I'm pulling the core SCA27A literature from PubMed now (the FGF14 point-variant and deletion papers, plus the mouse models) so I can write the report from abstracts I've actually checked.

I found about 40 FGF14/SCA27 abstracts already cached in the repo. I'm reading those now to pull exact quotes before I write the report.

Still reading: the 2026 SCA27A knock-in mouse paper and the episodic-ataxia (EA9) case series are the most important cached sources, so I'm going through those next.

Direct PubMed pages are blocked, so I'm switching to Europe PMC to get the uncached abstracts.

Found several recent SCA27A-specific papers (NYS4 structural variants 2023, childhood-onset series 2026, patient iPSC lines 2026), so I'm pulling their abstracts now.

I have the core literature. Now checking ontology IDs against the repo's local term caches so the suggested bindings aren't from memory.

Spinocerebellar Ataxia 27A (SCA27A; ATX‑FGF14): research report for the dismech entry

Target: MONDO:0008654 spinocerebellar ataxia 27A (the label matches cache/mondo/terms.csv) · Gene: FGF14 (hgnc:3671) · Category: Mendelian Prepared: 2026‑10‑01

How this was sourced. Quotes marked [cached] were read from the repository's references_cache/ files. Quotes marked [EPMC] were taken from the abstract text Europe PMC returned. [EPMC] quotes have not been checked against a cache file, so run just fetch-reference PMID:… and then just count-verified-snippets before using any of them as an evidence snippet.

Ontology IDs marked ✔ were looked up in the repository's cache/<prefix>/terms.csv during this session. Unmarked IDs are suggestions and need a lookup before they are bound.

I could not reach OMIM (HTTP 403), ClinGen or ClinVar directly; those gaps are flagged where they matter.

1. Disease information

Overview. SCA27A is a very rare autosomal dominant cerebellar ataxia. It is caused by heterozygous loss‑of‑function changes in FGF14: - missense variants - nonsense and frameshift variants - splice variants - an in‑frame deletion - partial duplication - deletions of 13q33.1 - balanced translocations that disrupt the gene

FGF14 encodes intracellular fibroblast growth factor 14 (iFGF14, also called FHF4). This protein is not secreted. It binds the C‑terminus of voltage‑gated sodium (Nav) channel α subunits and sets their availability.

The typical picture is: - postural tremor in childhood - slowly progressive cerebellar ataxia from young adulthood - nystagmus and other oculomotor signs - dyskinesias - cognitive, behavioural and psychiatric features - in some patients, fever‑ or stress‑triggered episodic ataxia

The suffix "A" separates this disease from SCA27B (GAA‑FGF14 ataxia). SCA27B is a common late‑onset ataxia caused by an intronic GAA repeat expansion in the same gene, and it already has its own entry (kb/disorders/Spinocerebellar_Ataxia_27B.yaml). Evidence from SCA27B papers must not be cited for SCA27A; this is a Named Entity Confusion risk.

Key identifiers

Synonyms: - SCA27, spinocerebellar ataxia type 27 - ATX‑FGF14 (the newer nomenclature; Türkdoğan 2025 writes "ATX‑FGF/SCA27A") - FGF14‑related ataxia - Nystagmus 4, congenital, autosomal dominant (NYS4) — now explained by an FGF14 deletion (Ceroni 2023) - Episodic ataxia type 9 (EA9), as proposed by Piarroux 2020 for the episodic presentation

Nature of the data. Everything below is aggregated from published families and case reports. There are no EHR or registry cohorts. The total published case count is in the low hundreds at most: a 2018 review counted 32 cases with clinical detail, and a 2025 review counted 32 cases in 11 families for microdeletions alone.

