult, mostly first decade (OMIM). One pure-ataxia patient was evaluated at 72; the age of onset was not stated.
• Onset pattern: insidious.
• Course: chronic, slowly progressive, lifelong. There are no formal stages, no remission, and no natural-history registry.
• Critical periods: developmental effects of the spectrin skeleton (AIS formation) suggest an early window. This is speculative for SPG91.

9. Inheritance and population

• Inheritance: autosomal dominant, HP:0000006 (verify). De novo occurrence is frequent, especially in ataxia-predominant cases (4 of 6 ataxia patients de novo in PMID:35150594).
• Penetrance and expressivity:
• Expressivity is variable: pure HSP, HSP with neuropathy or ataxia, and complicated forms all occur with the same p.Arg19Trp variant.
• Incomplete penetrance has been described for SPTAN1 truncating HMN alleles ("Variable penetrance was noted", PMID:31332438). For SPG91 alleles, penetrance has not been quantified.
• Anticipation: none (not a repeat expansion).
• Founder effects: none documented. p.Arg19Trp recurs across unrelated families of different ancestries (European, Taiwanese in Lan 2025), which is consistent with a mutational hotspot (CpG C>T).
• Prevalence: unknown. Fewer than about 50 published patients means ultra-rare. In dismech terms: measure_type: CASES_IN_LITERATURE, prevalence_class: ULTRA_RARE or NOT_YET_DOCUMENTED.
• As a proxy for yield, Morsy found 12 of 1,142 HA/HSP index families carried rare damaging SPTAN1 variants, about 1%.
• Sex ratio: no bias expected (autosomal). The published cases include both sexes.

10. Diagnostics

• Genetic testing is the only way to diagnose SPG91. Use an HSP/ataxia multigene panel or exome/genome sequencing. SPTAN1 is on PanelApp HSP, ataxia and neuropathy panels (Genomics England PanelApp; PanelApp Australia).
• Copy-number analysis (exome CNV calling or CMA) can detect intragenic deletions such as the exons 25–27 deletion.
• Splice variants may need RNA studies.
• Imaging: brain MRI is often normal. It may show cerebellar (vermian) atrophy in ataxic cases. Spinal MRI is used to exclude structural mimics.
• Electrophysiology: NCS/EMG to detect axonal sensorimotor neuropathy. Motor evoked potentials can show corticospinal involvement (generic HSP practice).
• Other tests: optic coherence tomography or visual evoked potentials if optic neuropathy is suspected. EEG if seizures occur.
• Biomarkers: none. Fibroblast αII-spectrin aggregation is a research readout only.
• Differential diagnosis:
• Other AD-HSPs (SPAST/SPG4, ATL1/SPG3A, KIF5A/SPG10, REEP1/SPG31)
• Spastic ataxias (SACS/ARSACS, SPAX genes, SCA3/ATXN3, SCA1)
• SPTBN2 (SCA5)
• Leukodystrophies
• Cerebral palsy mimics (SPTAN1 appears in genetic cerebral-palsy-like cohorts)
• Structural myelopathy
• B12 or copper deficiency
• Screening: cascade testing of relatives. No newborn or population screening exists.

11. Outcome and prognosis

• Life expectancy: not reported. It is presumably normal in pure forms, since patients are documented at 40–72 years.
• Morbidity: progressive gait disability and need for walking aids. Neuropathy, bladder dysfunction, and in complicated cases seizures and ID.
• Prognostic factors: possibly genotype (p.Arg19Trp gives HSP; de novo mid-rod variants give ataxia, sometimes with ID or epilepsy). No validated prognostic markers.
• Quality-of-life data: none.

12. Treatment

There is no disease-modifying therapy. Management is the standard symptomatic care for HSP and ataxia.

• Experimental: D-aspartate improved motility in sptan1-null zebrafish (Lu et al. 2025, PMID:39988451: "supplementation with the amino acid D-aspartate improved motility in sptan1-null zebrafish, supporting its use for α-II spectrin-associated motor dysfunction"). This is preclinical, in a loss-of-function model, and no human trial exists. A caregiver survey of SPTAN1 families exists (PMID:40261672) but is mainly about the neurodevelopmental phenotypes.
• Clinical trials: none found specific to SPG91 or SPTAN1.
• Gene, RNA or cell therapy: none. Allele-specific knockdown of dominant-negative alleles is a theoretical option.
• Pharmacogenomics: not applicable.

