Spinocerebellar ataxia 27B

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Classifications

Harrison's Chapter

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Inheritance

1

Autosomal dominant HP:0000006

SCA27B is inherited in an autosomal dominant manner. Most affected individuals inherit the expanded FGF14 (GAA) allele from a parent who may carry a high-normal, reduced-penetrance, or fully pathogenic repeat; each child of an affected individual has a 50% chance of inheriting the allele. Penetrance is age-dependent and incomplete at shorter expansion sizes, and de novo generation of an expansion during meiosis has been inferred from haplotype analysis.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Parent-of-origin effect: Repeat size is more likely to expand on maternal transmission and to contract on paternal transmission, an intergenerational instability that underlies variable anticipation within families.

Show evidence (3 references)

PMID:38271551 SUPPORT Other

"GAA-FGF14-related ataxia is inherited in an autosomal dominant manner."

GeneReviews states the mode of inheritance directly. Evidence source is OTHER because GeneReviews is an expert-curated clinical synthesis rather than a primary study.

PMID:38271551 SUPPORT Other

"the size of the GAA repeat is more likely to expand upon maternal transmission and to contract upon paternal transmission"

Supports the recorded parent-of-origin effect on intergenerational repeat instability.

PMID:36493768 SUPPORT Human Clinical

"identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division"

Supports both inherited transmission and de novo generation of the expansion.

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Discussions and Knowledge Gaps

3

What is the true pathogenic threshold for the FGF14 intronic GAA expansion, and how should length and motif purity be combined into a single interpretive rule?

KNOWLEDGE GAP OPEN sca27b_pathogenic_threshold

Attached to

pathophysiology#FGF14 Intronic GAA Repeat Expansion

Every major cohort has proposed a different cut-off. The discovery study supported (GAA)>=250 from family cosegregation; an independent Australian/German cohort concluded (GAA)>335 is fully penetrant with (GAA)>250 likely pathogenic at reduced penetrance; GeneReviews adopts (GAA)>300 for a definitive diagnosis with a 250-300 reduced-penetrance zone; a downbeat-nystagmus cohort found (GAA)200-249 alleles enriched 15-fold over controls with an indistinguishable phenotype; and long-read work argues that once the repeat is known to be uninterrupted, enrichment begins at 180-200 repeats. The disagreement is not merely statistical: it reflects that total allele length is the wrong variable. The pathogenically relevant quantity appears to be the longest pure GAA tract, since GAAGGA/AAGGAG hexameric expansions are equally common in patients and controls, and mosaic interruptions that shorten the pure tract are enriched in unaffected carriers. No consensus interpretive rule combining these dimensions exists, so laboratories currently report the same allele differently.

Proposed experiments

Motif-aware case-control threshold derivation by long-read sequencing

exp_sca27b_motif_aware_threshold

Long-read resequencing of a large multi-ancestry case-control set, reporting the longest pure GAA tract rather than total allele size, to derive a motif-aware pathogenic threshold with calibrated penetrance estimates.

Decision criterion

A motif-aware rule is preferable to a length-only rule if pure-tract length separates cases from controls with materially higher accuracy than total allele length in held-out cohorts.

Prospective penetrance follow-up of intermediate-range carriers

exp_sca27b_carrier_penetrance_cohort

Prospective longitudinal follow-up of asymptomatic carriers of 200-300-repeat alleles to measure age-dependent penetrance directly rather than inferring it from cross-sectional case-control enrichment.

Decision criterion

Age-stratified conversion rates would establish whether the 200-300 zone is genuinely reduced-penetrance pathogenic or simply a common non-pathogenic polymorphism enriched by ascertainment.

Cerebellum-versus-blood somatic repeat mosaicism

exp_sca27b_somatic_mosaicism_tissue

Systematic assay of somatic repeat mosaicism in cerebellum versus blood from the same individuals, since a blood-derived repeat size may not represent the size present in the pathogenically relevant tissue.

Decision criterion

Substantial cerebellum-specific somatic expansion would explain why blood-based thresholds disagree across cohorts and would argue for tissue-adjusted interpretation.

Show evidence (4 references)

PMID:36493768 SUPPORT Human Clinical

"while (GAA)>250 is likely pathogenic with reduced penetrance"

One of the several competing threshold definitions in the literature.

PMID:38507876 SUPPORT Human Clinical

"It provides preliminary evidence that (GAA)200-249 alleles might be pathogenic."

Extends candidate pathogenicity below the previously accepted cut-off, widening rather than resolving the uncertainty.

PMID:39227614 SUPPORT Human Clinical

"We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process."

The authors themselves call the current thresholds into question and ask for motif-aware reinterpretation.

+ 1 more reference

By what molecular route does the intronic GAA expansion reduce FGF14 expression - transcriptional elongation blockade, R-loop formation, repressive chromatin, or another mechanism?

KNOWLEDGE GAP OPEN sca27b_intronic_repeat_to_expression_route

Attached to

pathophysiology#FGF14 Intronic GAA Repeat Expansion pathophysiology#Reduced FGF14 Expression in Cerebellar Neurons

Reduced FGF14 RNA and protein have been demonstrated in patient postmortem cerebellum and patient-derived neurons, and the pathogenic tract is a GAA repeat in the first intron - the same sequence and genomic context as the FXN intron 1 expansion in Friedreich ataxia, where heterochromatin formation and transcriptional silencing are established. Whether SCA27B uses the same machinery, however, has not been shown. Until it is, the causal edge from expansion to reduced expression carries unknown intermediates, and a whole class of candidate therapeutic strategies (transcriptional de-repression, HDAC inhibition, R-loop modulation) cannot be rationally prioritised.

Proposed experiments

Chromatin and methylation profiling of the FGF14 locus

exp_sca27b_fgf14_locus_chromatin

Chromatin state and DNA methylation profiling across the FGF14 locus in expansion-carrier versus control cerebellum and in iPSC-derived Purkinje-like neurons.

Decision criterion

Repressive chromatin marks or hypermethylation spreading from the repeat in carriers would implicate the Friedreich-ataxia-like silencing mechanism.

Nascent-transcription analysis for elongation stalling at the repeat

exp_sca27b_nascent_transcription

PRO-seq or TT-seq analysis of expansion-carrier versus control neurons to test whether RNA polymerase II stalls within FGF14 intron 1 at the GAA tract.

Decision criterion

A carrier-specific drop in nascent transcription immediately downstream of the repeat would establish elongation blockade as the route.

R-loop mapping at the FGF14 intron 1 tract

exp_sca27b_rloop_drip

DRIP-seq for R-loop accumulation at the FGF14 intron 1 GAA tract in carrier versus control cells.

Decision criterion

Carrier-specific R-loop enrichment at the repeat would implicate co-transcriptional R-loop formation and nominate R-loop-directed therapeutics.

Test of transcriptional de-repression agents on FGF14 expression

exp_sca27b_derepression_rescue

Test whether transcriptional de-repression agents with efficacy in Friedreich ataxia models (for example HDAC inhibitors) restore FGF14 RNA and protein in patient-derived neurons.

Decision criterion

Restoration of FGF14 expression would both confirm a silencing mechanism and identify a repurposable therapeutic class.

Show evidence (1 reference)

PMID:36516086 SUPPORT Human Clinical

"Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein."

Establishes the endpoint (reduced expression) without establishing the route, which is precisely the gap.

Is the clinical deficit in SCA27B driven primarily by reversible Purkinje firing failure or by irreversible Purkinje neuron loss, and does that balance shift over the disease course?