2. Etiology

• Cause. Heterozygous germline FGF14 loss of function, which acts mainly through haploinsufficiency (§4 and §6). There are no environmental causes.
• Genetic risk factors. Only the causal FGF14 variants. No modifier genes have been identified.
• Biallelic loss. One consanguineous Turkish family had a homozygous truncating variant, c.75del (p.Leu26Serfs*51) (PMID:39704271):
• The homozygous child had a severe congenital non‑progressive cerebellar disorder with intellectual disability and paroxysmal non‑kinesigenic dyskinesia.
• The heterozygous parents had mild gait ataxia and tremor in their 40s.
• This is consistent with a dosage effect.
• Triggers rather than risk factors. Fever, emotional stress and exertion precipitate or worsen episodic attacks (PMID:24252256, PMID:32162847). There is no evidence on causal environmental exposures or protective factors.
• Gene–environment interaction. The leading hypothesis is that temperature sensitivity of Nav gating lowers an already reduced Nav reserve below threshold during fever. Coebergh 2014 states: "Sodium channels can be fever sensitive." This is inferred and has not been demonstrated in SCA27A tissue.

3. Phenotypes

Frequency data

Groth & Berman 2018 (PMID:29416937), review of 33 cases [EPMC]:

"early-onset tremor (12.1 ± 10.5 years) was present in 95.8%, while gait ataxia tended to present later in life (23.7 ± 16.7 years) and was accompanied by limb ataxia, dysarthria, and nystagmus. Other features of SCA27 that may distinguish it from other SCAs include the potential for episodic ataxia, accompanying psychiatric symptoms, and cognitive impairment."

Conci 2025 (PMID:41099962), microdeletion carriers, 32 cases in 11 families [EPMC]:

"75% (24/32) nystagmus, 46% (15/32) ataxia, 21% (7/32) episodic ataxia, 21% (7/32) tremor, 15% (5/32) dysarthria, 34% (11/32) learning disability, 28% (8/32) neuropsychiatric disease."

Phenotype table

Abstract quotes supporting the table: - Brusse 2006 (PMID:16211615) [cached]: "The patients showed a childhood-onset postural tremor and a slowly progressive ataxia evolving from young adulthood. Dyskinesia was often present, suggesting basal ganglia involvement…" and "Neuropsychological testing indicated low IQ and deficits in memory and executive functioning. Behavioral problems were also observed." - Coebergh 2014 (PMID:24252256) [cached]: "mild ataxia and abnormal eye movements repeatedly deteriorated with fever, making him unable to sit or walk during fever episodes." - Piarroux 2020 (PMID:32162847) [cached]: "Attacks were triggered by fever, lasted several days, and had variable frequencies. Nystagmus and/or postural tremor and/or learning disabilities were noticed in individuals harboring FGF14 mutation with or without episodic ataxia."

Quality‑of‑life impact. No EQ‑5D, SF‑36 or other formal QoL data exist. - Most patients stay ambulatory. Piarroux 2020's background states that motor function "is maintained through life in most of the patients." - In children, the main burden is learning and educational support and fever‑triggered loss of walking. - In adults, the burden comes from tremor and psychiatric comorbidity.

4. Genetic and molecular information

Gene. FGF14 is at 13q33.1 (older papers place it at 13q34). It has two major N‑terminal isoforms from alternative first exons, 1A and 1B. FGF14‑1b is the predominant brain isoform (PMID:19471976). Residue F145 in FGF14‑1a numbering corresponds to F150 in FGF14‑1b (PMID:41558966).

Reported pathogenic and likely pathogenic alleles

Variant classification. I did not reach ClinVar or ClinGen. No CGGV: file for FGF14 exists in references_cache/, so gene_disease_validity should stay absent until a record is fetched. just clingen-list will show whether ClinGen has classified FGF14–SCA27A; ClinGen's dosage map (CGDS:HGNC_3671) is also worth checking, given the deletion data.

Variant origin and consequence. - All alleles are germline. Most are inherited; the t(13;21) was de novo. - Truncating variants, CNVs and the F145S knock‑in all point to loss of function / haploinsufficiency (functional_impact_category: LOSS_OF_FUNCTION). - F145S was originally proposed to act as a dominant negative in overexpression systems (PMID:17978045). The 2026 knock‑in mouse instead shows reduced protein and phenocopies the Fgf14+/− mouse (PMID:41558966). So LOSS_OF_FUNCTION is the better‑supported category, with DOMINANT_NEGATIVE recorded as a superseded in‑vitro hypothesis.

