Spinocerebellar Ataxia 27A

Mendelian MONDO:0008654 Pathograph 27 Show in embeddings browser

Spinocerebellar ataxia 27A (SCA27A, ATX-FGF14) is a rare, usually autosomal dominant cerebellar disorder caused by heterozygous loss-of-function changes in FGF14: missense, nonsense, frameshift, splice and in-frame variants, 13q33.1 deletions, a partial duplication and gene-disrupting translocations. FGF14 encodes intracellular fibroblast growth factor 14 (iFGF14), a non-secreted protein that binds the C-terminus of voltage-gated sodium (Nav) channel alpha subunits and keeps them available for firing. In mice, loss of one copy shifts Purkinje neuron Nav inactivation to more negative voltages, so the cells lose their tonic high-frequency firing. The typical picture is a childhood-onset postural tremor followed by a very slowly progressive cerebellar ataxia from young adulthood, with nystagmus, dysarthria, dyskinesia, cognitive and psychiatric features, and in some families fever-triggered episodic ataxia. SCA27A is distinct from SCA27B, the common late-onset ataxia caused by an intronic GAA repeat expansion in the same gene.

Ask OpenScientist

Ask a research question about Spinocerebellar Ataxia 27A. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

2
Inheritance
8
Pathophys.
15
Phenotypes
27
Pathograph
1
Genes
5
Medical Actions
4
Differentials
3
Models
5
References
1
Deep Research
👪

Inheritance

2
Autosomal dominant HP:0000006
Expressivity is highly variable within families, from isolated childhood tremor or nystagmus to ataxia with severe intellectual disability; some carriers never seek medical attention. Most families show dominant transmission of a single loss-of-function allele. One consanguineous family had a homozygous truncating variant: the child had a congenital nonprogressive cerebellar disorder with intellectual disability, and the heterozygous parents developed mild gait ataxia and tremor in their 40s, which fits a dosage effect.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (3 references)
PMID:24252256 SUPPORT Human Clinical
"This family demonstrates phenotypic variability of FGF14 deletions (SCA 27), fever sensitivity of ataxia and the added value of SNP-array analysis in making a diagnosis."
Variable expressivity across three generations with one deletion.
PMID:24252256 SUPPORT Human Clinical
"The mother was unable to perform tandem gait walking and had abnormal eye movements but had never sought medical attention."
A mildly affected carrier who had never been diagnosed.
PMID:39704271 SUPPORT Human Clinical
"Segregation analysis confirmed that the homozygous variant was inherited from heterozygous parents who developed mild gait ataxia and tremor in their 40s."
Heterozygous parents are mildly affected while the homozygous child is severely affected.
Autosomal recessive HP:0000007
One consanguineous family: a homozygous truncating variant (c.75del, p.Leu26Serfs*51) caused a severe congenital nonprogressive cerebellar disorder, while the heterozygous parents were mildly affected in later life.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:39704271 SUPPORT Human Clinical
"We report the first case of autosomal recessive FGF14-related cerebellar ataxia caused by a c.75del variant resulting in p.Leu26Serfs*51 truncation of the FGF14 protein."
The only reported biallelic case.
⚙