OPEN QUESTION OPEN sca27b_firing_failure_versus_cell_loss

Attached to

pathophysiology#Impaired Purkinje Neuron Intrinsic Excitability and Firing pathophysiology#Purkinje Neuron Degeneration and Cerebellar Atrophy

Several observations point towards a functional rather than degenerative dominant mechanism: the striking episodic phase, the rapid and substantial response to 4-aminopyridine, the mild SARA progression rate with a plateau at moderate severity, and serum neurofilament light that is not elevated relative to controls. Against that, autopsy in genetically confirmed cases shows definite Purkinje neuron loss. If the deficit is largely a reversible channel-availability problem for much of the disease course, that has direct consequences for trial endpoint choice (symptomatic versus disease-modifying), for the therapeutic window, and for whether restoring FGF14 expression late in disease could help.

Proposed experiments

Longitudinal neurofilament light and cerebellar volumetry

exp_sca27b_longitudinal_nfl_volumetry

Longitudinal serum and CSF neurofilament light measurement plus cerebellar volumetry in a genetically defined SCA27B cohort, testing whether a degenerative signal emerges at a definable disease stage.

Decision criterion

A stage-dependent rise in neurofilament light with accelerating volume loss would mark the transition from functional to degenerative pathophysiology and define the therapeutic window.

Quantitative Purkinje cell counts stratified by disease duration

exp_sca27b_purkinje_counts_duration

Quantitative Purkinje cell counts correlated with disease duration across a larger SCA27B autopsy series than the four brains reported to date.

Decision criterion

Substantial Purkinje loss in short-duration cases would favour early degeneration; preserved counts in short-duration cases would favour a primarily functional early phase.

Rescue electrophysiology in patient-derived Purkinje-like neurons

exp_sca27b_ipsc_purkinje_rescue

Electrophysiological characterisation of iPSC-derived Purkinje-like neurons from expansion carriers, testing whether restoring FGF14 expression or applying 4-aminopyridine rescues firing independently of any effect on survival.

Decision criterion

Full firing rescue without a survival effect would establish the deficit as functional and reversible at the cellular level.

Show evidence (2 references)

PMID:37165652 SUPPORT Human Clinical

"Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls."

Absence of a neuroaxonal damage biomarker signal argues for a largely functional deficit.

PMID:39263992 PARTIAL Human Clinical

"The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis."

Establishes that genuine neuron loss does occur, counterbalancing the purely functional interpretation; PARTIAL because four brains without quantitative counts or duration stratification cannot settle the balance.

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Pathophysiology

6

FGF14 Intronic GAA Repeat Expansion

A heterozygous (GAA)n repeat expansion deep in intron 1 of FGF14 is the initiating molecular lesion. Because the repeat lies in non-coding sequence, it does not produce an altered FGF14 protein; instead, expansion beyond a length- and motif-dependent threshold destabilises expression of the allele. Repeat length correlates inversely with age at onset, and the tract's motif composition (pure GAA versus GAAGGA/AAGGAG interruptions) gates whether an expansion is pathogenic at all.

FGF14 hgnc:3671

cerebellar cortex UBERON:0002129

Downstream

Reduced FGF14 Expression in Cerebellar Neurons Expansion of the intronic GAA tract beyond the pathogenic threshold reduces FGF14 RNA and protein levels in patient cerebellum and in patient-derived neurons.

Show evidence (2 references)

PMID:36516086 SUPPORT Human Clinical

"In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14."

Identifies the trigger lesion.

PMID:36516086 SUPPORT Human Clinical

"There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series"

Establishes the case-control association between the expansion and late-onset cerebellar ataxia (reported odds ratio 105.60, P<0.001).

Reduced FGF14 Expression in Cerebellar Neurons

The expanded allele is expressed at reduced level, producing functional FGF14 haploinsufficiency in cerebellar neurons. FGF14 is an intracellular fibroblast growth factor (iFGF/FGF homologous factor) that is not secreted and does not signal through FGF receptors; it acts intracellularly as a binding partner and regulator of voltage-gated sodium channels. Reduced FGF14 RNA and protein have been demonstrated in postmortem patient cerebellum and in patient-derived iPSC neurons.

cerebellar Purkinje cell CL:0000121

regulation of gene expression GO:0010468 ↓ DECREASED

sodium channel regulator activity GO:0017080 ↓ DECREASED

cerebellar cortex UBERON:0002129

Downstream

Impaired Purkinje Neuron Intrinsic Excitability and Firing Loss of intracellular FGF14 removes a required regulator of voltage-gated sodium channels at the Purkinje neuron axon initial segment, attenuating spontaneous and repetitive firing.

Show evidence (2 references)

PMID:36516086 SUPPORT Human Clinical

"Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein."

Demonstrates reduced FGF14 expression in human patient material, establishing haploinsufficiency as the proximate consequence.

PMID:18930825 SUPPORT Other

"FGF14 belongs to the intracellular fibroblast growth factor subfamily (iFGF) that also includes FGFs 11–14"

Establishes FGF14 as an intracellular FGF rather than a secreted growth factor. Evidence source is OTHER because this statement is background framing in the article rather than a result of the reported experiments.

Impaired Purkinje Neuron Intrinsic Excitability and Firing

Intracellular FGF14 binds the C-terminus of voltage-gated sodium (Nav) channel alpha subunits and is concentrated at the Purkinje neuron axon initial segment, where Nav1.6-mediated resurgent sodium current sustains the high-frequency pacemaking that defines these cells. Loss of FGF14 produces a hyperpolarizing shift in the voltage dependence of steady-state Nav inactivation and reduced Nav1.6 availability, so Purkinje neurons fail to fire spontaneously and cannot sustain repetitive firing to depolarizing input. This is a functional excitability defect that precedes and is separable from cell death, and it is the node targeted by 4-aminopyridine.

cerebellar Purkinje cell CL:0000121

neuronal action potential GO:0019228 ↓ DECREASED membrane depolarization during action potential GO:0086010 ↓ DECREASED

voltage-gated sodium channel activity GO:0005248 ↓ DECREASED

cerebellar cortex UBERON:0002129

Downstream

Purkinje Neuron Degeneration and Cerebellar Atrophy Chronic failure of Purkinje pacemaking is accompanied, over years, by Purkinje neuron loss, most severe in the anterior vermis in human autopsy series.

Loss of Cerebellar Cortical Output Because Purkinje cells are the sole output of the cerebellar cortex, silencing them directly removes cerebellar cortical output even before cell loss occurs.

Show evidence (3 references)

PMID:18930825 SUPPORT Model Organism

"Current clamp recordings from Purkinje neurons in cerebellar slices revealed attenuated spontaneous firing in Fgf14(-/-) neurons. 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."

Direct electrophysiological demonstration in Fgf14-null mice that loss of FGF14 abolishes spontaneous and repetitive Purkinje firing.

PMID:18930825 SUPPORT Model Organism

"FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and that the loss of FGF14 impairs spontaneous and repetitive firing in Purkinje neurons by altering the expression of Nav1.6 channels"

Identifies the voltage-gated sodium channel Nav1.6 as the effector through which FGF14 loss degrades Purkinje firing.

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"

Defines the biophysical mechanism (shifted Nav steady-state inactivation) by which iFGF14 loss silences Purkinje neurons.

Purkinje Neuron Degeneration and Cerebellar Atrophy

Over the disease course, loss of cerebellar Purkinje neurons develops, most severe in the anterior vermis, together with cerebellar (predominantly vermian) atrophy on imaging. Degeneration is comparatively mild and slow relative to the polyglutamine SCAs, consistent with the slow clinical progression, the absence of elevated serum neurofilament light, and the limited extra-cerebellar involvement.

cerebellar Purkinje cell CL:0000121

neuron apoptotic process GO:0051402 ↑ INCREASED

cerebellar cortex UBERON:0002129

Downstream

Loss of Cerebellar Cortical Output Purkinje neuron loss permanently removes the sole inhibitory output of the cerebellar cortex to the deep cerebellar nuclei.

Show evidence (2 references)

PMID:39263992 SUPPORT Human Clinical

"The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis."

Direct human neuropathological evidence of Purkinje neuron loss in genetically confirmed SCA27B.

PMID:37165652 PARTIAL Human Clinical

"Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls."