Population frequency. Variants are absent from controls: p.Lys177* was absent from 502 Japanese controls and from public databases. Point variants are a rare cause of dominant ataxia. Stevanin 2004 (PMID:15365159) is titled "Mutations in the FGF14 gene are not a major cause of spinocerebellar ataxia in Caucasians", but there is no abstract in the cache to quote. Dalski 2005 found 1 frameshift among 208 familial cases.

Modifiers and epigenetics. None reported.

Chromosomal abnormalities. Two balanced translocations and several interstitial 13q33.1 deletions (58 kb to 545 kb, often including ITGBL1) plus one partial duplication. CNVs are an established mechanism: Ghorbani 2023 (PMID:38058854) [cached] lists FGF14 among the three SCA genes with reported CNVs.

5. Environmental information

There are no causal environmental, lifestyle or infectious factors. Fever, often from intercurrent viral illness, intense stress and fatigue act as attack triggers (PMID:32162847, PMID:24252256). A curator could record fever as an environmental entry with environmental_effect: EXACERBATES on the episodic node, citing PMID:24252256 or PMID:32162847.

6. Mechanism and pathophysiology

Ordered causal chain

1. A heterozygous FGF14 LoF allele (truncation, CNV, translocation, or a destabilizing missense such as F145S) leads to reduced iFGF14 protein.
2. Demonstrated in the knock‑in mouse: "Western blot analyses confirmed reduced iFGF14 protein expression in cerebellar lysates prepared from Fgf14F145S/+ (and Fgf14+/-) animals" (PMID:41558966) [cached].
3. F145S was originally "predicted to reduce the stability of the protein" by modelling (PMID:12489043).
4. Reduced iFGF14 leads to loss of its regulatory binding to the Nav α‑subunit C‑terminus, mainly Nav1.6 (SCN8A, hgnc:10596 ✔) and Nav1.1, in cerebellar Purkinje and granule neurons.
5. Co‑IP evidence: FGF14 "is a component of the NaV1.6 macromolecular complex in mouse cerebellum" (PMID:25269146) [cached].
6. Branch (in vitro, overexpression only): mutant F145S "does not interact directly with Na(v) channel alpha subunits… [and] disrupts the interaction between wild-type FGF14 and Na(v) alpha subunits" — a dominant‑negative mechanism (PMID:17978045) [EPMC]. In vivo data now favour plain haploinsufficiency (step 1).
7. Loss of FGF14 regulation leads to a hyperpolarizing shift in the voltage dependence of steady‑state (closed‑state) Nav inactivation, so fewer channels are available at rest. Two further effects contribute:
8. faster inactivation and loss of resurgent and late current (PMID:25269146)
9. reduced Nav1.6 protein in Purkinje cells in the null mouse (PMID:18930825)

Bosch 2015 (PMID:25926453) [cached]: "the loss of iFGF14 results in a marked hyperpolarizing shift in the voltage dependence of steady-state inactivation of the Nav currents in adult Purkinje neurons."