Pathophysiology

8
Heterozygous FGF14 Loss-of-Function Variants
Mechanism confidence: Established
One FGF14 allele is inactivated. The reported spectrum is a founding missense change (p.Phe145Ser), frameshift and nonsense variants, an intron 1 splice variant, an in-frame deletion (p.Val119del), 13q33.1 deletions of 58 kb to 545 kb that often also remove ITGBL1, a partial duplication, and two balanced translocations with breakpoints in FGF14.
FGF14 hgnc:3671 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGF14 (hgnc:3671). hgnc:3671 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Germline, usually inherited; one translocation arose de novo. Truncating variants, whole-gene deletions and the F145S knock-in mouse all point to haploinsufficiency.
Downstream
Reduced iFGF14 Protein
Show evidence (6 references)
PMID:12489043 SUPPORT Human Clinical
"We describe a large, three-generation family with early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia, not associated with any of the known SCA loci, and a mutation in the fibroblast growth factor 14 (FGF14) gene on chromosome 13q34."
The founding family carrying the F145S missense variant.
PMID:19471976 SUPPORT Human Clinical
"Truncation of one allele in our patients suggests that haploinsuffiency of FGF14 can cause SCA27."
A translocation disrupting one FGF14 allele causes the disease, supporting haploinsufficiency.
PMID:24252256 SUPPORT Human Clinical
"SNP-array analysis identified a 202 kb deletion in chromosome 13q33.1 containing the fibroblast growth factor (FGF)14 gene, which is associated with spinocerebellar ataxia (SCA) 27."
A whole-gene deletion segregating over three generations.
+ 3 more references
Reduced iFGF14 Protein
Mechanism confidence: Established
Less iFGF14 is present in cerebellar neurons. FGF14-1b, the isoform that predominates in brain, is the one disrupted by the t(5;13) translocation.
Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
FGF14 hgnc:3671 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGF14 (hgnc:3671). hgnc:3671 is a gene from the HUGO Gene Nomenclature Committee.
sodium channel regulator activity GO:0017080 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased sodium channel regulator activity (GO:0017080). GO:0017080 is a molecular function from the Gene Ontology.
Downstream
Loss of FGF14 Regulation of Purkinje Neuron Nav Channels
Show evidence (2 references)
PMID:41558966 SUPPORT Model Organism
"Western blot analyses confirmed reduced iFGF14 protein expression in cerebellar lysates prepared from Fgf14F145S/+ (and Fgf14+/- ) animals"
Reduced protein in the cerebellum of knock-in and heterozygous null mice.
PMID:19471976 SUPPORT Human Clinical
"FGF14-1b is the predominant isoform in brain, where it interacts with the voltage gated Na channel."
Identifies the brain isoform and its Nav channel partner.
Loss of FGF14 Regulation of Purkinje Neuron Nav Channels
Mechanism confidence: Established
Without enough iFGF14 bound to their C-terminus, Purkinje neuron Nav channels (largely Nav1.6) inactivate at more negative voltages, inactivate faster and carry less late and resurgent current, so fewer channels are available at resting potential. The null mouse also has less Nav1.6 protein in Purkinje cells. Parallel changes in cerebellar granule neurons are shown in Fgf12/Fgf14 double-null mice.
Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology. cerebellar granule cell CL:0001031 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar granule cell (CL:0001031). CL:0001031 is a cell type from the Cell Ontology.
FGF14 hgnc:3671 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGF14 (hgnc:3671). hgnc:3671 is a gene from the HUGO Gene Nomenclature Committee. SCN8A (Nav1.6) hgnc:10596 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCN8A (Nav1.6), annotated with SCN8A (hgnc:10596). hgnc:10596 is a gene from the HUGO Gene Nomenclature Committee.
regulation of sodium ion transmembrane transport GO:1902305 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of sodium ion transmembrane transport (GO:1902305). GO:1902305 is a biological process from the Gene Ontology.
voltage-gated sodium channel complex GO:0001518 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves voltage-gated sodium channel complex (GO:0001518). GO:0001518 is a cellular component from the Gene Ontology.
Downstream
Impaired Purkinje Neuron Repetitive Firing
Show evidence (4 references)
PMID:25926453 SUPPORT Model Organism
"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"
The core channel defect in adult Purkinje neurons.
PMID:41558966 SUPPORT Model Organism
"voltage-clamp experiments revealed a hyperpolarizing shift in the voltage dependence of closed-state Nav channel inactivation in Fgf14F145S/+ (and Fgf14+/- ) Purkinje neurons"
The same shift with a single mutant or null allele, matching the human genotype.
PMID:18930825 SUPPORT Model Organism
"Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14(-/-) Purkinje neurons."
Reduced Nav1.6 protein in null Purkinje neurons.
+ 1 more reference
Impaired Purkinje Neuron Repetitive Firing
Mechanism confidence: Established
Purkinje neurons, the only output of the cerebellar cortex, lose their spontaneous tonic high-frequency firing. Heterozygous null and F145S knock-in cells fire in prolonged bursts; most homozygous null cells fall silent. The defect is intrinsic to the cell and present in adults: knocking iFGF14 down only in adult Purkinje neurons is enough to cause it, and re-expressing iFGF14 in adult null neurons restores firing. The link to ataxia is not settled at the patients' genotype: knockdown and homozygous null mice are ataxic, but heterozygous null and F145S knock-in mice, which have the firing defect, performed normally on a balance beam.
Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
neuronal action potential GO:0019228 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuronal action potential (GO:0019228). GO:0019228 is a biological process from the Gene Ontology.
cerebellar cortex UBERON:0002129 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellar cortex (UBERON:0002129). UBERON:0002129 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Fgf14 F145S knock-in mouse Mouse recapitulates Same genotype as the patients; reproduces the firing defect and its Nav basis.
Fgf14 knockout mouse Mouse recapitulates
Downstream
Progressive cerebellar ataxia
Postural tremor
Nystagmus
Dysarthria
Dysmetric saccades
Episodic ataxia
Show evidence (3 references)
PMID:41558966 SUPPORT Model Organism
"Current-clamp recordings from Purkinje neurons in acute cerebellar slices from adult male and female Fgf14F145S/+ mice revealed that high-frequency repetitive firing, which is characteristic of wild-type Purkinje neurons, was replaced by prolonged bursts of action potentials."
Burst firing replaces tonic firing in mice carrying the patient allele.
PMID:18930825 SUPPORT Model Organism
"Unlike in the wild type animals, more than 80% of Fgf14(-/-) Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections."
Near-complete loss of repetitive firing in null Purkinje neurons.
PMID:25926453 SUPPORT Model Organism
"the acute and selective Fgf14-targeted short hairpin RNA (shRNA)-mediated in vivo "knock-down" of iFGF14 in adult Purkinje neurons attenuates spontaneous and evoked action potential firing"
Shows the firing defect is a physiological requirement in adults, not only a developmental one.
Fever-Sensitive Sodium Channel Decompensation
Mechanism confidence: Hypothetical
Proposed explanation for the attacks of episodic ataxia: with Nav availability already reduced, fever or other stressors push cerebellar excitability below threshold for days at a time. It rests on clinical observations (fever-triggered attacks, response to acetazolamide) and on the known temperature sensitivity of sodium channels; it has not been tested experimentally in an FGF14 model.
Downstream
Episodic ataxia
Show evidence (2 references)
PMID:24252256 SUPPORT INDIRECT Human Clinical
"FGF14 regulates brain sodium channels, especially in the cerebellum. Sodium channels can be fever sensitive."
The authors' proposed link between fever sensitivity and the FGF14 sodium channel defect.
PMID:41099962 SUPPORT INDIRECT Human Clinical
"We propose the hypothesis that the episodic symptoms in SCA27A align with the molecular pathology of a channelopathy and propose management strategies based on this insight."
States the channelopathy hypothesis for the episodic symptoms as a hypothesis.
Basal Ganglia Dopaminergic Dysfunction
Mechanism confidence: Provisional
FGF14 loss alters basal ganglia function. Null mice have a paroxysmal hyperkinetic movement disorder and reduced responses to dopamine agonists, and functional imaging in one patient supported basal ganglia involvement. This is the proposed basis of the dyskinesia, but the step from mouse to patient is not established.
basal ganglia UBERON:0010011 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in basal ganglia, annotated with collection of basal ganglia (UBERON:0010011). UBERON:0010011 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Fgf14 knockout mouse Mouse partially recapitulates
Downstream
Dyskinesia
Show evidence (2 references)
PMID:12123606 SUPPORT Model Organism
"Neuropharmacological studies showed that Fgf14-deficient mice have reduced responses to dopamine agonists."
Altered dopaminergic responses in the null mouse.
PMID:16211615 SUPPORT Human Clinical
"Dyskinesia was often present, suggesting basal ganglia involvement, which was supported by functional imaging in 1 patient."
Clinical and imaging evidence for basal ganglia involvement in patients.
Impaired Hippocampal Synaptic Plasticity
Mechanism confidence: Provisional
Fgf14 null mice show impaired spatial learning and defective theta-burst induced long-term potentiation in hippocampal slices. This is the proposed basis of the cognitive impairment, but it has been shown only in mice.
long-term synaptic potentiation GO:0060291 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased long-term synaptic potentiation (GO:0060291). GO:0060291 is a biological process from the Gene Ontology.
hippocampal formation UBERON:0002421 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in hippocampal formation (UBERON:0002421). UBERON:0002421 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Fgf14 knockout mouse Mouse partially recapitulates
Downstream
Cognitive impairment
Show evidence (1 reference)
PMID:17236779 SUPPORT Model Organism
"Impaired theta burst initiated long-term synaptic potentiation was also found in hippocampal slices from Fgf14(-/-) mice."
Defective hippocampal LTP in the null mouse.
Prefrontal Cortical Dysfunction
Mechanism confidence: Provisional
Patients from a whole-gene deletion family show medial prefrontal hypometabolism on FDG PET, most pronounced in the member with psychosis, and Fgf14 null mice have reduced VGAT, an inhibitory synapse marker, in the medial prefrontal cortex. This is the proposed basis of the psychiatric features, but the link rests on one family and one mouse finding.
prefrontal cortex UBERON:0000451 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in prefrontal cortex (UBERON:0000451). UBERON:0000451 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Psychiatric and behavioral disturbance
Psychosis
Attention deficit hyperactivity disorder
Show evidence (2 references)
PMID:32112487 SUPPORT Human Clinical
"New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients."
Prefrontal hypometabolism in every affected member of a deletion family.
PMID:32112487 SUPPORT Model Organism
"Reduced expression of VGAT was found in the mPFC of fgf14-/- mice."
Reduced inhibitory marker in the prefrontal cortex of null mice.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spinocerebellar Ataxia 27A Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Eye 2
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41099962 SUPPORT REVIEW SYNTHESIS Human Clinical
"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"
Nystagmus in 75% of microdeletion carriers.
PMID:36207621 SUPPORT Human Clinical
"Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic FGF14 variants, and highlights the importance of screening FGF14 in apparently isolated early onset nystagmus."
Early-onset nystagmus can be the main presentation.
PMID:30607796 SUPPORT Human Clinical
"On clinical examination, interictally, the patient presented with gaze-evoked nystagmus and rebound nystagmus and slight dysarthria."
Gaze-evoked and rebound nystagmus between attacks.
Dysmetric saccades HP:0000641 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmetric saccades (HP:0000641). HP:0000641 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30017992 SUPPORT Human Clinical
"He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia."
Saccadic dysmetria in an adult patient.
Head and Neck 1
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19471976 SUPPORT Human Clinical
"Clinically, both show signs of SCA, although the daughter is the most affected with early onset cerebellar ataxia, microcephaly, and severe mental retardation."
Single-case report.
Nervous System 11
Postural tremor HP:0002174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postural tremor (HP:0002174). HP:0002174 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29416937 SUPPORT REVIEW SYNTHESIS Human Clinical
"Including our case, we found that early-onset tremor (12.1 ± 10.5 years) was present in 95.8%"
Frequency and age of onset of tremor across 33 reported cases.
PMID:16211615 SUPPORT Human Clinical
"The patients showed a childhood-onset postural tremor and a slowly progressive ataxia evolving from young adulthood."
Childhood-onset postural tremor in the founding family.
PMID:41099962 SUPPORT REVIEW SYNTHESIS Human Clinical
"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"
Tremor is less frequent (21%) among microdeletion carriers.
Progressive cerebellar ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cerebellar ataxia (HP:0002073). HP:0002073 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29416937 SUPPORT REVIEW SYNTHESIS Human Clinical
"gait ataxia tended to present later in life (23.7 ± 16.7 years) and was accompanied by limb ataxia, dysarthria, and nystagmus"
Age of onset and associated cerebellar signs across reported cases.
PMID:16211615 SUPPORT Human Clinical
"The patients showed a childhood-onset postural tremor and a slowly progressive ataxia evolving from young adulthood."
Slowly progressive ataxia from young adulthood in the founding family.
PMID:30017992 SUPPORT Human Clinical
"The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47."
Adult onset at 47 years with a nonsense variant.
Episodic ataxia HP:0002131 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Episodic ataxia (HP:0002131). HP:0002131 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:32162847 SUPPORT Human Clinical
"We report four patients from two families who presented attacks of childhood-onset episodic ataxia associated with pathogenic mutations in the FGF14 gene."
Childhood-onset episodic ataxia in two families.
PMID:25566820 SUPPORT Human Clinical
"Our findings expand the phenotypic spectrum of SCA27 by underlining the possible episodic nature of this ataxia."
Episodic ataxia in a two-generation family with a frameshift variant.
PMID:24252256 SUPPORT Human Clinical
"We present a young boy whose mild ataxia and abnormal eye movements repeatedly deteriorated with fever, making him unable to sit or walk during fever episodes."
Fever-triggered loss of sitting and walking in a child with a deletion.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30017992 SUPPORT Human Clinical
"He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia."
Dysarthria in an adult patient.
PMID:41099962 SUPPORT REVIEW SYNTHESIS Human Clinical
"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"
Dysarthria in 15% of microdeletion carriers.
Dyskinesia HP:0100660 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyskinesia (HP:0100660). HP:0100660 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16211615 SUPPORT Human Clinical
"Dyskinesia was often present, suggesting basal ganglia involvement, which was supported by functional imaging in 1 patient."
Frequent dyskinesia in the founding family.
PMID:21600715 SUPPORT Human Clinical
"FGF14 disruption caused by a de novo reciprocal chromosomal translocation between chromosomes 13 and 21 was identified in a patient with the phenotype of paroxysmal non-kinesigenic dyskinesia (PNKD)."
A PNKD-like presentation with a de novo FGF14-disrupting translocation.
Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:16211615 SUPPORT Human Clinical
"Neuropsychological testing indicated low IQ and deficits in memory and executive functioning."
Cognitive profile in the founding family.
PMID:19471976 SUPPORT Human Clinical
"Clinically, both show signs of SCA, although the daughter is the most affected with early onset cerebellar ataxia, microcephaly, and severe mental retardation."
Severe intellectual disability in a translocation carrier.
PMID:41099962 SUPPORT REVIEW SYNTHESIS Human Clinical
"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"
Learning disability in 34% of microdeletion carriers.
Psychiatric and behavioral disturbance Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:16211615 SUPPORT Human Clinical
"Behavioral problems were also observed."
Behavioral problems in the founding family.
PMID:32112487 SUPPORT Human Clinical
"New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients."
Psychosis and ADHD in a Swedish deletion family.
PMID:29416937 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other features of SCA27 that may distinguish it from other SCAs include the potential for episodic ataxia, accompanying psychiatric symptoms, and cognitive impairment."
Psychiatric symptoms as a distinguishing feature across reported cases.
Psychosis HP:0000709 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Psychosis (HP:0000709). HP:0000709 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32112487 SUPPORT Human Clinical
"New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients."
Psychosis reported as a new feature in the Swedish family.
Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32112487 SUPPORT Human Clinical
"New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients."
ADHD reported as a new feature in the Swedish family.
Parkinsonism HP:0001300 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Parkinsonism (HP:0001300). HP:0001300 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29416937 SUPPORT Human Clinical
"We report here a case of a 70-year-old male who presented with slowly worsening tremor and gait instability that began in his early adulthood along with additional features of parkinsonism on examination."
Single-case report of parkinsonism.
Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:16211615 SUPPORT Human Clinical
"Magnetic resonance imaging (MRI) of the brain showed only moderate cerebellar atrophy in the 2 eldest patients."
Atrophy only in the oldest members of the founding family.
PMID:30017992 SUPPORT Human Clinical
"Brain MRI showed cerebellar atrophy without brainstem involvement."
Cerebellar atrophy in a 63-year-old patient.
PMID:30607796 REFUTE Human Clinical
"MRI of the brain was normal and peripheral-vestibular function was bilaterally intact."
A normal MRI in an episodic-ataxia patient, showing atrophy is not constant.
Constitutional 1
Trigeminal neuralgia HP:0100661 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Trigeminal neuralgia (HP:0100661). HP:0100661 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41099962 SUPPORT Human Clinical
"Patient 2 carries a 545 kb deletion and developed episodic ataxia and trigeminal neuralgia, a novel feature not previously described in this cohort."
Single-case report.
🧬

Genetic Associations

1
FGF14 (Heterozygous coding, splice and structural loss-of-function variants in FGF14 cause SCA27A. Point variants are a rare cause of dominant ataxia: one frameshift was found among 208 unrelated familial ataxia cases. The intronic GAA expansion in the same gene causes the separate disease SCA27B and is not part of this entry.)
Gene: FGF14 hgnc:3671 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FGF14 (hgnc:3671). hgnc:3671 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:15470364 SUPPORT Human Clinical
"In one patient, we detected a novel single base pair deletion in exon 4 (c.487delA) creating a frameshift mutation."
One frameshift among 208 familial ataxia cases, showing the gene is a rare cause.
PMID:39704271 SUPPORT Human Clinical
"ATX-FGF/SCA27A has been exclusively associated with heterozygous variants in the FGF14 gene, presenting with postural tremor, slowly progressive cerebellar ataxia, and psychiatric and behavioral disturbances."
Summarizes the established gene-disease relationship.
PMID:40156335 SUPPORT Human Clinical
"A novel heterozygous in-frame deletion (p.Val119del) in FGF14 was identified in this family affected by childhood-onset tremor followed by late-onset progressive ataxia."
Segregation of an in-frame deletion in a five-generation family.
💊