Supports the qualifier that neuroaxonal degeneration in SCA27B is mild; classified PARTIAL because a normal serum neurofilament level constrains rather than demonstrates the degree of Purkinje loss.

Loss of Cerebellar Cortical Output

Purkinje cells provide the sole output of the cerebellar cortex to the deep cerebellar nuclei. Their functional silencing and, later, loss corrupt the motor-coordination and oculomotor signals relayed downstream. In SCA27B the dysfunction is initially intermittent and reversible, which explains the prominent episodic phase and the responsiveness to a drug that restores Purkinje pacemaking precision.

cerebellar Purkinje cell CL:0000121

nervous system process GO:0050877 ⚠ ABNORMAL

cerebellum UBERON:0002037

Downstream

Progressive Late-Onset Cerebellar Ataxia

Show evidence (2 references)

PMID:25926453 SUPPORT Model Organism

"The selective shRNA-mediated in vivo "knock-down" of iFGF14 in adult Purkinje neurons also impairs motor coordination and balance."

Demonstrates that FGF14-dependent loss of Purkinje output translates into a motor-coordination deficit in vivo.

PMID:37165652 SUPPORT Human Clinical

"pancerebellar syndrome, partly combined with afferent sensory deficits (55%) and dysautonomia (28%)"

Confirms that the clinical picture in patients is a pancerebellar (cortical-output) syndrome.

Progressive Late-Onset Cerebellar Ataxia

The convergent clinical consequence: a mid- to late-adult-onset, slowly progressive pancerebellar syndrome of gait and limb ataxia, cerebellar oculomotor signs including downbeat nystagmus, and dysarthria, often preceded by an episodic phase. Progression is mild (about 0.29 SARA points per year) and severity plateaus at a moderate level even in advanced disease, distinguishing SCA27B from SCA1/2/3.

Show evidence (2 references)

PMID:37165652 SUPPORT Human Clinical

"not exceeding a moderate disease severity even in advanced stages (maximum SARA score: 18 points)."

Quantifies the plateau in severity that characterises this clinical consequence; the accompanying rate figure in the same sentence is 0.29 SARA points per year.

PMID:38271551 SUPPORT Other

"GAA-FGF14-related ataxia is a mid to late adult-onset slowly progressive cerebellar syndrome with predominant gait involvement."

GeneReviews summary of the convergent clinical syndrome. Evidence source is OTHER because GeneReviews is an expert clinical synthesis.

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Histopathology

1

Purkinje cell loss with anterior vermian predominance

Post-mortem examination of genetically confirmed SCA27B brains shows loss of Purkinje neurons, most severe in the vermis and particularly the anterior vermis.

Show evidence (1 reference)

PMID:39263992 SUPPORT Human Clinical

"The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis."

Primary neuropathological description of SCA27B.

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Pathograph

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

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Phenotypes

13

Ear 1

Vertigo and dizziness Vertigo HP:0002321

Temporal: RECURRENT

Show evidence (1 reference)

PMID:38271551 SUPPORT Other

"vertigo and/or dizziness, or dysarthria on average two to four years before the onset of progressive ataxia"

Documents vertigo/dizziness as an episodic prodromal manifestation with its characteristic lead time.

Eye 2

Diplopia and visual disturbance Diplopia HP:0000651

Temporal: RECURRENT

Show evidence (1 reference)

PMID:38271551 SUPPORT Other

"visual disturbances (diplopia, oscillopsia, and blurring)"

Documents diplopia as part of the episodic visual disturbance.

Oscillopsia Oscillopsia HP:0034773

Show evidence (1 reference)

PMID:38271551 SUPPORT Other

"visual disturbances (diplopia, oscillopsia, and blurring)"

Documents oscillopsia as an episodic visual manifestation.

Nervous System 5

Gait ataxia VERY_FREQUENT Gait ataxia HP:0002066

Course: PROGRESSIVE Onset: LATE

Show evidence (3 references)

PMID:39263992 SUPPORT Human Clinical

"Balance and gait impairment were almost always present at disease onset."

Supports both the phenotype and the VERY_FREQUENT band: "almost always" maps to the 80-100% HPO frequency range in a 102-patient cohort.

PMID:38271551 SUPPORT Other

"Median age at onset is 60 years (range: 21-87 years)."

Supports the LATE onset category recorded on this phenotype.

PMID:38271551 SUPPORT Other

"slowly progressive cerebellar syndrome with predominant gait involvement"

GeneReviews identifies gait involvement as the predominant feature.

Episodic ataxia FREQUENT Episodic ataxia HP:0002131

Temporal: RECURRENT

Show evidence (3 references)

PMID:39263992 SUPPORT Human Clinical

"we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients"

Direct quantitative support for both the phenotype and the FREQUENT band (51% falls in the 30-79% HPO range) in a 102-patient cohort.

PMID:39263992 SUPPORT Human Clinical

"Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset."

Supports the diagnostic value of the episodic presentation.

PMID:38271551 SUPPORT Other

"Episodic symptoms may persist after the onset of progressive ataxia and may be triggered by alcohol intake and physical activity."

Documents the persistence and the alcohol/exertion triggers.

Dysarthria Dysarthria HP:0001260

Severity: MILD

Show evidence (1 reference)

PMID:38271551 SUPPORT Other

"Dysarthria does not develop in all individuals and often remains mild to moderate."

Supports both the phenotype and its typically mild severity. Frequency is omitted because the source states only that it is not universal.

Dysautonomia OCCASIONAL Abnormal autonomic nervous system physiology HP:0012332

Course: PROGRESSIVE

Show evidence (2 references)

PMID:37165652 SUPPORT Human Clinical

"partly combined with afferent sensory deficits (55%) and dysautonomia (28%)"

Direct quantitative support for both the phenotype and the OCCASIONAL band (28% falls in the 5-29% HPO range).

PMID:37165652 SUPPORT Human Clinical

"Dysautonomia increased with duration while cognitive impairment remained infrequent, even in advanced stages."

Supports the progressive clinical course qualifier and, by contrast, the relative sparing of cognition.

Hyperreflexia Hyperreflexia HP:0001347

Show evidence (1 reference)

PMID:36493768 SUPPORT Human Clinical

"Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction."

Documents hyperreflexia as a variable accompanying feature. Frequency is omitted because the source calls it "variable" without quantification.

Other 5

Limb ataxia Limb ataxia HP:0002070

Show evidence (1 reference)

PMID:38271551 SUPPORT Other

"Nearly 50% of individuals may first experience episodic manifestations including gait and limb ataxia"

Documents limb ataxia as a manifestation of the disease. Frequency is deliberately omitted: the quoted figure describes the episodic phase, not the overall prevalence of limb ataxia.

Downbeat nystagmus Downbeat nystagmus HP:0010545

Show evidence (2 references)

PMID:38507876 SUPPORT Human Clinical

"Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN."

Establishes the strong association between SCA27B and downbeat nystagmus from the downbeat-nystagmus side of the relationship. Frequency is omitted because this cohort was ascertained on downbeat nystagmus and so cannot estimate how often SCA27B patients have the sign.

PMID:39227614 SUPPORT Human Clinical

"SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus"

Confirms downbeat nystagmus as a defining, recognisable feature of SCA27B.

Cerebellar oculomotor signs Gaze-evoked nystagmus HP:0000640

Show evidence (2 references)

PMID:38271551 SUPPORT Other

"Cerebellar oculomotor signs, including downbeat nystagmus, horizontal gaze-evoked nystagmus, and impaired visual fixation suppression of the vestibuloocular reflex, are common."

Documents gaze-evoked nystagmus as part of the oculomotor syndrome.

PMID:38507876 PARTIAL Human Clinical

"Additional cerebellar ocular motor signs were observed in 100% (82/82)"

Quantifies the near-universal presence of cerebellar oculomotor signs in expansion carriers; classified PARTIAL and no frequency band is asserted because this cohort was ascertained on downbeat nystagmus and is therefore enriched for cerebellar eye signs.