Yan 2014 (PMID:25269146) [cached]: "FGF14 knockdown biased NaV channels towards the inactivated state by decreasing channel availability, diminishing the 'late' NaV current, and accelerating channel inactivation rate, thereby reducing resurgent current and repetitive spiking." 4. Reduced Nav availability leads to failure of spontaneous, high‑frequency tonic firing in Purkinje neurons. Null cells fall silent; heterozygous and knock‑in cells fire in bursts. - PMID:41558966 [cached]: "high-frequency repetitive firing… was replaced by prolonged bursts of action potentials." - PMID:18930825 [cached]: "more than 80% of Fgf14(-/-) Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections." - This is a cell‑intrinsic defect: parallel‑fibre EPSCs are unchanged (PMID:18930825). - Parallel branch: granule cells also lose repetitive firing, shown in Fhf1/Fhf4 double‑null mice (PMID:17678857). 5. Disrupted Purkinje output from the cerebellar cortex leads to ataxia, tremor and abnormal eye movements. - The adult requirement is shown by shRNA knockdown in adult Purkinje cells, which "impairs motor coordination and balance". - Re‑expressing iFGF14 "rescues spontaneous firing and improves motor performance" (PMID:25926453) [cached]. - This means the deficit is physiological rather than purely developmental, which matters for treatment. 6. State‑dependent worsening (inferred). Because Nav availability is already reduced, perturbations such as fever, stress or fatigue lead to episodic ataxia attacks. This is supported clinically by fever triggering and by acetazolamide and 4‑AP responses, "supporting the hypothesis of a sodium channelopathy" (PMID:30607796) [cached]. It has not been tested mechanistically. 7. Extracerebellar branches. - Basal ganglia: dyskinesia, PNKD and parkinsonism. Fgf14‑null mice have "ataxia and a paroxysmal hyperkinetic movement disorder" and "reduced responses to dopamine agonists" (PMID:12123606) [EPMC]. Dutch‑family functional imaging also suggested basal ganglia involvement. - Hippocampus and prefrontal cortex lead to cognitive and psychiatric features: - Null mice show impaired spatial learning and theta‑burst LTP (PMID:17236779). - Null mice have reduced VGAT in the medial prefrontal cortex, and patients show prefrontal hypometabolism on FDG‑PET (PMID:32112487). 8. Late, mild neurodegeneration. Moderate cerebellar atrophy appears in older patients only. Whether it is secondary to chronic dysfunction is unknown; there is no SCA27A neuropathology. This should be framed as dysfunction‑predominant (Purkinje cell dysfunction > Purkinje cell loss).

Ontology suggestions

Cell types: - CL:0000121 Purkinje cell ✔ - CL:0001031 cerebellar granule cell ✔ - CL:0000540 neuron ✔ (hippocampal and cortical pyramidal neurons: search CL)

GO: - GO:0017080 sodium channel regulator activity ✔ (FGF14 molecular function) - GO:0035725 sodium ion transmembrane transport ✔ - GO:0019228 neuronal action potential ✔ (modifier: DECREASED) - GO:0060291 long‑term synaptic potentiation ✔ - GO:0007611 learning or memory ✔

Cellular components: - GO:0001518 voltage‑gated sodium channel complex ✔ - GO:0043194 axon initial segment ✔

Pathway framing. This is a channelopathy rather than a signalling cascade. iFGF14 does not activate FGF receptors. Its phosphorylation by GSK3 regulates the FGF14–Nav complex (PMID:23640885); that is relevant to pharmacology but has not been tied to the disease.

Omics. There are no single‑cell, transcriptomic or proteomic disease datasets. The only proteomic data are from Fgf14−/− mouse brain (PMID:30678040, sex‑specific). Patient iPSC lines now exist for future work (PMID:42372627). just discover-datasets could check GEO.

Module conformance. Look for an existing channelopathy or Purkinje‑firing module with just list-modules channel and just list-modules purkinje. cardiac_ion_channel_repolarization is out of scope.

7. Anatomical structures

• Primary:
• cerebellum UBERON:0002037 ✔
• cerebellar cortex UBERON:0002129 ✔ (Purkinje and granule layers)
• Secondary:
• collection of basal ganglia UBERON:0010011 ✔ and striatum UBERON:0002435 ✔ (dyskinesia, reduced dopamine response)
• prefrontal cortex UBERON:0000451 ✔ (PET hypometabolism)
• hippocampal formation UBERON:0002421 ✔ (mouse learning and LTP)
• the oculomotor and vestibulocerebellar system (nystagmus)
• mild peripheral sensory nerve involvement in a minority
• Subcellular: axon initial segment (GO:0043194 ✔) and the Nav channel complex (GO:0001518 ✔). Mouse FGF14 is axonally transported (PMID:12123606).
• Laterality: bilateral and symmetric. The NYS4 nystagmus is multidirectional.