Medical Actions

5
Acetazolamide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: acetazolamide CHEBI:27690 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses acetazolamide (CHEBI:27690). CHEBI:27690 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Carbonic anhydrase inhibitor used to reduce the frequency of episodic ataxia attacks; evidence is limited to case reports.
Target Phenotypes: Episodic ataxia HP:0002131 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Episodic ataxia (HP:0002131). HP:0002131 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30607796 SUPPORT Human Clinical
"Our patient responded well to acetazolamide (reduction in the frequency of attacks by about two thirds), supporting the hypothesis of a sodium channelopathy."
About two-thirds fewer attacks in a single patient.
PMID:32162847 SUPPORT REVIEW SYNTHESIS Human Clinical
"pharmacological responsiveness still unknown (improvement after acetazolamide treatment in 2 patients)"
Improvement in two patients across the literature, with responsiveness still described as unknown.
4-Aminopyridine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: 4-aminopyridine CHEBI:34385 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses 4-aminopyridine (CHEBI:34385). CHEBI:34385 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Potassium channel blocker that improved balance in two patients from one family. The larger 4-aminopyridine literature concerns SCA27B and is not cited here.
Target Phenotypes: Progressive cerebellar ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Progressive cerebellar ataxia (HP:0002073). HP:0002073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40156335 SUPPORT Human Clinical
"Two patients showed significant tremor reduction following STN-DBS and balance improvement with 4-AP."
Balance improvement in two patients.
Subthalamic Deep Brain Stimulation
Action: subthalamic nucleus deep brain stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is subthalamic nucleus deep brain stimulation, annotated with Deep Brain Stimulation (NCIT:C21024). NCIT:C21024 is a clinical intervention from the NCI Thesaurus. Ontology label: Deep Brain Stimulation NCIT:C21024
Platform: Surgery
Subthalamic nucleus deep brain stimulation for disabling tremor, reported in two patients.
Target Phenotypes: Postural tremor HP:0002174 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Postural tremor (HP:0002174). HP:0002174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40156335 SUPPORT Human Clinical
"Two patients showed significant tremor reduction following STN-DBS and balance improvement with 4-AP."
Tremor reduction after STN-DBS in two patients.
Amantadine and Levodopa
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: amantadine CHEBI:2618 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses amantadine (CHEBI:2618). CHEBI:2618 is a therapeutic agent from Chemical Entities of Biological Interest. levodopa CHEBI:15765 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levodopa, annotated with L-dopa (CHEBI:15765). CHEBI:15765 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Improved tremor, gait stability and parkinsonism in a single patient.
Target Phenotypes: Parkinsonism HP:0001300 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Parkinsonism (HP:0001300). HP:0001300 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29416937 SUPPORT Human Clinical
"The patient was started on amantadine, which improved his head tremor and led to marked improvement in falls with reduced gait instability."
Single-patient response to amantadine.
PMID:29416937 SUPPORT Human Clinical
"Work-up revealed a novel pathogenic mutation in the Fibroblast Growth Factor 14 gene, and symptoms improved with amantadine and levodopa."
Further improvement after adding levodopa in the same patient.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling on dominant inheritance with very variable expressivity; mildly affected parents are common.
🔬

Diagnosis

1
Sequencing with copy-number analysis
Exome or genome sequencing, or an ataxia or episodic-ataxia gene panel, combined with copy-number analysis (SNP array or sequencing-based CNV calling), since deletions are a common mechanism. Karyotyping detects balanced translocations.
Show evidence (1 reference)
PMID:24252256 SUPPORT Human Clinical
"This family demonstrates phenotypic variability of FGF14 deletions (SCA 27), fever sensitivity of ataxia and the added value of SNP-array analysis in making a diagnosis."
SNP-array detected the causal deletion.
📈

Progression

2
Childhood onset
Age: infancy to adolescence
Nystagmus can be present from infancy, tremor begins in childhood, and fever-triggered episodic attacks can begin in early childhood. Episodic symptoms, nystagmus, learning disability and psychiatric symptoms tend to appear earlier than ataxia.
Show evidence (1 reference)
PMID:41099962 SUPPORT Human Clinical
"Episodic symptoms, nystagmus, learning disability and neuropsychiatric symptoms occur at an earlier age."
Early-appearing features in microdeletion carriers.
Slowly progressive adult ataxia
Age: young adulthood onward
Ataxia begins in young adulthood and progresses very slowly; motor function is maintained through life in most patients.
Show evidence (1 reference)
PMID:32162847 SUPPORT BACKGROUND Human Clinical
"Symptom onset occurs early in life nevertheless the disease course is usually very slow and motor function is maintained through life in most of the patients."
Background summary of the disease course.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population prevalence has been published. A 2018 review counted 32 previously reported clinical cases with point variants or translocations, and a 2025 review counted 32 microdeletion carriers in 11 families. These are case counts, not prevalence.
Show evidence (2 references)
PMID:29416937 SUPPORT REVIEW SYNTHESIS Human Clinical
"Review of the literature revealed a total of 32 previously reported clinical cases of SCA27."
Case count up to 2018.
PMID:41099962 SUPPORT REVIEW SYNTHESIS Human Clinical
"We identified SCA27A microdeletions in 32 cases across 11 families."
Case count for microdeletion carriers.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Spinocerebellar Ataxia 27A:

Spinocerebellar ataxia 27B
Overlapping Features Allelic disorder caused by a heterozygous intronic GAA repeat expansion in FGF14. It is far more common, starts late in adult life and is not detected by standard exome or short-read sequencing, so the repeat must be sized separately.
Distinguishing Features
  • Intronic GAA repeat expansion rather than a coding or structural variant
  • Late adult onset without the childhood tremor and neurodevelopmental features of SCA27A
Show evidence (1 reference)
PMID:40156335 SUPPORT BACKGROUND Human Clinical
"This led to the assignment of two different names to the allelic disorders: SCA27A for ataxia caused by the rare coding variants and SCA27B (OMIM #620174) for ataxia caused by the more common intronic repeat expansion."
Defines the two allelic disorders.
Episodic ataxia types 1 and 2
Overlapping Features KCNA1 and CACNA1A episodic ataxias are the commonest genetic causes of episodic ataxia and are on the same gene panels.
Distinguishing Features
  • Fever triggering, childhood postural tremor and learning disability point towards FGF14
Show evidence (1 reference)
PMID:25566820 SUPPORT BACKGROUND Human Clinical
"Mutations in KCNA1 and CACNA1A account for the majority of EA cases worldwide."
Establishes the main alternative causes of episodic ataxia.
Paroxysmal non-kinesigenic dyskinesia
Overlapping Features PNKD caused by MR-1 (PNKD) variants can be mimicked by FGF14 disruption.
Show evidence (1 reference)
PMID:21600715 SUPPORT Human Clinical
"This indicated genetic heterogeneity of PNKD, since 60% of the patients with PNKD exhibit mutations in another gene responsible for PNKD, the myofibrillogenesis regulator 1 gene (MR-1)."
PNKD-like presentation with FGF14 disruption.
Isolated early-onset nystagmus
Overlapping Features Apparently isolated infantile nystagmus may be the presenting feature of an FGF14 deletion.
Show evidence (1 reference)
PMID:36207621 SUPPORT Human Clinical
"Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic FGF14 variants, and highlights the importance of screening FGF14 in apparently isolated early onset nystagmus."
Recommends FGF14 screening in isolated early nystagmus.
🐁

Animal Models

3
Fgf14 F145S knock-in mouse
Carries the founding patient allele at the mouse locus. Purkinje neurons fire in bursts, iFGF14 protein is reduced and Nav inactivation is shifted to more negative voltages, matching the heterozygous null.
Species
Mouse
Genotype
Fgf14 F145S/+ (heterozygous knock-in of the first human SCA27A allele)
Publication
PMID:41558966
Pathograph links
Impaired Purkinje Neuron Repetitive Firing recapitulates fidelity: high observes: cellular Same genotype as the patients; reproduces the firing defect and its Nav basis.
Limitations: Reproduces the cellular defect but not the motor phenotype: knock-in and heterozygous null mice performed like wild type on the elevated balance beam.
Show evidence (1 reference)
PMID:41558966 SUPPORT Model Organism
"Together, these results indicate that Fgf14 haploinsufficiency and reduced Nav channel availability underlie impaired firing in Fgf14F145S/+ Purkinje neurons."
Establishes the knock-in as a model of the firing node.
Show evidence (1 reference)
PMID:41558966 SUPPORT Model Organism
"To investigate the in vivo mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus (Fgf14F145S )."
Describes construction of the knock-in model.
Fgf14 knockout mouse
Homozygous null mice develop ataxia and a paroxysmal hyperkinetic movement disorder, have reduced responses to dopamine agonists, silent Purkinje neurons with reduced Nav1.6, and impaired spatial learning with defective hippocampal LTP.
Species
Mouse
Genotype
Fgf14 -/- (Fgf14 N-beta-Gal allele)
Publication
PMID:12123606
Pathograph links
Impaired Purkinje Neuron Repetitive Firing recapitulates fidelity: moderate observes: cellular
Limitations: Homozygous loss, whereas patients are heterozygous; the null phenotype is more severe (most Purkinje cells silent rather than bursting).
Show evidence (1 reference)
PMID:18930825 SUPPORT Model Organism
"Mice with a targeted disruption of the Fgf14 locus (Fgf14(-/-)) develop ataxia resembling human SCA27."
The null mouse is an accepted model of the human ataxia.
Impaired Hippocampal Synaptic Plasticity partially recapitulates fidelity: low observes: organism
Limitations: Mouse spatial-learning assays are a proxy for human cognitive impairment, the LTP defect has not been examined in patients, and the genotype is homozygous whereas patients are heterozygous.
Show evidence (1 reference)
PMID:17236779 SUPPORT Model Organism
"Here we extend the similarities between Fgf14(-/-) mice and FGF14(F145S) humans by showing that Fgf14(-/-) mice exhibit reliable acquisition (place learning) deficits in the Morris water maze."
Learning deficits parallel the human cognitive phenotype.
Basal Ganglia Dopaminergic Dysfunction partially recapitulates fidelity: low observes: organism
Limitations: Reduced responses to dopamine agonists in mice are a pharmacological proxy for basal ganglia dysfunction; the paroxysmal hyperkinetic disorder of the homozygous null is more severe than the dyskinesia of heterozygous patients.
Show evidence (1 reference)
PMID:12123606 SUPPORT Model Organism
"Neuropharmacological studies showed that Fgf14-deficient mice have reduced responses to dopamine agonists."
Altered dopaminergic responses in the null mouse model the basal ganglia node.
Show evidence (1 reference)
PMID:12123606 SUPPORT Model Organism
"Fgf14-deficient mice were viable, fertile, and anatomically normal, but developed ataxia and a paroxysmal hyperkinetic movement disorder."
Whole-animal phenotype of the null mouse.
Sheep familial episodic ataxia
Familial episodic ataxia of newborn lambs, autosomal dominant with variable expressivity; signs resolve as the lambs mature. A more severely affected homozygous lamb was observed. The authors describe the association as potential.
Species
Sheep
Genotype
FGF14 c.46C>T (p.Q16*) heterozygous, naturally occurring
Publication
PMID:29253853
Show evidence (1 reference)
PMID:29253853 SUPPORT Model Organism
"Familial episodic ataxia of lambs is a congenital transient autosomal dominant disorder of newborn lambs, with varying expressivity."
Naturally occurring dominant episodic ataxia in sheep with an FGF14 truncating variant.
{ }