Sensory ataxia and afferent sensory deficits FREQUENT Sensory ataxia HP:0010871

Show evidence (1 reference)

PMID:37165652 SUPPORT Human Clinical

"partly combined with afferent sensory deficits (55%) and dysautonomia (28%)"

Direct quantitative support for both the phenotype and the FREQUENT band (55% falls in the 30-79% HPO range) in a 50-patient cohort.

Vestibular hypofunction FREQUENT Vestibular hyporeflexia HP:0001756

Show evidence (2 references)

PMID:36493768 SUPPORT Human Clinical

"Six of 10 assessed had evidence of vestibular hypofunction on video head impulse test"

Direct quantitative support for both the phenotype and the FREQUENT band (6/10 = 60%, within the 30-79% HPO range) among formally assessed patients in the Australian discovery cohort.

PMID:38271551 SUPPORT Other

"Unilateral or bilateral vestibular hypofunction and tremor of the upper limbs may occur."

GeneReviews independently documents unilateral and bilateral vestibular hypofunction as a feature of the disease.

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Genetic Associations

1

FGF14 (Deep intronic (GAA) repeat expansion in intron 1 of FGF14)

Gene: FGF14 hgnc:3671 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (5 references)

PMID:36516086 SUPPORT Human Clinical

"In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14."

Establishes the causal lesion as a deep intronic GAA repeat expansion in FGF14 intron 1.

PMID:36516086 SUPPORT Human Clinical

"Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats"

Documents the originally proposed (GAA)>=250 pathogenic threshold from family cosegregation.

PMID:36493768 SUPPORT Human Clinical

"The combined data suggest (GAA)>335 are disease causing and fully penetrant"

Independent cohort defining a fully penetrant threshold, higher than the original >=250 estimate.

+ 2 more references

💊

Medical Actions

4

4-Aminopyridine

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: 4-aminopyridine CHEBI:34385

4-Aminopyridine (4-AP), a voltage-gated potassium channel blocker, is the principal symptomatic therapy for SCA27B and is the mechanistically rational choice: it does not increase inhibitory drive onto Purkinje cells but restores the precision of Purkinje pacemaking by prolonging the action potential and increasing the afterhyperpolarization, counteracting the firing failure caused by FGF14 loss. Across cohorts, 75-86% of treated patients report clinically meaningful benefit, and placebo-controlled video-oculography in a small number of expansion carriers showed a significant reduction in downbeat nystagmus slow-phase velocity on 4-AP but not placebo. Formal randomised trials in genetically defined SCA27B are still awaited.

Mechanism Target:

RESTORES Impaired Purkinje Neuron Intrinsic Excitability and Firing — Blockade of Kv1-family potassium channels prolongs the Purkinje action potential and deepens the afterhyperpolarization, restoring the precision of pacemaking that is degraded when FGF14 loss shifts Nav steady-state inactivation.

Show evidence (1 reference)

PMID:20505092 PARTIAL Model Organism

"4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization"

Defines the mechanism of action of 4-AP at the Purkinje pacemaking node. Classified PARTIAL because the model is EA2 (a P/Q-type calcium channelopathy) rather than FGF14 deficiency, so this supports the drug-target mechanism generically rather than demonstrating it in FGF14-deficient neurons.

Target Phenotypes: Downbeat nystagmus HP:0010545 Gait ataxia HP:0002066

Show evidence (4 references)

PMID:37165652 SUPPORT Human Clinical

"A treatment response to 4-AP with relevance for everyday living was reported by 86% of treated patients."

Quantifies real-world treatment response in a genetically defined cohort.

PMID:37165652 SUPPORT Human Clinical

"A series of three prospective n-of-1 treatment experiences with on/off design showed marked reduction in daily symptomatic time and symptom severity on 4-AP."

Provides prospective on/off within-patient evidence of benefit.

PMID:38507876 SUPPORT Human Clinical

"Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo."

The only placebo-controlled objective evidence to date, though in only four expansion carriers.

+ 1 more reference

Avoidance of episode triggers

Category: Counseling / Informational Action: Supportive Care NCIT:C15747

Patients should be informed that alcohol intake and strenuous physical activity may precipitate episodes of ataxia and worsen incoordination, and that medications with known cerebellar or vestibular toxicity should be avoided.

Show evidence (1 reference)

PMID:38271551 SUPPORT Other

"Inform affected individuals that alcohol intake and strenuous physical activity may precipitate episodes of ataxia and may exacerbate incoordination. Avoid medications with known toxicity to the cerebellum and the vestibular system."

GeneReviews "Agents/circumstances to avoid" guidance, quoted verbatim.

Multidisciplinary rehabilitation

Category: Therapeutic Action: Physical Therapy NCIT:C15302

There is no cure or disease-modifying therapy. Management aims to improve quality of life, maximise function, and reduce complications through multidisciplinary care including physical therapy, occupational therapy, and speech-language therapy.

Show evidence (1 reference)

PMID:38271551 SUPPORT Other

"This ideally involves multidisciplinary care by specialists in relevant fields, such as neurologists, ophthalmologists, orthoptists, physical therapists, occupational therapists, speech-language therapists, and psychologists."

GeneReviews management recommendation.

Genetic counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Counseling should cover the autosomal dominant 50% transmission risk, the age-dependent and incomplete penetrance of shorter expansions, and the intergenerational instability of the repeat (expansion on maternal, and contraction on paternal, transmission). Predictive and prenatal testing are technically possible but prognostically limited: clinical manifestations cannot be predicted from a fetal repeat size, and prenatal somatic instability is not characterised.

Show evidence (1 reference)

PMID:38271551 SUPPORT Other

"accurate prediction of future possible clinical manifestations in a fetus found to have an FGF14 GAA repeat expansion is not possible, and the current lack of knowledge regarding somatic instability of the repeat prenatally makes the interpretation of prenatal genetic test results challenging"

GeneReviews statement of the counseling limitations around predictive and prenatal testing.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Spinocerebellar ataxia 27B:

CANVAS MONDO:0044720

Overlapping Features RFC1-related CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome) is the closest clinical mimic and the most important differential in practice. Both are late-onset ataxias that combine cerebellar signs with vestibular hypofunction and sensory/afferent deficits, so the two are separated by genotype rather than by phenotype: CANVAS is autosomal recessive, caused by a biallelic intronic (AAGGG)n expansion in RFC1, whereas SCA27B is autosomal dominant and caused by a heterozygous intronic (GAA)n expansion in FGF14. The FGF14 expansion was explicitly identified as an alternative genetic cause in patients with CANVAS-like syndromes who test negative for biallelic RFC1 expansions, so a negative RFC1 result in a CANVAS-like presentation should prompt FGF14 repeat sizing rather than closing the workup.

Distinguishing Features

Autosomal recessive biallelic RFC1 (AAGGG)n expansion, versus autosomal dominant heterozygous FGF14 (GAA)n expansion
Prominent sensory neuronopathy and chronic cough are characteristic of CANVAS but not of SCA27B
Episodic ataxia and a marked 4-aminopyridine response point towards SCA27B

Show evidence (1 reference)

PMID:36493768 SUPPORT Human Clinical

"provides an alternative genetic cause in individuals with CANVAS-like syndromes negative for bi-allelic"

Establishes SCA27B as the alternative diagnosis to pursue in RFC1-negative CANVAS-like presentations, which is exactly why the two belong together as differentials. Quoted as an exact substring of the cached full text; the sentence continues "RFC1 RE", rendered without spacing in the cached PDF extraction.

Spinocerebellar ataxia 27A Not Yet Curated MONDO:0008654

Overlapping Features SCA27A (MONDO:0008654, OMIM:609307) is caused by FGF14 coding point variants (classically the F145S missense) rather than the intronic repeat. It shares the gene and, in some families, the episodic ataxia and downbeat nystagmus, but presents in childhood. Distinguishing the two is essential because literature about one does not transfer to the other.