13. Prevention

• Primary: none.
• Reproductive options: genetic counseling. The recurrence risk is 50% for offspring of an affected parent. For apparently de novo cases, the recurrence risk is low but not zero because of possible germline mosaicism. Prenatal or preimplantation testing is possible once the familial variant is known.
• Tertiary: prevent contractures, falls and urinary complications through physiotherapy, orthoses and bladder care.

14. Other species and natural disease

• I found no naturally occurring SPTAN1 spastic paraplegia in animals. No OMIA entry was identified.
• αII-spectrin is highly conserved across vertebrates. Orthologs:
• mouse Sptan1 (NCBI Gene 20740, verify)
• zebrafish sptan1
• Drosophila α-Spec

15. Model organisms

• Model gap: no model carrying an SPG91 allele (e.g. p.Arg19Trp knock-in) or iPSC-derived corticospinal motor neurons from an SPG91 patient has been reported.
• Mismatch: null and conditional KO models over-represent developmental and epileptic features compared with the human dominant-allele disease. This could be recorded as a HUMAN_MODEL_MISMATCH discussion.

Key citations (Europe PMC verified)

Gaps for the entry

• Not established: prevalence; ClinGen/GenCC validity; neuropathology; any SPG91-allele model; experimental proof of the dominant-negative versus haploinsufficiency mechanism for p.Arg19Trp; quality-of-life data.
• Curation risk, Named Entity Confusion: do not import DEE5, HMN or AR-HSP evidence as SPG91 phenotypes. Use it only as mechanistic, gene-level support, with directness: INDIRECT.
• Next steps:
• Run just fetch-reference PMID:35150594 and just fetch-reference PMID:36331550 (and the others) before quoting.
• Run just preflight-dr <report> MONDO:0957813.
• Validate every CURIE above.

Sources: - MedGen 1846222 - MalaCards SPG91 - Disease Ontology DOID:0070643 - Morsy et al. 2023, PMC10620943 - Genomics England PanelApp SPTAN1 - PanelApp Australia SPTAN1 - Gene Table of Neuromuscular Disorders ref 35150594 - Europe PMC REST API (abstract retrieval for all PMIDs above)

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

• PMID:36331550: "Irregular αII-spectrin aggregation… in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants"
• closest text in source: "Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants"

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMID:17331725 (2 mentions) - alphaII-spectrin is essential for assembly of the nodes of Ranvier in myelinated axons.
• shared terms: spectrin

Weighed against this report's own most characteristic terms: sptan1, spg91, ataxia, hsp, variant, patient, arg19trp, motor, spastic, verify, gene, seizure, cerebellar, morsy, neuropathy, phenotype, paraplegia, dominant-negative, ii-spectrin, spectrin.

Term Validation

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

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:0957813 (3 mentions) - the report calls it "MONDO"; MONDO calls it spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia
• DOID:0070643 (5 mentions) - the report calls it "Disease Ontology"; DOID calls it hereditary spastic paraplegia 91
• HP:0002500 (1 mention) - the report calls it "verify"; HP calls it Abnormal cerebral white matter morphology
• GO:0098794 (1 mention) - the report calls it "verify"; GO calls it postsynapse
• CL:2000062 (1 mention) - the report calls it "verify"; CL calls it placental villus capillary endothelial cell
• UBERON:0002707 (1 mention) - the report calls it "verify"; UBERON calls it corticospinal tract
• HP:0000006 (1 mention) - the report calls it "verify"; HP calls it Autosomal dominant inheritance
• NCIT:C15986 (4 mentions) - the report calls it "Antiseizure medication", "Bladder management (antimuscarinics)"; NCIT calls it Pharmacotherapy

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 (1 mention) - the report calls it "Cerebellar atrophy (MRI)"; HP calls it Cerebellar atrophy
• HP:0002495 (1 mention) - the report calls it "Impaired vibration sense"; HP calls it Impaired vibratory sensation, and lists "Impaired vibratory sense" among its other names

Terms named inconsistently

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

• NCIT:C15986 - called "Antiseizure medication", "Bladder management (antimuscarinics)"