8. Temporal development

• Onset:
• congenital or infantile: nystagmus, hypotonia, motor delay (NYS4, deletion families, Paucar 2020's "congenital onset")
• childhood: tremor, mean about 12 years; fever‑triggered EA from about 2 years
• young adult: ataxia, mean about 24 years
• late onset is reported: 47 years for p.Lys177*
• onset is insidious
• Course: very slowly progressive, with episodic exacerbations in some patients. In several children the EA attacks stopped after about 5–6 years of age (Piarroux family A). No staging system exists.
• Duration: lifelong.
• Critical windows: febrile illness in early childhood (attack risk). Adult re‑expression rescue in mice suggests therapy could work after development, although this is untested in humans.

9. Inheritance and population

• Inheritance: autosomal dominant. One family shows autosomal recessive inheritance, with mildly affected heterozygous parents (PMID:39704271).
• Penetrance: apparently high, but with marked variable expressivity:
• Family members range from isolated childhood tremor to severe ID (PMID:24252256, PMID:19471976).
• Some carriers never sought medical care.
• Ovine p.Q16* carriers show the same variable expressivity (PMID:29253853).
• Anticipation: none. This is not a repeat disorder, unlike SCA27B.
• De novo: one translocation (PMID:21600715). Germline mosaicism has not been reported.
• Founder effects: none known. Families are Dutch, German, French‑Canadian, French, Japanese, Swedish, British, Spanish, US and Turkish.
• Prevalence: unknown. Fewer than 100 published families; Orphanet class is probably <1/1,000,000 (fetch ORPHA:98764 to confirm). Use measure_type: CASES_IN_LITERATURE.
• Sex ratio: no sex bias reported.

10. Diagnostics

• Genetic testing is the only confirmatory test.
• Exome or genome sequencing, or ataxia and episodic‑ataxia panels: Piarroux used CACNA1A, KCNA1, CACNB4, SLC1A3, FGF14, SLC2A1, ATP1A3 and PRRT2.
• CNV analysis is essential: SNP‑array or chromosomal microarray, or exome/genome CNV calling. Karyotype is needed for translocations.
• Ceroni 2023 recommends screening FGF14 "in apparently isolated early onset nystagmus."
• The intronic GAA repeat must be tested separately (long‑read or RP‑PCR) to distinguish SCA27B; standard short‑read genome sequencing can miss it.
• Imaging: MRI is often normal or shows mild late cerebellar atrophy. FDG‑PET can show widespread hypometabolism, particularly prefrontal (PMID:32112487).
• Electrophysiology: nerve conduction may show mild sensory axonal neuropathy. Formal oculomotor recording (saccadic dysmetria, gaze‑evoked and rebound nystagmus) is useful.
• No biomarkers or laboratory tests.
• Differential diagnosis:
• episodic ataxias EA1 (KCNA1) and EA2 (CACNA1A)
• SCA6
• SCA27B
• essential tremor (when tremor dominates)
• PNKD (PNKD/MR‑1)
• congenital idiopathic or FRMD7 nystagmus
• an autoimmune mimic has been reported (Hoshina 2023, PMID:37460234, title only)
• Screening: cascade testing of relatives. There is no newborn or population screening.

11. Outcome and prognosis

• Survival: no data. Life expectancy is presumed normal; no deaths are attributed to the disease.
• Function:
• Most patients remain ambulant. The Japanese patient walked without a cane at 63.
• Disability comes mainly from tremor, learning and intellectual impairment, psychiatric illness, and transient loss of walking during attacks.
• Prognostic factors:
• Episodic attacks may wane after early childhood.
• Large deletions or translocations can be associated with more severe neurodevelopmental phenotypes, but this rests on a single case.
• There are no prognostic biomarkers.

12. Treatment

All treatment is symptomatic and supported only by case reports or small series. There are no trials (NCT/ICTRP searches would be expected to return nothing; not run).