Distinguishing Features

Coding point variant in FGF14 rather than an intronic GAA repeat expansion
Childhood rather than sixth-decade onset

Show evidence (2 references)

PMID:39227614 SUPPORT Human Clinical

"similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A)"

Confirms that SCA27A is a separate, coding-variant entity whose presentation overlaps SCA27B.

PMID:18930825 SUPPORT Other

"A missense mutation in the fibroblast growth factor 14 (FGF14) gene underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans."

Documents the coding missense basis of the originally described SCA27 (now SCA27A). Evidence source is OTHER because this is background framing rather than a result of the reported experiments.

{ }

Source YAML

click to show

name: Spinocerebellar ataxia 27B
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
synonyms:
- SCA27B
- GAA-FGF14 ataxia
- GAA-FGF14 disease
- GAA-FGF14-related ataxia
- SCA50
- ATX-FGF14
description: >-
  Spinocerebellar ataxia 27B (SCA27B), also called GAA-FGF14 ataxia, is an
  autosomal dominant, mid- to late-adult-onset, slowly progressive cerebellar
  syndrome caused by a deep intronic (GAA) repeat expansion in intron 1 of
  FGF14. First reported in 2022-2023, it has rapidly emerged as one of the most
  common genetic causes of late-onset cerebellar ataxia, accounting for a
  substantial fraction of previously undiagnosed adult-onset ataxia cohorts.
  Median age at onset is about 57-60 years. The clinical core is a
  pancerebellar syndrome with gait ataxia, cerebellar oculomotor signs (notably
  downbeat nystagmus), and dysarthria, frequently preceded for years by
  episodic ataxia, vertigo, and visual disturbance. Mechanistically the
  expansion reduces FGF14 expression; FGF14 is an intracellular fibroblast
  growth factor (iFGF/FHF) that binds voltage-gated sodium channels at the
  Purkinje neuron axon initial segment and is required for normal spontaneous
  and repetitive Purkinje firing, so its loss degrades cerebellar cortical
  output and, over time, is accompanied by Purkinje neuron loss. SCA27B is
  notable as a treatable ataxia: a large majority of patients report meaningful
  symptomatic benefit from 4-aminopyridine.

  SCA27B is a distinct disease entity from SCA27A (MONDO:0008654,
  OMIM:609307), which is caused by FGF14 coding point variants and presents in
  childhood; the two share a gene but not a mutational mechanism, onset, or
  natural history.
disease_term:
  preferred_term: Spinocerebellar ataxia 27B, late-onset
  term:
    id: MONDO:0859340
    label: spinocerebellar ataxia 27B, late-onset
parents:
- Hereditary cerebellar ataxia
- Neurodegenerative Disease
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC

inheritance:
- name: Autosomal dominant
  description: >-
    SCA27B is inherited in an autosomal dominant manner. Most affected
    individuals inherit the expanded FGF14 (GAA) allele from a parent who may
    carry a high-normal, reduced-penetrance, or fully pathogenic repeat; each
    child of an affected individual has a 50% chance of inheriting the allele.
    Penetrance is age-dependent and incomplete at shorter expansion sizes, and
    de novo generation of an expansion during meiosis has been inferred from
    haplotype analysis.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  parent_of_origin_effect: >-
    Repeat size is more likely to expand on maternal transmission and to
    contract on paternal transmission, an intergenerational instability that
    underlies variable anticipation within families.
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GAA-FGF14-related ataxia is inherited in an autosomal dominant manner.
    explanation: >-
      GeneReviews states the mode of inheritance directly. Evidence source is
      OTHER because GeneReviews is an expert-curated clinical synthesis rather
      than a primary study.
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the size of the GAA repeat is more likely to expand upon maternal
      transmission and to contract upon paternal transmission
    explanation: >-
      Supports the recorded parent-of-origin effect on intergenerational repeat
      instability.
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identification of a shared haplotype in a minority of individuals
      suggests that the expansion can be inherited or generated de novo during
      meiotic division
    explanation: >-
      Supports both inherited transmission and de novo generation of the
      expansion.

genetic:
- name: FGF14
  gene_term:
    preferred_term: FGF14
    term:
      id: hgnc:3671
      label: FGF14
  association: Deep intronic (GAA) repeat expansion in intron 1 of FGF14
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: Positive
  notes: >-
    The pathogenic lesion is a heterozygous (GAA)n repeat expansion located
    deep within the first intron of FGF14 (equivalently written (AAG)n on the
    opposite strand in some reports). Reported thresholds have shifted as
    cohorts have grown: the original French Canadian cosegregation analysis
    supported (GAA) >= 250; the Australian/German discovery cohort concluded
    (GAA) > 335 is disease causing and fully penetrant while (GAA) > 250 is
    likely pathogenic with reduced penetrance; GeneReviews uses (GAA) > 300 for
    a definitive molecular diagnosis with a reduced-penetrance 250-300 zone; and
    a subsequent long-read study argued that uninterrupted expansions are
    already enriched in patients from 180-200 repeats. Repeat length correlates
    inversely with age at onset. Motif purity is a key modifier: pure GAA
    (AAG) expansions are pathogenic, whereas GAAGGA/AAGGAG hexameric expansions
    are found equally in patients and controls, and mosaic divergent repeat
    interruptions (mDRILS) that shorten the longest pure GAA tract are more
    frequent in unaffected carriers.
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  evidence:
  - reference: PMID:36516086
    reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the six French Canadian patients, we identified a GAA repeat
      expansion deep in the first intron of FGF14, which encodes fibroblast
      growth factor 14.
    explanation: >-
      Establishes the causal lesion as a deep intronic GAA repeat expansion in
      FGF14 intron 1.
  - reference: PMID:36516086
    reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cosegregation of the repeat expansion with disease in the families
      supported a pathogenic threshold of at least 250 GAA repeats
    explanation: >-
      Documents the originally proposed (GAA)>=250 pathogenic threshold from
      family cosegregation.
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combined data suggest (GAA)>335 are disease causing and fully
      penetrant
    explanation: >-
      Independent cohort defining a fully penetrant threshold, higher than the
      original >=250 estimate.
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A negative correlation between age at onset and repeat length was
      observed
    explanation: >-
      Supports the inverse relationship between expansion size and age at
      onset.
  - reference: PMID:39227614
    reference_title: Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Uninterrupted AAG expansions are significantly enriched in patients with
      ataxia from a lower threshold (180-200 repeats) than previously reported
      based on expansion size alone. Conversely, AAGGAG hexameric expansions
      are equally frequent in patients and controls.
    explanation: >-
      Establishes the motif-purity distinction: pure GAA/AAG tracts are
      pathogenic while GAAGGA/AAGGAG hexameric expansions are not, and lowers
      the length threshold once motif is accounted for.
  case_fractions:
  - population: French Canadian late-onset cerebellar ataxia index patients
    case_fraction_percent: 61.0
    notes: Founder-enriched population with the highest reported SCA27B share.
    evidence:
    - reference: PMID:36516086
      reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The repeat expansion was present in 61%, 18%, 15%, and 10% of
        French Canadian, German, Australian, and Indian index patients,
        respectively.
      explanation: Reports the per-population share of index patients carrying the expansion.
  - population: German late-onset cerebellar ataxia index patients
    case_fraction_percent: 18.0
    evidence:
    - reference: PMID:36516086
      reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The repeat expansion was present in 61%, 18%, 15%, and 10% of
        French Canadian, German, Australian, and Indian index patients,
        respectively.
      explanation: Reports the per-population share of index patients carrying the expansion.
  - population: Indian late-onset cerebellar ataxia index patients
    case_fraction_percent: 10.0
    evidence:
    - reference: PMID:36516086
      reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The repeat expansion was present in 61%, 18%, 15%, and 10% of
        French Canadian, German, Australian, and Indian index patients,
        respectively.
      explanation: Reports the per-population share of index patients carrying the expansion.