Source YAML

click to show 
name: Spinocerebellar Ataxia 27A
creation_date: "2026-10-01T00:00:00Z"
category: Mendelian
synonyms:
- SCA27A
- SCA27
- spinocerebellar ataxia type 27
- ATX-FGF14
- FGF14-related spinocerebellar ataxia
- nystagmus 4, congenital, autosomal dominant
- NYS4
description: >-
  Spinocerebellar ataxia 27A (SCA27A, ATX-FGF14) is a rare, usually autosomal
  dominant cerebellar disorder caused by heterozygous loss-of-function changes
  in FGF14: missense, nonsense, frameshift, splice and in-frame variants,
  13q33.1 deletions, a partial duplication and gene-disrupting translocations.
  FGF14 encodes intracellular fibroblast growth factor 14 (iFGF14), a
  non-secreted protein that binds the C-terminus of voltage-gated sodium (Nav)
  channel alpha subunits and keeps them available for firing. In mice, loss of one
  copy shifts Purkinje neuron Nav inactivation to more negative voltages, so the
  cells lose their tonic high-frequency firing. The typical picture is a
  childhood-onset postural tremor followed by a very slowly progressive
  cerebellar ataxia from young adulthood, with nystagmus, dysarthria,
  dyskinesia, cognitive and psychiatric features, and in some families
  fever-triggered episodic ataxia. SCA27A is distinct from SCA27B, the common
  late-onset ataxia caused by an intronic GAA repeat expansion in the same
  gene.
disease_term:
  preferred_term: spinocerebellar ataxia 27A
  term:
    id: MONDO:0008654
    label: spinocerebellar ataxia 27A
references:
- reference: PMID:12489043
  title: "A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]."
- reference: PMID:16211615
  title: "Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype."
- reference: PMID:29416937
  title: "Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype."
- reference: PMID:41099962
  title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
- reference: PMID:41558966
  title: "In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons."
pathophysiology:
- name: Heterozygous FGF14 Loss-of-Function Variants
  biological_scale: MOLECULAR
  role: initiating genetic lesion
  mechanism_confidence: ESTABLISHED
  description: >-
    One FGF14 allele is inactivated. The reported spectrum is a founding
    missense change (p.Phe145Ser), frameshift and nonsense variants, an intron
    1 splice variant, an in-frame deletion (p.Val119del), 13q33.1 deletions of
    58 kb to 545 kb that often also remove ITGBL1, a partial duplication, and
    two balanced translocations with breakpoints in FGF14.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Germline, usually inherited; one translocation arose de novo. Truncating
      variants, whole-gene deletions and the F145S knock-in mouse all point to
      haploinsufficiency.
  genes:
  - preferred_term: FGF14
    term:
      id: hgnc:3671
      label: FGF14
  downstream:
  - target: Reduced iFGF14 Protein
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41558966
      reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Western blot analyses confirmed reduced iFGF14 protein expression in cerebellar lysates prepared from Fgf14F145S/+ (and Fgf14+/- ) animals"
      explanation: >-
        The patient missense allele knocked into the mouse lowers iFGF14
        protein, as a heterozygous null allele does, so the variant acts at
        least partly by loss of protein.
  evidence:
  - reference: PMID:12489043
    reference_title: "A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a large, three-generation family with early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia, not associated with any of the known SCA loci, and a mutation in the fibroblast growth factor 14 (FGF14) gene on chromosome 13q34."
    explanation: The founding family carrying the F145S missense variant.
  - reference: PMID:19471976
    reference_title: "SCA27 caused by a chromosome translocation: further delineation of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Truncation of one allele in our patients suggests that haploinsuffiency of FGF14 can cause SCA27."
    explanation: A translocation disrupting one FGF14 allele causes the disease, supporting haploinsufficiency.
  - reference: PMID:24252256
    reference_title: A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SNP-array analysis identified a 202 kb deletion in chromosome 13q33.1 containing the fibroblast growth factor (FGF)14 gene, which is associated with spinocerebellar ataxia (SCA) 27."
    explanation: A whole-gene deletion segregating over three generations.
  - reference: PMID:30017992
    reference_title: Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By exome analysis, we identified a novel heterozygous variant (NM_004115, c.529A>T; Lys177X) in exon 4 of the FGF14 gene."
    explanation: A heterozygous nonsense variant in an adult-onset patient.
  - reference: PMID:40156335
    reference_title: "Novel In-Frame FGF14 Deletion Causes Spinocerebellar Ataxia Type 27A: Clinical Response to Deep Brain Stimulation and 4-Aminopyridine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCA27A is usually caused by loss-of-function FGF14 variants."
    explanation: States the loss-of-function mechanism for the disease as a whole.
  - reference: PMID:17978045
    reference_title: The FGF14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability.
    supports: REFUTE
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "suggesting that the mutant FGF14(F145S) protein acts as a dominant negative, interfering with the interaction between wild-type FGF14 and Na(v) channel alpha subunits and altering neuronal excitability"
    explanation: >-
      In overexpression experiments the F145S protein behaved as a dominant
      negative rather than a simple loss of function. The later knock-in mouse
      (PMID:41558966) found reduced protein and a phenotype matching the
      heterozygous null, so haploinsufficiency is recorded as the mechanism and
      this result is kept as the contrary in vitro finding.
- name: Reduced iFGF14 Protein
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Less iFGF14 is present in cerebellar neurons. FGF14-1b, the isoform that
    predominates in brain, is the one disrupted by the t(5;13) translocation.
  genes:
  - preferred_term: FGF14
    term:
      id: hgnc:3671
      label: FGF14
  molecular_functions:
  - preferred_term: sodium channel regulator activity
    modifier: DECREASED
    term:
      id: GO:0017080
      label: sodium channel regulator activity
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  downstream:
  - target: Loss of FGF14 Regulation of Purkinje Neuron Nav Channels
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41558966
      reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Together, these results indicate that Fgf14 haploinsufficiency and reduced Nav channel availability underlie impaired firing in Fgf14F145S/+ Purkinje neurons."
      explanation: Links the reduced protein dose to reduced Nav channel availability.
  evidence:
  - reference: PMID:41558966
    reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Western blot analyses confirmed reduced iFGF14 protein expression in cerebellar lysates prepared from Fgf14F145S/+ (and Fgf14+/- ) animals"
    explanation: Reduced protein in the cerebellum of knock-in and heterozygous null mice.
  - reference: PMID:19471976
    reference_title: "SCA27 caused by a chromosome translocation: further delineation of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FGF14-1b is the predominant isoform in brain, where it interacts with the voltage gated Na channel."
    explanation: Identifies the brain isoform and its Nav channel partner.
- name: Loss of FGF14 Regulation of Purkinje Neuron Nav Channels
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Without enough iFGF14 bound to their C-terminus, Purkinje neuron Nav
    channels (largely Nav1.6) inactivate at more negative voltages, inactivate
    faster and carry less late and resurgent current, so fewer channels are
    available at resting potential. The null mouse also has less Nav1.6
    protein in Purkinje cells. Parallel changes in cerebellar granule neurons
    are shown in Fgf12/Fgf14 double-null mice.
  genes:
  - preferred_term: FGF14
    term:
      id: hgnc:3671
      label: FGF14
  - preferred_term: SCN8A (Nav1.6)
    term:
      id: hgnc:10596
      label: SCN8A
  cellular_components:
  - preferred_term: voltage-gated sodium channel complex
    term:
      id: GO:0001518
      label: voltage-gated sodium channel complex
  biological_processes:
  - preferred_term: regulation of sodium ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:1902305
      label: regulation of sodium ion transmembrane transport
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  downstream:
  - target: Impaired Purkinje Neuron Repetitive Firing
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25269146
      reference_title: FGF14 modulates resurgent sodium current in mouse cerebellar Purkinje neurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "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."
      explanation: The Nav changes produced by FGF14 knockdown are shown to reduce repetitive spiking.
    - reference: PMID:41558966
      reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A shift from tonic to burst firing was mimicked in wild-type Purkinje neurons by bath application of the Nav channel toxin, tetrodotoxin."
      explanation: Lowering Nav availability pharmacologically reproduces the mutant firing pattern.
  evidence:
  - reference: PMID:25926453
    reference_title: Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "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"
    explanation: The core channel defect in adult Purkinje neurons.
  - reference: PMID:41558966
    reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "voltage-clamp experiments revealed a hyperpolarizing shift in the voltage dependence of closed-state Nav channel inactivation in Fgf14F145S/+ (and Fgf14+/- ) Purkinje neurons"
    explanation: The same shift with a single mutant or null allele, matching the human genotype.
  - reference: PMID:18930825
    reference_title: FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14(-/-) Purkinje neurons."
    explanation: Reduced Nav1.6 protein in null Purkinje neurons.
  - reference: PMID:17678857
    reference_title: Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Sodium channels in Fhf1-/-Fhf4-/- granule neurons inactivate at more negative membrane potential, inactivate more rapidly, and are slower to recover from the inactivated state."
    explanation: >-
      The same Nav inactivation defect in cerebellar granule neurons, shown in
      mice lacking both Fgf12 (Fhf1) and Fgf14 (Fhf4); indirect because the
      model is digenic.
- name: Impaired Purkinje Neuron Repetitive Firing
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Purkinje neurons, the only output of the cerebellar cortex, lose their
    spontaneous tonic high-frequency firing. Heterozygous null and F145S
    knock-in cells fire in prolonged bursts; most homozygous null cells fall
    silent. The defect is intrinsic to the cell and present in adults:
    knocking iFGF14 down only in adult Purkinje neurons is enough to cause it,
    and re-expressing iFGF14 in adult null neurons restores firing. The link
    to ataxia is not settled at the patients' genotype: knockdown and
    homozygous null mice are ataxic, but heterozygous null and F145S knock-in
    mice, which have the firing defect, performed normally on a balance beam.
  biological_processes:
  - preferred_term: neuronal action potential
    modifier: DECREASED
    term:
      id: GO:0019228
      label: neuronal action potential
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellar cortex
    term:
      id: UBERON:0002129
      label: cerebellar cortex
  downstream:
  - target: Progressive cerebellar ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25926453
      reference_title: Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The selective shRNA-mediated in vivo \"knock-down\" of iFGF14 in adult Purkinje neurons also impairs motor coordination and balance."
      explanation: Removing iFGF14 from adult Purkinje neurons alone is enough to cause incoordination.
    - reference: PMID:25926453
      reference_title: Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We also show here that expressing iFGF14 selectively in adult Fgf14(-/-) Purkinje neurons rescues spontaneous firing and improves motor performance."
      explanation: Restoring Purkinje firing improves motor performance, linking the firing defect to the motor phenotype.
    - reference: PMID:41558966
      reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
      supports: REFUTE
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The results here also revealed that adult (6–8-week-old) Fgf14+/− and Fgf14F145S/+ animals, which express one wild-type Fgf14 allele, performed similarly to age-matched wild-type controls on the elevated balance beam test, indicating that mice harboring a single Fgf14F145S mutation do not recapitulate the motor phenotypes expressed in humans."
      explanation: >-
        Mice with one mutant or null allele have the firing defect but no
        measurable balance deficit, so a single-copy firing defect has not
        been shown to be sufficient for ataxia in mice.
  - target: Postural tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dysmetric saccades
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Episodic ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:41558966
    reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Current-clamp recordings from Purkinje neurons in acute cerebellar slices from adult male and female Fgf14F145S/+ mice revealed that high-frequency repetitive firing, which is characteristic of wild-type Purkinje neurons, was replaced by prolonged bursts of action potentials."
    explanation: Burst firing replaces tonic firing in mice carrying the patient allele.
  - reference: PMID:18930825
    reference_title: FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unlike in the wild type animals, more than 80% of Fgf14(-/-) Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections."
    explanation: Near-complete loss of repetitive firing in null Purkinje neurons.
  - reference: PMID:25926453
    reference_title: Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the acute and selective Fgf14-targeted short hairpin RNA (shRNA)-mediated in vivo \"knock-down\" of iFGF14 in adult Purkinje neurons attenuates spontaneous and evoked action potential firing"
    explanation: Shows the firing defect is a physiological requirement in adults, not only a developmental one.
- name: Fever-Sensitive Sodium Channel Decompensation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Proposed explanation for the attacks of episodic ataxia: with Nav
    availability already reduced, fever or other stressors push cerebellar
    excitability below threshold for days at a time. It rests on clinical
    observations (fever-triggered attacks, response to acetazolamide) and on
    the known temperature sensitivity of sodium channels; it has not been
    tested experimentally in an FGF14 model.
  downstream:
  - target: Episodic ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32162847
      reference_title: "FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Attacks were triggered by fever, lasted several days, and had variable frequencies."
      explanation: Fever precipitates the episodic attacks in two families.
  evidence:
  - reference: PMID:24252256
    reference_title: A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "FGF14 regulates brain sodium channels, especially in the cerebellum. Sodium channels can be fever sensitive."
    explanation: The authors' proposed link between fever sensitivity and the FGF14 sodium channel defect.
  - reference: PMID:41099962
    reference_title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose the hypothesis that the episodic symptoms in SCA27A align with the molecular pathology of a channelopathy and propose management strategies based on this insight."
    explanation: States the channelopathy hypothesis for the episodic symptoms as a hypothesis.
- name: Basal Ganglia Dopaminergic Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    FGF14 loss alters basal ganglia function. Null mice have a paroxysmal
    hyperkinetic movement disorder and reduced responses to dopamine agonists,
    and functional imaging in one patient supported basal ganglia involvement.
    This is the proposed basis of the dyskinesia, but the step from mouse to
    patient is not established.
  locations:
  - preferred_term: basal ganglia
    term:
      id: UBERON:0010011
      label: collection of basal ganglia
  downstream:
  - target: Dyskinesia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12123606
      reference_title: Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Fgf14-deficient mice were viable, fertile, and anatomically normal, but developed ataxia and a paroxysmal hyperkinetic movement disorder."
      explanation: The null mouse has a paroxysmal movement disorder resembling the human dyskinesia.
  evidence:
  - reference: PMID:12123606
    reference_title: Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Neuropharmacological studies showed that Fgf14-deficient mice have reduced responses to dopamine agonists."
    explanation: Altered dopaminergic responses in the null mouse.
  - reference: PMID:16211615
    reference_title: "Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dyskinesia was often present, suggesting basal ganglia involvement, which was supported by functional imaging in 1 patient."
    explanation: Clinical and imaging evidence for basal ganglia involvement in patients.
- name: Impaired Hippocampal Synaptic Plasticity
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Fgf14 null mice show impaired spatial learning and defective theta-burst