Experimental and preclinical approaches: - Gene re‑expression rescues adult Fgf14−/− mice (PMID:25926453). - FGF14/Nav1.6 interface peptidomimetics and small molecules exist as research probes (PMID:34948337, PMID:29359916), but none have been tested in disease.

Pharmacogenomics: none.

13. Prevention

• Primary prevention: not possible beyond reproductive options. Prenatal or preimplantation testing is available for a known familial variant.
• Secondary prevention: cascade testing, and testing infants who present with nystagmus or fever‑triggered ataxia.
• Tertiary prevention: prompt treatment of fever, avoiding triggers, acetazolamide prophylaxis for frequent attacks, and early educational support.
• Genetic counselling: emphasize variable expressivity; mildly affected parents are common.

14. Other species and natural disease

Sheep, Ovis aries (NCBITaxon:9940). Familial episodic ataxia of lambs is associated with FGF14 c.46C>T, p.Q16*. It is autosomal dominant with variable expressivity, and a more severely affected homozygote was observed (PMID:29253853) [EPMC]:

"Familial episodic ataxia of lambs is a congenital transient autosomal dominant disorder of newborn lambs, with varying expressivity."

Signs resolve as the lambs mature. This parallels the waning of childhood EA in humans, and the authors note that the "mechanism behind the apparent recovery of lambs" is unknown. The causal link is described as "potentially associated", so it should be graded as such.

Other notes: - Ask OMIA for any further records. - FGF14 is conserved across vertebrates; mouse Fgf14 is MGI:109189 (look up). - No zoonotic relevance.

15. Model organisms

For the animal_models/experimental_models blocks: - The knock‑in links PARTIALLY_RECAPITULATES to the Purkinje‑firing node with model_scale: CELLULAR. - The null mouse should note the SPECIES_MISMATCH and genotype‑dose caveat.

Resources: MGI, IMSR, MMRRC.

Curation notes for the YAML draft

• The draft binds preferred_term: Cerebellar ataxia to HP:0001251, whose canonical label is "Ataxia" ✔. The label matches, but HPO has a narrower Cerebellar ataxia term. Look that term up rather than assuming its ID; it is not in the local cache.
• Do not reuse SCA27B evidence. Many cached FGF14 files are about SCA27B: PMID:36516086, 37165652, 38507876, 38271551, 39227614, 40379261, 38279833 and others.
• Fetch before use:
• PMID:12489043, 15470364, 12123606, 17978045, 17236779, 19471976, 21600715, 29416937, 32112487, 36207621, 39704271, 40156335, 41099962, 29253853, 17678857 (abstracts read via Europe PMC)
• ORPHA:98764
• The cached abstracts for PMID:28192817 (Amado 2017) and PMID:15365159 (Stevanin 2004) are empty, so they cannot support snippets. The abstract for PMID:41895131 (Regnier 2026, childhood SCA27A) was not returned and needs a full‑text look.
• genetic_context.functional_impact_category: LOSS_OF_FUNCTION is well supported. Record the F145S dominant‑negative result (PMID:17978045) as a REFUTE/INDIRECT or discussion item against the in‑vivo haploinsufficiency evidence (PMID:41558966), not as a co‑equal mechanism.

Sources

• Europe PMC REST API — abstracts for PMIDs 12489043, 15470364, 29416937, 29253853, 12123606, 17978045, 17236779, 19471976, 21600715, 17678857, 36207621, 32112487, 39704271, 40156335, 41099962, 40204701, 42372627
• NCBI E‑utilities esearch — literature census
• OMIM #193003 (mirror) — synonyms, NYS4, ORPHA:98764 link
• MalaCards SCA27A
• Local references_cache/ abstracts: PMID 16211615, 18930825, 24252256, 25269146, 25566820, 25926453, 30017992, 30607796, 32162847, 38058854, 41558966, 20723845

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

All extracted references resolved successfully.

Term Validation

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

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: ORPHA, MGI.

57 of 59 terms resolved to a current term; the rest could not be looked up either way.