variants:
- name: FGF14 intron 1 (GAA)n repeat expansion
  description: >-
    Heterozygous expansion of a (GAA) short tandem repeat located deep in
    intron 1 of FGF14. Pathogenicity depends jointly on the length of the
    longest pure GAA tract and on the presence of interrupting motifs; the
    non-coding location means the mechanism is loss of expression rather than
    an altered protein product.
  gene:
    preferred_term: FGF14
    term:
      id: hgnc:3671
      label: FGF14
  clinical_significance: PATHOGENIC
  type: short tandem repeat expansion
  regulatory_category: LOE
  evidence:
  - reference: PMID:36516086
    reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postmortem cerebellum specimens and iPSC-derived motor neurons from
      patients showed reduced expression of FGF14 RNA and protein.
    explanation: >-
      Supports classification as a loss-of-expression regulatory variant: the
      intronic expansion reduces FGF14 RNA and protein rather than altering
      coding sequence.
- name: FGF14 GAAGGA / AAGGAG interrupted hexameric repeat configuration
  description: >-
    Expanded FGF14 repeat alleles whose tract is composed of, or heavily
    interrupted by, GAAGGA/AAGGAG hexameric motifs. These configurations occur
    at equal frequency in patients and controls and are treated as
    non-pathogenic; mosaic divergent repeat interruptions that shorten the
    remaining pure GAA tract are enriched in unaffected expansion carriers.
  gene:
    preferred_term: FGF14
    term:
      id: hgnc:3671
      label: FGF14
  clinical_significance: LIKELY_BENIGN
  type: interrupted short tandem repeat
  evidence:
  - reference: PMID:39227614
    reference_title: Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conversely, AAGGAG hexameric expansions are equally frequent in patients
      and controls.
    explanation: >-
      Directly supports the non-pathogenic status of the hexameric motif
      configuration.
  - reference: PMID:39227614
    reference_title: Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats
      form different secondary structures.
    explanation: >-
      Offers a biophysical rationale for the motif-dependent pathogenicity.
      Evidence source is IN_VITRO because the secondary-structure comparison is
      a molecular assay outside an organism.
  - reference: PMID:40379261
    reference_title: "FGF14 repeat length and mosaic interruptions: modifiers of spinocerebellar ataxia 27B?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with a higher mosaic frequency of interruptions in unaffected
      individuals compared with patients
    explanation: >-
      Supports interruptions acting as a protective modifier of pathogenicity.

pathophysiology:
- name: FGF14 Intronic GAA Repeat Expansion
  description: >-
    A heterozygous (GAA)n repeat expansion deep in intron 1 of FGF14 is the
    initiating molecular lesion. Because the repeat lies in non-coding
    sequence, it does not produce an altered FGF14 protein; instead, expansion
    beyond a length- and motif-dependent threshold destabilises expression of
    the allele. Repeat length correlates inversely with age at onset, and the
    tract's motif composition (pure GAA versus GAAGGA/AAGGAG interruptions)
    gates whether an expansion is pathogenic at all.
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  gene:
    preferred_term: FGF14
    term:
      id: hgnc:3671
      label: FGF14
  locations:
  - preferred_term: cerebellar cortex
    term:
      id: UBERON:0002129
      label: cerebellar cortex
  evidence:
  - reference: PMID:36516086
    reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the six French Canadian patients, we identified a GAA repeat
      expansion deep in the first intron of FGF14, which encodes fibroblast
      growth factor 14.
    explanation: Identifies the trigger lesion.
  - reference: PMID:36516086
    reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was significant association between FGF14 (GAA)≥250 expansions and
      LOCA in the French Canadian series
    explanation: >-
      Establishes the case-control association between the expansion and
      late-onset cerebellar ataxia (reported odds ratio 105.60, P<0.001).
  downstream:
  - target: Reduced FGF14 Expression in Cerebellar Neurons
    description: >-
      Expansion of the intronic GAA tract beyond the pathogenic threshold
      reduces FGF14 RNA and protein levels in patient cerebellum and in
      patient-derived neurons.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36516086
      reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Postmortem cerebellum specimens and iPSC-derived motor neurons from
        patients showed reduced expression of FGF14 RNA and protein.
      explanation: >-
        Links the expansion directly to reduced FGF14 expression in patient
        tissue. The intervening molecular steps (the transcriptional or
        epigenetic route from an intronic GAA tract to reduced expression) are
        not established in FGF14, hence INDIRECT_UNKNOWN_INTERMEDIATES.

- name: Reduced FGF14 Expression in Cerebellar Neurons
  description: >-
    The expanded allele is expressed at reduced level, producing functional
    FGF14 haploinsufficiency in cerebellar neurons. FGF14 is an intracellular
    fibroblast growth factor (iFGF/FGF homologous factor) that is not secreted
    and does not signal through FGF receptors; it acts intracellularly as a
    binding partner and regulator of voltage-gated sodium channels. Reduced
    FGF14 RNA and protein have been demonstrated in postmortem patient
    cerebellum and in patient-derived iPSC neurons.
  role: amplifier
  biological_scale: MOLECULAR
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Neuron Insult"
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: regulation of gene expression
    term:
      id: GO:0010468
      label: regulation of gene expression
    modifier: DECREASED
  molecular_functions:
  - preferred_term: sodium channel regulator activity
    term:
      id: GO:0017080
      label: sodium channel regulator activity
    modifier: DECREASED
  locations:
  - preferred_term: cerebellar cortex
    term:
      id: UBERON:0002129
      label: cerebellar cortex
  evidence:
  - reference: PMID:36516086
    reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postmortem cerebellum specimens and iPSC-derived motor neurons from
      patients showed reduced expression of FGF14 RNA and protein.
    explanation: >-
      Demonstrates reduced FGF14 expression in human patient material,
      establishing haploinsufficiency as the proximate consequence.
  - reference: PMID:18930825
    reference_title: FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FGF14 belongs to the intracellular fibroblast growth factor subfamily
      (iFGF) that also includes FGFs 11–14
    explanation: >-
      Establishes FGF14 as an intracellular FGF rather than a secreted growth
      factor. Evidence source is OTHER because this statement is background
      framing in the article rather than a result of the reported experiments.
  downstream:
  - target: Impaired Purkinje Neuron Intrinsic Excitability and Firing
    description: >-
      Loss of intracellular FGF14 removes a required regulator of
      voltage-gated sodium channels at the Purkinje neuron axon initial
      segment, attenuating spontaneous and repetitive firing.
    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 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: >-
        Acute in vivo knockdown in adult mouse Purkinje neurons isolates
        reduced iFGF14 as the direct cause of impaired firing, matching the
        haploinsufficiency mechanism inferred in patients.