    induced long-term potentiation in hippocampal slices. This is the proposed
    basis of the cognitive impairment, but it has been shown only in mice.
  locations:
  - preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  biological_processes:
  - preferred_term: long-term synaptic potentiation
    modifier: DECREASED
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
  downstream:
  - target: Cognitive impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17236779
      reference_title: Impaired spatial learning and defective theta burst induced LTP in mice lacking fibroblast growth factor 14.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "These results suggest a role for FGF14 in certain spatial learning functions and synaptic plasticity."
      explanation: Hippocampal plasticity and learning deficits in the null mouse as a basis for the cognitive phenotype.
  evidence:
  - reference: PMID:17236779
    reference_title: Impaired spatial learning and defective theta burst induced LTP in mice lacking fibroblast growth factor 14.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Impaired theta burst initiated long-term synaptic potentiation was also found in hippocampal slices from Fgf14(-/-) mice."
    explanation: Defective hippocampal LTP in the null mouse.
- name: Prefrontal Cortical Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Patients from a whole-gene deletion family show medial prefrontal
    hypometabolism on FDG PET, most pronounced in the member with psychosis,
    and Fgf14 null mice have reduced VGAT, an inhibitory synapse marker, in the
    medial prefrontal cortex. This is the proposed basis of the psychiatric
    features, but the link rests on one family and one mouse finding.
  locations:
  - preferred_term: prefrontal cortex
    term:
      id: UBERON:0000451
      label: prefrontal cortex
  downstream:
  - target: Psychiatric and behavioral disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32112487
      reference_title: Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypometabolism in the PFC was far more pronounced in a SCA27 patient with psychosis."
      explanation: Prefrontal dysfunction tracks the psychiatric phenotype in one family.
  - target: Psychosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32112487
      reference_title: Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypometabolism in the PFC was far more pronounced in a SCA27 patient with psychosis."
      explanation: >-
        The family member with psychosis had the most marked prefrontal
        hypometabolism. This is a single patient, and the authors note her
        long-standing psychotropic medication complicates interpretation.
  - target: Attention deficit hyperactivity disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32112487
      reference_title: Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
      supports: SUPPORT
      directness: INDIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypometabolism in the frontal regions characterizes un-medicated ADHD patients"
      explanation: >-
        The authors relate the frontal hypometabolism seen in all family members
        to the frontal hypometabolism known in ADHD. The quoted sentence states
        that background finding from other work; it is not a measurement in
        SCA27A patients with ADHD.
  evidence:
  - reference: PMID:32112487
    reference_title: Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients."
    explanation: Prefrontal hypometabolism in every affected member of a deletion family.
  - reference: PMID:32112487
    reference_title: Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Reduced expression of VGAT was found in the mPFC of fgf14-/- mice."
    explanation: Reduced inhibitory marker in the prefrontal cortex of null mice.
phenotypes:
- category: Neurologic
  name: Postural tremor
  diagnostic: true
  description: >-
    Usually the first sign, beginning in childhood (mean about 12 years) and
    affecting the upper limbs and sometimes the head. Present in nearly all
    point-variant carriers but in only about a fifth of microdeletion carriers.
  phenotype_term:
    preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: PMID:29416937
    reference_title: "Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Including our case, we found that early-onset tremor (12.1 ± 10.5 years) was present in 95.8%"
    explanation: Frequency and age of onset of tremor across 33 reported cases.
  - reference: PMID:16211615
    reference_title: "Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients showed a childhood-onset postural tremor and a slowly progressive ataxia evolving from young adulthood."
    explanation: Childhood-onset postural tremor in the founding family.
  - reference: PMID:41099962
    reference_title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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"
    explanation: Tremor is less frequent (21%) among microdeletion carriers.
- category: Neurologic
  name: Progressive cerebellar ataxia
  diagnostic: true
  description: >-
    Gait and limb ataxia beginning in young adulthood (mean about 24 years)
    and progressing very slowly; most patients stay ambulant. Onset as late as
    47 years is reported. About half of microdeletion carriers have ataxia.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:29416937
    reference_title: "Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "gait ataxia tended to present later in life (23.7 ± 16.7 years) and was accompanied by limb ataxia, dysarthria, and nystagmus"
    explanation: Age of onset and associated cerebellar signs across reported cases.
  - reference: PMID:16211615
    reference_title: "Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients showed a childhood-onset postural tremor and a slowly progressive ataxia evolving from young adulthood."
    explanation: Slowly progressive ataxia from young adulthood in the founding family.
  - reference: PMID:30017992
    reference_title: Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47."
    explanation: Adult onset at 47 years with a nonsense variant.
- category: Neurologic
  name: Episodic ataxia
  description: >-
    Attacks of ataxia lasting days, often triggered by fever, beginning in
    childhood or later; some children stop having attacks as they grow older.
    Reported in about a fifth of microdeletion carriers and in several
    point-variant families. Piarroux et al. (2020) proposed calling the FGF14
    form episodic ataxia type 9, but MONDO assigns that name to a different
    disorder (MONDO:0030064), so it is not used as a synonym here.
  phenotype_term:
    preferred_term: Episodic ataxia
    term:
      id: HP:0002131
      label: Episodic ataxia
  evidence:
  - reference: PMID:32162847
    reference_title: "FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four patients from two families who presented attacks of childhood-onset episodic ataxia associated with pathogenic mutations in the FGF14 gene."
    explanation: Childhood-onset episodic ataxia in two families.
  - reference: PMID:25566820
    reference_title: A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings expand the phenotypic spectrum of SCA27 by underlining the possible episodic nature of this ataxia."
    explanation: Episodic ataxia in a two-generation family with a frameshift variant.
  - reference: PMID:24252256
    reference_title: A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a young boy whose mild ataxia and abnormal eye movements repeatedly deteriorated with fever, making him unable to sit or walk during fever episodes."
    explanation: Fever-triggered loss of sitting and walking in a child with a deletion.
- category: Neurologic
  name: Nystagmus
  description: >-
    Nystagmus, often gaze-evoked or multidirectional, from infancy onward. It
    is the commonest sign in microdeletion carriers (75%), and the NYS4
    early-onset nystagmus locus turned out to be an FGF14 deletion.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:41099962
    reference_title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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"
    explanation: Nystagmus in 75% of microdeletion carriers.
  - reference: PMID:36207621
    reference_title: Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic FGF14 variants, and highlights the importance of screening FGF14 in apparently isolated early onset nystagmus."
    explanation: Early-onset nystagmus can be the main presentation.
  - reference: PMID:30607796
    reference_title: Acetazolamide-Responsive Episodic Ataxia Linked to Novel Splice Site Variant in FGF14 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On clinical examination, interictally, the patient presented with gaze-evoked nystagmus and rebound nystagmus and slight dysarthria."
    explanation: Gaze-evoked and rebound nystagmus between attacks.
- category: Neurologic
  name: Dysmetric saccades
  description: Saccadic dysmetria and saccadic intrusions into smooth pursuit.
  phenotype_term:
    preferred_term: Dysmetric saccades
    term:
      id: HP:0000641
      label: Dysmetric saccades
  evidence:
  - reference: PMID:30017992
    reference_title: Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia."
    explanation: Saccadic dysmetria in an adult patient.
- category: Neurologic
  name: Dysarthria
  description: Cerebellar dysarthria, usually later in the course.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:30017992
    reference_title: Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia."
    explanation: Dysarthria in an adult patient.
  - reference: PMID:41099962
    reference_title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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"
    explanation: Dysarthria in 15% of microdeletion carriers.
- category: Neurologic
  name: Dyskinesia
  description: >-
    Orofacial and limb dyskinesia, often present in the founding family. A
    phenotype resembling paroxysmal non-kinesigenic dyskinesia is reported
    with a de novo translocation and in the recessive case.
  phenotype_term:
    preferred_term: Dyskinesia
    term:
      id: HP:0100660
      label: Dyskinesia
  evidence:
  - reference: PMID:16211615
    reference_title: "Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dyskinesia was often present, suggesting basal ganglia involvement, which was supported by functional imaging in 1 patient."
    explanation: Frequent dyskinesia in the founding family.
  - reference: PMID:21600715
    reference_title: Spinocerebellar ataxias type 27 derived from a disruption of the fibroblast growth factor 14 gene with mimicking phenotype of paroxysmal non-kinesigenic dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FGF14 disruption caused by a de novo reciprocal chromosomal translocation between chromosomes 13 and 21 was identified in a patient with the phenotype of paroxysmal non-kinesigenic dyskinesia (PNKD)."
    explanation: A PNKD-like presentation with a de novo FGF14-disrupting translocation.
- category: Neurologic
  name: Cognitive impairment
  description: >-
    Low IQ with deficits in memory and executive function; severe
    intellectual disability and microcephaly in a child with a translocation;
    learning disability in about a third of microdeletion carriers.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:16211615
    reference_title: "Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuropsychological testing indicated low IQ and deficits in memory and executive functioning."
    explanation: Cognitive profile in the founding family.
  - reference: PMID:19471976
    reference_title: "SCA27 caused by a chromosome translocation: further delineation of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, both show signs of SCA, although the daughter is the most affected with early onset cerebellar ataxia, microcephaly, and severe mental retardation."
    explanation: Severe intellectual disability in a translocation carrier.
  - reference: PMID:41099962
    reference_title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "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"
    explanation: Learning disability in 34% of microdeletion carriers.
- category: Psychiatric
  name: Psychiatric and behavioral disturbance
  description: >-
    Behavioral problems, attention deficit hyperactivity disorder and
    psychosis; neuropsychiatric disease in 28% of microdeletion carriers.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:16211615
    reference_title: "Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Behavioral problems were also observed."
    explanation: Behavioral problems in the founding family.
  - reference: PMID:32112487
    reference_title: Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients."
    explanation: Psychosis and ADHD in a Swedish deletion family.
  - reference: PMID:29416937
    reference_title: "Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Other features of SCA27 that may distinguish it from other SCAs include the potential for episodic ataxia, accompanying psychiatric symptoms, and cognitive impairment."
    explanation: Psychiatric symptoms as a distinguishing feature across reported cases.
- category: Psychiatric
  name: Psychosis
  description: Psychotic disorder in one member of a Swedish 13q33.1 deletion family, with marked prefrontal hypometabolism.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:32112487
    reference_title: Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients."
    explanation: Psychosis reported as a new feature in the Swedish family.
- category: Psychiatric
  name: Attention deficit hyperactivity disorder
  description: ADHD reported in the Swedish 13q33.1 deletion family.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:32112487
    reference_title: Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients."
    explanation: ADHD reported as a new feature in the Swedish family.
- category: Neurologic
  name: Microcephaly
  description: Reported in a single child carrying a t(5;13) translocation that disrupts FGF14-1b, together with severe intellectual disability.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:19471976
    reference_title: "SCA27 caused by a chromosome translocation: further delineation of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, both show signs of SCA, although the daughter is the most affected with early onset cerebellar ataxia, microcephaly, and severe mental retardation."
    explanation: Single-case report.
- category: Neurologic
  name: Parkinsonism
  description: Parkinsonism improving with amantadine and levodopa, reported in one older patient.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:29416937
    reference_title: "Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here a case of a 70-year-old male who presented with slowly worsening tremor and gait instability that began in his early adulthood along with additional features of parkinsonism on examination."
    explanation: Single-case report of parkinsonism.
- category: Neurologic
  name: Cerebellar atrophy
  description: >-
    Brain MRI is often normal; moderate cerebellar atrophy is reported in
    older patients.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:16211615
    reference_title: "Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) of the brain showed only moderate cerebellar atrophy in the 2 eldest patients."
    explanation: Atrophy only in the oldest members of the founding family.
  - reference: PMID:30017992
    reference_title: Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI showed cerebellar atrophy without brainstem involvement."
    explanation: Cerebellar atrophy in a 63-year-old patient.
  - reference: PMID:30607796
    reference_title: Acetazolamide-Responsive Episodic Ataxia Linked to Novel Splice Site Variant in FGF14 Gene.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI of the brain was normal and peripheral-vestibular function was bilaterally intact."
    explanation: A normal MRI in an episodic-ataxia patient, showing atrophy is not constant.
- category: Neurologic
  name: Trigeminal neuralgia
  description: Reported once, in a carrier of a 545 kb deletion with episodic ataxia.
  phenotype_term:
    preferred_term: Trigeminal neuralgia
    term:
      id: HP:0100661
      label: Trigeminal neuralgia
  evidence:
  - reference: PMID:41099962
    reference_title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2 carries a 545 kb deletion and developed episodic ataxia and trigeminal neuralgia, a novel feature not previously described in this cohort."
    explanation: Single-case report.
genetic:
- name: FGF14
  gene_term:
    preferred_term: FGF14
    term:
      id: hgnc:3671
      label: FGF14
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Heterozygous coding, splice and structural loss-of-function variants in
    FGF14 cause SCA27A. Point variants are a rare cause of dominant ataxia: one
    frameshift was found among 208 unrelated familial ataxia cases. The
    intronic GAA expansion in the same gene causes the separate disease SCA27B
    and is not part of this entry.
  evidence:
  - reference: PMID:15470364
    reference_title: "Mutation analysis in the fibroblast growth factor 14 gene: frameshift mutation and polymorphisms in patients with inherited ataxias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In one patient, we detected a novel single base pair deletion in exon 4 (c.487delA) creating a frameshift mutation."
    explanation: One frameshift among 208 familial ataxia cases, showing the gene is a rare cause.
  - reference: PMID:39704271
    reference_title: The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non-kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ATX-FGF/SCA27A has been exclusively associated with heterozygous variants in the FGF14 gene, presenting with postural tremor, slowly progressive cerebellar ataxia, and psychiatric and behavioral disturbances."
    explanation: Summarizes the established gene-disease relationship.
  - reference: PMID:40156335
    reference_title: "Novel In-Frame FGF14 Deletion Causes Spinocerebellar Ataxia Type 27A: Clinical Response to Deep Brain Stimulation and 4-Aminopyridine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel heterozygous in-frame deletion (p.Val119del) in FGF14 was identified in this family affected by childhood-onset tremor followed by late-onset progressive ataxia."
    explanation: Segregation of an in-frame deletion in a five-generation family.
  notes: >-
    No ClinGen gene-disease validity record for FGF14 is cached in this
    repository, so gene_disease_validity is left empty.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    Expressivity is highly variable within families, from isolated childhood
    tremor or nystagmus to ataxia with severe intellectual disability; some
    carriers never seek medical attention. Most families show dominant transmission of a single loss-of-function
    allele. One consanguineous family had a homozygous truncating variant: the
    child had a congenital nonprogressive cerebellar disorder with intellectual
    disability, and the heterozygous parents developed mild gait ataxia and
    tremor in their 40s, which fits a dosage effect.
  evidence:
  - reference: PMID:24252256
    reference_title: A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This family demonstrates phenotypic variability of FGF14 deletions (SCA 27), fever sensitivity of ataxia and the added value of SNP-array analysis in making a diagnosis."
    explanation: Variable expressivity across three generations with one deletion.
  - reference: PMID:24252256
    reference_title: A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mother was unable to perform tandem gait walking and had abnormal eye movements but had never sought medical attention."
    explanation: A mildly affected carrier who had never been diagnosed.
  - reference: PMID:39704271
    reference_title: The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non-kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Segregation analysis confirmed that the homozygous variant was inherited from heterozygous parents who developed mild gait ataxia and tremor in their 40s."
    explanation: Heterozygous parents are mildly affected while the homozygous child is severely affected.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    One consanguineous family: a homozygous truncating variant (c.75del,
    p.Leu26Serfs*51) caused a severe congenital nonprogressive cerebellar
    disorder, while the heterozygous parents were mildly affected in later
    life.
  evidence:
  - reference: PMID:39704271
    reference_title: The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non-kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first case of autosomal recessive FGF14-related cerebellar ataxia caused by a c.75del variant resulting in p.Leu26Serfs*51 truncation of the FGF14 protein."
    explanation: The only reported biallelic case.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence has been published. A 2018 review counted 32
    previously reported clinical cases with point variants or translocations,
    and a 2025 review counted 32 microdeletion carriers in 11 families. These
    are case counts, not prevalence.
  evidence:
  - reference: PMID:29416937
    reference_title: "Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Review of the literature revealed a total of 32 previously reported clinical cases of SCA27."
    explanation: Case count up to 2018.
  - reference: PMID:41099962
    reference_title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "We identified SCA27A microdeletions in 32 cases across 11 families."
    explanation: Case count for microdeletion carriers.
progression:
- phase: Childhood onset
  age_range: infancy to adolescence
  notes: >-
    Nystagmus can be present from infancy, tremor begins in childhood, and
    fever-triggered episodic attacks can begin in early childhood. Episodic
    symptoms, nystagmus, learning disability and psychiatric symptoms tend to
    appear earlier than ataxia.
  evidence:
  - reference: PMID:41099962
    reference_title: "Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Episodic symptoms, nystagmus, learning disability and neuropsychiatric symptoms occur at an earlier age."
    explanation: Early-appearing features in microdeletion carriers.
- phase: Slowly progressive adult ataxia
  age_range: young adulthood onward
  notes: >-
    Ataxia begins in young adulthood and progresses very slowly; motor
    function is maintained through life in most patients.
  evidence:
  - reference: PMID:32162847
    reference_title: "FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Symptom onset occurs early in life nevertheless the disease course is usually very slow and motor function is maintained through life in most of the patients."
    explanation: Background summary of the disease course.
treatments:
- name: Acetazolamide
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Carbonic anhydrase inhibitor used to reduce the frequency of episodic
    ataxia attacks; evidence is limited to case reports.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetazolamide
      term:
        id: CHEBI:27690
        label: acetazolamide
  target_phenotypes:
  - preferred_term: Episodic ataxia
    term:
      id: HP:0002131
      label: Episodic ataxia
  evidence:
  - reference: PMID:30607796
    reference_title: Acetazolamide-Responsive Episodic Ataxia Linked to Novel Splice Site Variant in FGF14 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient responded well to acetazolamide (reduction in the frequency of attacks by about two thirds), supporting the hypothesis of a sodium channelopathy."
    explanation: About two-thirds fewer attacks in a single patient.
  - reference: PMID:32162847
    reference_title: "FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "pharmacological responsiveness still unknown (improvement after acetazolamide treatment in 2 patients)"
    explanation: Improvement in two patients across the literature, with responsiveness still described as unknown.
- name: 4-Aminopyridine
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Potassium channel blocker that improved balance in two patients from one
    family. The larger 4-aminopyridine literature concerns SCA27B and is not
    cited here.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: 4-aminopyridine
      term:
        id: CHEBI:34385
        label: 4-aminopyridine
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:40156335
    reference_title: "Novel In-Frame FGF14 Deletion Causes Spinocerebellar Ataxia Type 27A: Clinical Response to Deep Brain Stimulation and 4-Aminopyridine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients showed significant tremor reduction following STN-DBS and balance improvement with 4-AP."
    explanation: Balance improvement in two patients.
- name: Subthalamic Deep Brain Stimulation
  therapeutic_modality: SURGERY
  description: Subthalamic nucleus deep brain stimulation for disabling tremor, reported in two patients.
  treatment_term:
    preferred_term: subthalamic nucleus deep brain stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  target_phenotypes:
  - preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: PMID:40156335
    reference_title: "Novel In-Frame FGF14 Deletion Causes Spinocerebellar Ataxia Type 27A: Clinical Response to Deep Brain Stimulation and 4-Aminopyridine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients showed significant tremor reduction following STN-DBS and balance improvement with 4-AP."
    explanation: Tremor reduction after STN-DBS in two patients.
- name: Amantadine and Levodopa
  therapeutic_modality: SMALL_MOLECULE
  description: Improved tremor, gait stability and parkinsonism in a single patient.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amantadine
      term:
        id: CHEBI:2618
        label: amantadine
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  target_phenotypes:
  - preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:29416937
    reference_title: "Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was started on amantadine, which improved his head tremor and led to marked improvement in falls with reduced gait instability."
    explanation: Single-patient response to amantadine.
  - reference: PMID:29416937
    reference_title: "Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Work-up revealed a novel pathogenic mutation in the Fibroblast Growth Factor 14 gene, and symptoms improved with amantadine and levodopa."
    explanation: Further improvement after adding levodopa in the same patient.
- name: Genetic Counseling
  description: >-
    Counseling on dominant inheritance with very variable expressivity; mildly
    affected parents are common.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  notes: >-
    Standard care for a dominant disorder; no study has evaluated it in this
    disease, so it carries no evidence block.
differential_diagnoses:
- name: Spinocerebellar ataxia 27B
  description: >-
    Allelic disorder caused by a heterozygous intronic GAA repeat expansion in
    FGF14. It is far more common, starts late in adult life and is not detected
    by standard exome or short-read sequencing, so the repeat must be sized
    separately.
  distinguishing_features:
  - Intronic GAA repeat expansion rather than a coding or structural variant
  - Late adult onset without the childhood tremor and neurodevelopmental features of SCA27A
  evidence:
  - reference: PMID:40156335
    reference_title: "Novel In-Frame FGF14 Deletion Causes Spinocerebellar Ataxia Type 27A: Clinical Response to Deep Brain Stimulation and 4-Aminopyridine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "This led to the assignment of two different names to the allelic disorders: SCA27A for ataxia caused by the rare coding variants and SCA27B (OMIM #620174) for ataxia caused by the more common intronic repeat expansion."
    explanation: Defines the two allelic disorders.
- name: Episodic ataxia types 1 and 2
  description: >-
    KCNA1 and CACNA1A episodic ataxias are the commonest genetic causes of
    episodic ataxia and are on the same gene panels.
  distinguishing_features:
  - Fever triggering, childhood postural tremor and learning disability point towards FGF14
  evidence:
  - reference: PMID:25566820
    reference_title: A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Mutations in KCNA1 and CACNA1A account for the majority of EA cases worldwide."
    explanation: Establishes the main alternative causes of episodic ataxia.
- name: Paroxysmal non-kinesigenic dyskinesia
  description: >-
    PNKD caused by MR-1 (PNKD) variants can be mimicked by FGF14 disruption.
  evidence:
  - reference: PMID:21600715
    reference_title: Spinocerebellar ataxias type 27 derived from a disruption of the fibroblast growth factor 14 gene with mimicking phenotype of paroxysmal non-kinesigenic dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This indicated genetic heterogeneity of PNKD, since 60% of the patients with PNKD exhibit mutations in another gene responsible for PNKD, the myofibrillogenesis regulator 1 gene (MR-1)."
    explanation: PNKD-like presentation with FGF14 disruption.
- name: Isolated early-onset nystagmus
  description: >-
    Apparently isolated infantile nystagmus may be the presenting feature of an
    FGF14 deletion.
  evidence:
  - reference: PMID:36207621
    reference_title: Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic FGF14 variants, and highlights the importance of screening FGF14 in apparently isolated early onset nystagmus."
    explanation: Recommends FGF14 screening in isolated early nystagmus.
diagnosis:
- name: Sequencing with copy-number analysis
  description: >-
    Exome or genome sequencing, or an ataxia or episodic-ataxia gene panel,
    combined with copy-number analysis (SNP array or sequencing-based CNV
    calling), since deletions are a common mechanism. Karyotyping detects
    balanced translocations.
  evidence:
  - reference: PMID:24252256
    reference_title: A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This family demonstrates phenotypic variability of FGF14 deletions (SCA 27), fever sensitivity of ataxia and the added value of SNP-array analysis in making a diagnosis."
    explanation: SNP-array detected the causal deletion.
animal_models:
- name: Fgf14 F145S knock-in mouse
  species: Mouse
  genotype: Fgf14 F145S/+ (heterozygous knock-in of the first human SCA27A allele)
  description: >-
    Carries the founding patient allele at the mouse locus. Purkinje neurons
    fire in bursts, iFGF14 protein is reduced and Nav inactivation is shifted
    to more negative voltages, matching the heterozygous null.
  publication: PMID:41558966
  evidence:
  - reference: PMID:41558966
    reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To investigate the in vivo mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus (Fgf14F145S )."
    explanation: Describes construction of the knock-in model.
  modeled_mechanisms:
  - target: Impaired Purkinje Neuron Repetitive Firing
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Same genotype as the patients; reproduces the firing defect and its Nav basis.
    limitations: >-
      Reproduces the cellular defect but not the motor phenotype: knock-in
      and heterozygous null mice performed like wild type on the elevated
      balance beam.
    evidence:
    - reference: PMID:41558966
      reference_title: In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Together, these results indicate that Fgf14 haploinsufficiency and reduced Nav channel availability underlie impaired firing in Fgf14F145S/+ Purkinje neurons."
      explanation: Establishes the knock-in as a model of the firing node.
- name: Fgf14 knockout mouse
  species: Mouse
  genotype: Fgf14 -/- (Fgf14 N-beta-Gal allele)
  description: >-
    Homozygous null mice develop ataxia and a paroxysmal hyperkinetic movement
    disorder, have reduced responses to dopamine agonists, silent Purkinje
    neurons with reduced Nav1.6, and impaired spatial learning with defective
    hippocampal LTP.
  publication: PMID:12123606
  evidence:
  - reference: PMID:12123606
    reference_title: Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Fgf14-deficient mice were viable, fertile, and anatomically normal, but developed ataxia and a paroxysmal hyperkinetic movement disorder."
    explanation: Whole-animal phenotype of the null mouse.
  modeled_mechanisms:
  - target: Impaired Purkinje Neuron Repetitive Firing
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Homozygous loss, whereas patients are heterozygous; the null phenotype is
      more severe (most Purkinje cells silent rather than bursting).
    evidence:
    - reference: PMID:18930825
      reference_title: FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice with a targeted disruption of the Fgf14 locus (Fgf14(-/-)) develop ataxia resembling human SCA27."
      explanation: The null mouse is an accepted model of the human ataxia.
  - target: Impaired Hippocampal Synaptic Plasticity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    limitations: >-
      Mouse spatial-learning assays are a proxy for human cognitive
      impairment, the LTP defect has not been examined in patients, and the
      genotype is homozygous whereas patients are heterozygous.
    evidence:
    - reference: PMID:17236779
      reference_title: Impaired spatial learning and defective theta burst induced LTP in mice lacking fibroblast growth factor 14.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we extend the similarities between Fgf14(-/-) mice and FGF14(F145S) humans by showing that Fgf14(-/-) mice exhibit reliable acquisition (place learning) deficits in the Morris water maze."
      explanation: Learning deficits parallel the human cognitive phenotype.
  - target: Basal Ganglia Dopaminergic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    limitations: >-
      Reduced responses to dopamine agonists in mice are a pharmacological
      proxy for basal ganglia dysfunction; the paroxysmal hyperkinetic disorder
      of the homozygous null is more severe than the dyskinesia of
      heterozygous patients.
    evidence:
    - reference: PMID:12123606
      reference_title: Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Neuropharmacological studies showed that Fgf14-deficient mice have reduced responses to dopamine agonists."
      explanation: Altered dopaminergic responses in the null mouse model the basal ganglia node.
- name: Sheep familial episodic ataxia
  species: Sheep
  genotype: FGF14 c.46C>T (p.Q16*) heterozygous, naturally occurring
  description: >-
    Familial episodic ataxia of newborn lambs, autosomal dominant with variable
    expressivity; signs resolve as the lambs mature. A more severely affected
    homozygous lamb was observed. The authors describe the association as
    potential.
  publication: PMID:29253853
  evidence:
  - reference: PMID:29253853
    reference_title: Familial episodic ataxia in lambs is potentially associated with a mutation in the fibroblast growth factor 14 (FGF14) gene.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Familial episodic ataxia of lambs is a congenital transient autosomal dominant disorder of newborn lambs, with varying expressivity."
    explanation: Naturally occurring dominant episodic ataxia in sheep with an FGF14 truncating variant.
notes: >-
  The GAA repeat-expansion disease in the same gene is curated separately as
  Spinocerebellar_Ataxia_27B; evidence from SCA27B studies, including the
  larger 4-aminopyridine literature, is deliberately not used here. No
  GeneReviews chapter exists for SCA27A. Two patient-derived iPSC lines (PMID:42372627) exist
  but have no phenotype data yet.
📚