- name: Impaired Purkinje Neuron Intrinsic Excitability and Firing
  description: >-
    Intracellular FGF14 binds the C-terminus of voltage-gated sodium (Nav)
    channel alpha subunits and is concentrated at the Purkinje neuron axon
    initial segment, where Nav1.6-mediated resurgent sodium current sustains
    the high-frequency pacemaking that defines these cells. Loss of FGF14
    produces a hyperpolarizing shift in the voltage dependence of steady-state
    Nav inactivation and reduced Nav1.6 availability, so Purkinje neurons fail
    to fire spontaneously and cannot sustain repetitive firing to depolarizing
    input. This is a functional excitability defect that precedes and is
    separable from cell death, and it is the node targeted by
    4-aminopyridine.
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  notes: >-
    This node is deliberately NOT declared as conforming to
    "cerebellar_purkinje_degeneration#Purkinje Cell Calcium and Proteostasis
    Dysregulation". That module node models calcium-handling and
    proteostatic/aggregation stress as the amplifying step, which is the
    polyglutamine and calcium-channelopathy SCA pattern. In SCA27B the
    amplifying lesion is sodium-channel-dependent intrinsic excitability
    failure, with no evidence of a proteotoxic or calcium-homeostasis
    intermediate. Asserting conformance here would misrepresent the mechanism.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: neuronal action potential
    term:
      id: GO:0019228
      label: neuronal action potential
    modifier: DECREASED
  - preferred_term: membrane depolarization during action potential
    term:
      id: GO:0086010
      label: membrane depolarization during action potential
    modifier: DECREASED
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: DECREASED
  locations:
  - preferred_term: cerebellar cortex
    term:
      id: UBERON:0002129
      label: cerebellar cortex
  evidence:
  - reference: PMID:18930825
    reference_title: FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Current clamp recordings from Purkinje neurons in cerebellar slices
      revealed attenuated spontaneous firing in Fgf14(-/-) neurons. 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: >-
      Direct electrophysiological demonstration in Fgf14-null mice that loss of
      FGF14 abolishes spontaneous and repetitive Purkinje firing.
  - reference: PMID:18930825
    reference_title: FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and
      that the loss of FGF14 impairs spontaneous and repetitive firing in
      Purkinje neurons by altering the expression of Nav1.6 channels
    explanation: >-
      Identifies the voltage-gated sodium channel Nav1.6 as the effector
      through which FGF14 loss degrades Purkinje firing.
  - 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: >-
      Defines the biophysical mechanism (shifted Nav steady-state inactivation)
      by which iFGF14 loss silences Purkinje neurons.
  downstream:
  - target: Purkinje Neuron Degeneration and Cerebellar Atrophy
    description: >-
      Chronic failure of Purkinje pacemaking is accompanied, over years, by
      Purkinje neuron loss, most severe in the anterior vermis in human
      autopsy series.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39263992
      reference_title: Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The principal finding on post-mortem examination of 4 brain specimens
        was loss of Purkinje neurons that was most severe in the vermis most
        particularly in the anterior vermis.
      explanation: >-
        Human neuropathology confirms Purkinje neuron loss in SCA27B. The
        causal steps linking chronic firing failure to eventual neuron loss are
        not established, hence INDIRECT_UNKNOWN_INTERMEDIATES.
  - target: Loss of Cerebellar Cortical Output
    description: >-
      Because Purkinje cells are the sole output of the cerebellar cortex,
      silencing them directly removes cerebellar cortical output even before
      cell loss occurs.
    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: >-
        iFGF14 is required for spontaneous and evoked action potential firing
        in adult Purkinje neurons, thereby controlling the output of these
        cells and the regulation of motor coordination and balance
      explanation: >-
        Explicitly links iFGF14-dependent Purkinje firing to cerebellar output
        and motor coordination.

- name: Purkinje Neuron Degeneration and Cerebellar Atrophy
  description: >-
    Over the disease course, loss of cerebellar Purkinje neurons develops, most
    severe in the anterior vermis, together with cerebellar (predominantly
    vermian) atrophy on imaging. Degeneration is comparatively mild and slow
    relative to the polyglutamine SCAs, consistent with the slow clinical
    progression, the absence of elevated serum neurofilament light, and the
    limited extra-cerebellar involvement.
  role: effector
  biological_scale: TISSUE
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  mechanism_confidence: ESTABLISHED
  notes: >-
    The GO annotation "neuron apoptotic process" reflects the module's
    canonical degenerative mechanism. The human evidence in SCA27B documents
    Purkinje neuron loss but does not establish the mode of cell death, so this
    annotation should be read as the inherited module expectation rather than a
    demonstrated SCA27B finding.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: cerebellar cortex
    term:
      id: UBERON:0002129
      label: cerebellar cortex
  evidence:
  - reference: PMID:39263992
    reference_title: Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The principal finding on post-mortem examination of 4 brain specimens
      was loss of Purkinje neurons that was most severe in the vermis most
      particularly in the anterior vermis.
    explanation: >-
      Direct human neuropathological evidence of Purkinje neuron loss in
      genetically confirmed SCA27B.
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corresponding to slow progression and low extra-cerebellar involvement,
      sNfL was not increased relative to controls.
    explanation: >-
      Supports the qualifier that neuroaxonal degeneration in SCA27B is mild;
      classified PARTIAL because a normal serum neurofilament level constrains
      rather than demonstrates the degree of Purkinje loss.
  downstream:
  - target: Loss of Cerebellar Cortical Output
    causal_link_type: DIRECT
    description: >-
      Purkinje neuron loss permanently removes the sole inhibitory output of
      the cerebellar cortex to the deep cerebellar nuclei.

- name: Loss of Cerebellar Cortical Output
  description: >-
    Purkinje cells provide the sole output of the cerebellar cortex to the deep
    cerebellar nuclei. Their functional silencing and, later, loss corrupt the
    motor-coordination and oculomotor signals relayed downstream. In SCA27B the
    dysfunction is initially intermittent and reversible, which explains the
    prominent episodic phase and the responsiveness to a drug that restores
    Purkinje pacemaking precision.
  role: effector
  biological_scale: TISSUE
  conforms_to: "cerebellar_purkinje_degeneration#Loss of Cerebellar Cortical Output"
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: nervous system process
    term:
      id: GO:0050877
      label: nervous system process
    modifier: ABNORMAL
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  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: >-
      Demonstrates that FGF14-dependent loss of Purkinje output translates into
      a motor-coordination deficit in vivo.
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pancerebellar syndrome, partly combined with afferent sensory deficits
      (55%) and dysautonomia (28%)
    explanation: >-
      Confirms that the clinical picture in patients is a pancerebellar
      (cortical-output) syndrome.
  downstream:
  - target: Progressive Late-Onset Cerebellar Ataxia
    causal_link_type: DIRECT

- name: Progressive Late-Onset Cerebellar Ataxia
  description: >-
    The convergent clinical consequence: a mid- to late-adult-onset,
    slowly progressive pancerebellar syndrome of gait and limb ataxia,
    cerebellar oculomotor signs including downbeat nystagmus, and dysarthria,
    often preceded by an episodic phase. Progression is mild (about 0.29 SARA
    points per year) and severity plateaus at a moderate level even in advanced
    disease, distinguishing SCA27B from SCA1/2/3.
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Ataxia"
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      not exceeding a moderate disease severity even in advanced stages
      (maximum SARA score: 18 points).
    explanation: >-
      Quantifies the plateau in severity that characterises this clinical
      consequence; the accompanying rate figure in the same sentence is 0.29
      SARA points per year.
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GAA-FGF14-related ataxia is a mid to late adult-onset slowly progressive
      cerebellar syndrome with predominant gait involvement.
    explanation: >-
      GeneReviews summary of the convergent clinical syndrome. Evidence source
      is OTHER because GeneReviews is an expert clinical synthesis.

phenotypes:
- category: Neurological
  name: Gait ataxia
  description: >-
    Progressive unsteadiness of gait is the cardinal and usually the presenting
    feature; balance and gait impairment were almost always present at disease
    onset in the largest reported cohort.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
    clinical_course: PROGRESSIVE
    onset:
      onset_category: LATE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39263992
    reference_title: Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Balance and gait impairment were almost always present at disease onset.
    explanation: >-
      Supports both the phenotype and the VERY_FREQUENT band: "almost always"
      maps to the 80-100% HPO frequency range in a 102-patient cohort.
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Median age at onset is 60 years (range: 21-87 years).
    explanation: >-
      Supports the LATE onset category recorded on this phenotype.
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      slowly progressive cerebellar syndrome with predominant gait involvement
    explanation: GeneReviews identifies gait involvement as the predominant feature.

- category: Neurological
  name: Limb ataxia
  description: >-
    Appendicular incoordination is part of the pancerebellar syndrome and also
    occurs as an episodic manifestation before progressive ataxia is
    established.
  phenotype_term:
    preferred_term: Limb ataxia
    term:
      id: HP:0002070
      label: Limb ataxia
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nearly 50% of individuals may first experience episodic manifestations
      including gait and limb ataxia
    explanation: >-
      Documents limb ataxia as a manifestation of the disease. Frequency is
      deliberately omitted: the quoted figure describes the episodic phase, not
      the overall prevalence of limb ataxia.