References & Deep Research

References

5
PMID:12489043
A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected].
No top-level findings curated for this source.
PMID:16211615
Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype.
No top-level findings curated for this source.
PMID:29416937
Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype.
No top-level findings curated for this source.
PMID:41099962
Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions.
No top-level findings curated for this source.
PMID:41558966
In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.
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)

Create: Spinocerebellar_Ataxia_27A · 2026-10-08T14:29:31Z · View source

New entry for SCA27A (MONDO:0008654, FGF14). Deep research: claude_code provider (falcon not configured), report validated (35/35 references resolved). Pathophysiology is built as a chain from heterozygous FGF14 loss of function through reduced iFGF14 protein and a hyperpolarizing shift in Purkinje Nav inactivation to loss of tonic Purkinje firing, with the F145S knock-in mouse (PMID:41558966) as the main evidence for haploinsufficiency; the earlier in vitro dominant-negative result (PMID:17978045) is recorded as REFUTE/INDIRECT. Fever-triggered episodic ataxia is a HYPOTHETICAL node. SCA27B (GAA expansion) evidence was deliberately excluded. No GeneReviews chapter and no ClinGen record exist. ORPHA:98764 could not be cached (no local Orphadata XML) and is not cited. Validated with just validate (84/84 snippets verified) and the offline gates.

Claude Code ▸
Spinocerebellar Ataxia 27A (SCA27A; ATX‑FGF14): research report for the dismech entry
claude-haiku-4-5-20251001, claude-opus-5-5 4 citations 2026-10-01T10:59:14.439852

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

System ID Status
MONDO MONDO:0008654 spinocerebellar ataxia 27A ✔
OMIM #193003 SCA27A from an OMIM mirror
Orphanet ORPHA:98764 listed on the OMIM mirror's external links; no ORPHA_98764.md cache exists, so fetch it before citing
Gene FGF14, OMIM *601515, hgnc:3671 ✔, 13q33.1
ICD‑10 G11.8 (other hereditary ataxias) not confirmed
MeSH Spinocerebellar Degenerations / Spinocerebellar Ataxias indexing terms on the source papers

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

Phenotype HPO suggestion Onset / course Frequency Key source
Postural / upper‑limb tremor (often the first sign) HP:0002174 Postural tremor ✔; HP:0001337 Tremor ✔; HP:0002346 Head tremor ✔ childhood, mean 12 y; stable or slow 95.8% (point variants); 21% (deletions) PMID:16211615, PMID:29416937
Slowly progressive cerebellar ataxia (gait, limb) HP:0001251 Ataxia ✔ (a Cerebellar ataxia term should be looked up; it is not in the cache); HP:0002066 Gait ataxia ✔; HP:0002070 Limb ataxia ✔; HP:0007240 Progressive gait ataxia ✔ young adult, mean 23.7 y; slow progression majority (point variants); 46% (deletions) PMID:12489043, PMID:16211615
Episodic ataxia, often fever‑triggered, lasting days HP:0002131 Episodic ataxia ✔ childhood to adult 21% (deletions); several families PMID:25566820, PMID:30607796, PMID:32162847, PMID:24252256
Nystagmus (multidirectional, horizontal, gaze‑evoked; infantile in NYS4) HP:0000639 ✔; HP:0000640 Gaze‑evoked ✔; HP:0000666 Horizontal ✔ infancy onward 75% (deletions) PMID:36207621, PMID:32162847
Saccadic dysmetria, saccadic pursuit HP:0000571 Hypometric saccades ✔ (the source says "dysmetria", which is not necessarily hypometria) adult case level PMID:30017992
Dysarthria HP:0001260 ✔ adult 15% (deletions); common in point‑variant families PMID:30017992
Orofacial dyskinesia / dyskinesia HP:0002310 ✔; HP:0007166 Paroxysmal dyskinesia ✔ variable "often present" in the Dutch family PMID:16211615, PMID:12489043
Paroxysmal non‑kinesigenic dyskinesia (PNKD‑like) HP:0007166 ✔ childhood translocation case; biallelic case PMID:21600715, PMID:39704271
Parkinsonism (responsive to levodopa/amantadine in one case) HP:0001300 ✔ late rare PMID:29416937
Low IQ, memory and executive deficits HP:0100543 Cognitive impairment ✔; HP:0002354 Memory impairment ✔; HP:0001249 Intellectual disability ✔ developmental or progressive common PMID:16211615, PMID:19471976
Learning disability, motor and speech delay HP:0001270 Motor delay ✔; HP:0000750 ✔; HP:0001263 ✔ childhood 34% (deletions) PMID:32162847, PMID:41099962
Behavioural and psychiatric problems: aggression, depression, ADHD, psychosis HP:0000708 ✔; HP:0000718 ✔; HP:0000716 ✔; HP:0007018 ✔; HP:0000709 ✔ childhood or adult 28% neuropsychiatric (deletions) PMID:16211615, PMID:32112487
Mild sensory axonal neuropathy, pes cavus HP:0003390 ✔; HP:0001761 ✔ adult occasional (OMIM synopsis; mildly reduced vibration sense in PMID:30017992) PMID:30017992
Microcephaly, severe ID (translocation daughter) HP:0000252 ✔ congenital single case PMID:19471976
Trigeminal neuralgia (novel) HP:0100661 ✔ adult single case PMID:41099962
Cerebellar atrophy on MRI (moderate, late, inconsistent) HP:0001272 ✔ late eldest patients only; MRI often normal PMID:16211615, PMID:30607796

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

Allele Type Phenotype PMID
p.Phe145Ser (F145S; F150S in 1b) missense large three‑generation Dutch family (14 affected) 12489043, 16211615
c.487delA (p.Asp163fs*12) frameshift one of 208 familial ataxia probands 15470364
t(5;13)(q31.2;q33.1) disrupting FGF14‑1b balanced translocation mother and daughter; daughter has microcephaly and severe ID 19471976
de novo t(13;21) disrupting FGF14 translocation PNKD‑like phenotype 21600715
c.211_212insA (p.Ile71Asnfs*27) frameshift two‑generation episodic‑ataxia family 25566820
202 kb 13q33.1 deletion CNV three generations; fever‑sensitive ataxia 24252256
FGF14 deletion CNV twin sisters 28192817 (no abstract available)
c.529A>T (p.Lys177*) nonsense Japanese adult, onset at 47 y 30017992
intron 1 splice variant splice sporadic, acetazolamide‑responsive EA 30607796
c.439G>T (p.Glu147*); c.486_487del (p.Tyr162*) nonsense two families with fever‑triggered EA ("EA9") 32162847
13q33.1 deletion covering FGF14 + ITGBL1 CNV Swedish family, 9 with ataxia; psychosis, ADHD 32112487
161 kb deletion (FGF14 + ITGBL1); partial FGF14 duplication CNV NYS4 family; second nystagmus family 36207621
p.Val119del in‑frame deletion five‑generation family; DBS and 4‑AP response 40156335
58 kb and 545 kb deletions CNV paroxysmal movement disorder; EA with trigeminal neuralgia 41099962
c.75del (p.Leu26Serfs*51), homozygous biallelic LoF congenital ataxia, ID, PNKD 39704271

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).

Treatment Evidence Suggested binding
Acetazolamide about two‑thirds reduction in attack frequency (PMID:30607796) [cached]: "Our patient responded well to acetazolamide (reduction in the frequency of attacks by about two thirds), supporting the hypothesis of a sodium channelopathy." NCIT:C15986 Pharmacotherapy ✔ + CHEBI:27690 acetazolamide ✔; SMALL_MOLECULE
4‑Aminopyridine (fampridine) "balance improvement with 4-AP" in two p.Val119del patients (PMID:40156335) [EPMC]. Note: the large 4‑AP literature is in SCA27B and must not be cited here. CHEBI:34385 4‑aminopyridine ✔
STN deep brain stimulation for disabling tremor "Two patients showed significant tremor reduction following STN-DBS" (PMID:40156335) NCIT surgical/neurostimulation term needed (look up "Deep Brain Stimulation"); SURGERY or DEVICE
Levodopa, amantadine for parkinsonism improvement in one case (PMID:29416937) CHEBI:2618 amantadine ✔; levodopa CHEBI needs lookup
Antiseizure drugs for paroxysmal dyskinesia "drug-responsive" PNKD in the biallelic case; the agent is not named in the abstract (PMID:39704271) omit the agent until the full text is read
Fever control during intercurrent illness; physiotherapy, speech, educational and psychiatric support management suggestions (PMID:41099962, PMID:41895131) NCIT:C15302 Physical Therapy ✔; NCIT:C15315 Rehabilitation ✔
Genetic counselling 50% recurrence risk (AD) NCIT:C15240 ✔

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

Model Key phenotype Fidelity / limitation PMID
Fgf14−/− (N‑βGal) mouse ataxia, paroxysmal hyperkinetic dyskinesia, reduced dopamine‑agonist response; silent Purkinje cells; reduced Nav1.6; impaired spatial learning and LTP; reduced mPFC VGAT; resilience to depression‑like behaviour (female) homozygous null, whereas the human disease is heterozygous; anatomically normal 12123606, 18930825, 17236779, 32112487, 40204701
Fgf14+/− mouse Purkinje burst firing; reduced protein; hyperpolarized Nav inactivation genotype‑faithful; behaviour not reported in the abstract 41558966
Fgf14^F145S/+ knock‑in (the first patient allele) Purkinje tonic firing replaced by bursts; reduced iFGF14; reduced Nav availability; phenocopies +/− (haploinsufficiency) best genotype fidelity; behavioural ataxia not stated in the abstract 41558966
Adult Purkinje‑specific shRNA knockdown / AAV re‑expression motor incoordination; rescued by re‑expression establishes an adult requirement 25926453
Cultured Purkinje neurons with FGF14b knockdown loss of resurgent and late Na current in vitro, neonatal 25269146
Fhf1/Fhf4 (Fgf12/Fgf14) double null severe ataxia; granule‑cell Nav inactivation defects digenic; overstates the human phenotype 17678857
Hippocampal neurons / HEK cells overexpressing F145S dominant‑negative Nav disruption overexpression artefact; not supported in vivo 17978045
Sheep FGF14 p.Q16* (natural) episodic neonatal ataxia naturally occurring, but causality "potentially associated" 29253853
Patient iPSC lines (2 SCA27A donors) resource for neuronal differentiation no phenotype data yet 42372627

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.

Outcome Count
References checked 35
Resolved 35
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 6
Quoted claims found in source 6
Quoted claims not found in source 0
References weighed for topical relevance 35
On topic 20
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 59
Resolved 57
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 1
Terms named correctly 1
Terms named as a different term 0

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.