- category: Neurological
  name: Episodic ataxia
  description: >-
    Roughly half of patients experience discrete episodes of ataxia, vertigo,
    dysarthria, and visual disturbance for two to four years before
    progressive ataxia begins; episodes may persist afterwards and are commonly
    triggered by alcohol intake and physical exertion. Episodic onset is a
    strong diagnostic pointer to SCA27B in an undiagnosed late-onset ataxia
    patient.
  phenotype_term:
    preferred_term: Episodic ataxia
    term:
      id: HP:0002131
      label: Episodic ataxia
    temporality: RECURRENT
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:39263992
    reference_title: Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found that SCA27B was a late-onset (57 ± 12.5 years) slowly
      progressive ataxia with an episodic component in 51% of patients
    explanation: >-
      Direct quantitative support for both the phenotype and the FREQUENT band
      (51% falls in the 30-79% HPO range) in a 102-patient cohort.
  - reference: PMID:39263992
    reference_title: Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Testing for SCA27B should be considered in all undiagnosed ataxia
      patients, especially those with episodic onset.
    explanation: Supports the diagnostic value of the episodic presentation.
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Episodic symptoms may persist after the onset of progressive ataxia and
      may be triggered by alcohol intake and physical activity.
    explanation: Documents the persistence and the alcohol/exertion triggers.

- category: Neurological
  name: Downbeat nystagmus
  description: >-
    Downbeat nystagmus is a hallmark cerebellar oculomotor sign of SCA27B and
    can be the dominant or presenting manifestation. Conversely, FGF14
    (GAA)>=250 expansions account for roughly half of patients presenting with
    otherwise idiopathic downbeat nystagmus, making SCA27B the single most
    common identified cause of that syndrome.
  phenotype_term:
    preferred_term: Downbeat nystagmus
    term:
      id: HP:0010545
      label: Downbeat nystagmus
  diagnostic: true
  evidence:
  - reference: PMID:38507876
    reference_title: "GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients
      with idiopathic DBN.
    explanation: >-
      Establishes the strong association between SCA27B and downbeat nystagmus
      from the downbeat-nystagmus side of the relationship. Frequency is
      omitted because this cohort was ascertained on downbeat nystagmus and so
      cannot estimate how often SCA27B patients have the sign.
  - reference: PMID:39227614
    reference_title: Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SCA27B is a recognizable clinical entity characterized by frequent
      episodic ataxia and downbeat nystagmus
    explanation: >-
      Confirms downbeat nystagmus as a defining, recognisable feature of
      SCA27B.

- category: Neurological
  name: Cerebellar oculomotor signs
  description: >-
    Beyond downbeat nystagmus, horizontal gaze-evoked nystagmus and impaired
    visual fixation suppression of the vestibulo-ocular reflex are common.
    Cerebellar ocular motor signs were present in every expansion carrier in
    the downbeat nystagmus cohort.
  phenotype_term:
    preferred_term: Gaze-evoked nystagmus
    term:
      id: HP:0000640
      label: Gaze-evoked nystagmus
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cerebellar oculomotor signs, including downbeat nystagmus, horizontal
      gaze-evoked nystagmus, and impaired visual fixation suppression of the
      vestibuloocular reflex, are common.
    explanation: Documents gaze-evoked nystagmus as part of the oculomotor syndrome.
  - reference: PMID:38507876
    reference_title: "GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional cerebellar ocular motor signs were observed in 100% (82/82)
    explanation: >-
      Quantifies the near-universal presence of cerebellar oculomotor signs in
      expansion carriers; classified PARTIAL and no frequency band is asserted
      because this cohort was ascertained on downbeat nystagmus and is
      therefore enriched for cerebellar eye signs.

- category: Neurological
  name: Dysarthria
  description: >-
    Cerebellar dysarthria occurs but is not universal and usually remains mild
    to moderate, unlike in SCA1/2/3.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    severity: MILD
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dysarthria does not develop in all individuals and often remains mild to
      moderate.
    explanation: >-
      Supports both the phenotype and its typically mild severity. Frequency is
      omitted because the source states only that it is not universal.

- category: Neurological
  name: Diplopia and visual disturbance
  description: >-
    Episodic visual disturbance including diplopia, oscillopsia, and blurring
    is a common early manifestation, typically preceding progressive ataxia.
  phenotype_term:
    preferred_term: Diplopia
    term:
      id: HP:0000651
      label: Diplopia
    temporality: RECURRENT
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      visual disturbances (diplopia, oscillopsia, and blurring)
    explanation: Documents diplopia as part of the episodic visual disturbance.

- category: Neurological
  name: Oscillopsia
  description: >-
    Illusory movement of the visual scene, reflecting the cerebellar and
    vestibular ocular motor dysfunction, occurs as part of the episodic visual
    disturbance.
  phenotype_term:
    preferred_term: Oscillopsia
    term:
      id: HP:0034773
      label: Oscillopsia
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      visual disturbances (diplopia, oscillopsia, and blurring)
    explanation: Documents oscillopsia as an episodic visual manifestation.

- category: Neurological
  name: Vertigo and dizziness
  description: >-
    Vertigo and/or dizziness are frequent episodic manifestations and may be
    the earliest symptom; unilateral or bilateral vestibular hypofunction may
    also be found.
  phenotype_term:
    preferred_term: Vertigo
    term:
      id: HP:0002321
      label: Vertigo
    temporality: RECURRENT
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      vertigo and/or dizziness, or dysarthria on average two to four years
      before the onset of progressive ataxia
    explanation: >-
      Documents vertigo/dizziness as an episodic prodromal manifestation with
      its characteristic lead time.

- category: Neurological
  name: Sensory ataxia and afferent sensory deficits
  description: >-
    Afferent (proprioceptive) sensory deficits were documented in just over
    half of a deeply phenotyped cohort, contributing an additional sensory
    component to the ataxia in some patients.
  phenotype_term:
    preferred_term: Sensory ataxia
    term:
      id: HP:0010871
      label: Sensory ataxia
  frequency: FREQUENT
  evidence:
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      partly combined with afferent sensory deficits (55%) and dysautonomia
      (28%)
    explanation: >-
      Direct quantitative support for both the phenotype and the FREQUENT band
      (55% falls in the 30-79% HPO range) in a 50-patient cohort.

- category: Neurological
  name: Dysautonomia
  description: >-
    Autonomic dysfunction was present in roughly a quarter of a deeply
    phenotyped cohort and increased with disease duration.
  phenotype_term:
    preferred_term: Abnormal autonomic nervous system physiology
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      partly combined with afferent sensory deficits (55%) and dysautonomia
      (28%)
    explanation: >-
      Direct quantitative support for both the phenotype and the OCCASIONAL
      band (28% falls in the 5-29% HPO range).
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysautonomia increased with duration while cognitive impairment remained
      infrequent, even in advanced stages.
    explanation: >-
      Supports the progressive clinical course qualifier and, by contrast, the
      relative sparing of cognition.

- category: Neurological
  name: Vestibular hypofunction
  description: >-
    Unilateral or bilateral vestibular hypofunction is detectable on video head
    impulse testing in a majority of formally assessed patients, and an
    abnormal video visually enhanced vestibulo-ocular reflex accompanies
    bilateral hypofunction. This vestibular component is part of why the
    syndrome can present as imbalance and oscillopsia rather than as pure
    limb incoordination.
  phenotype_term:
    preferred_term: Vestibular hypofunction
    term:
      id: HP:0001756
      label: Vestibular hyporeflexia
  frequency: FREQUENT
  evidence:
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of 10 assessed had evidence of vestibular hypofunction on video head
      impulse test
    explanation: >-
      Direct quantitative support for both the phenotype and the FREQUENT band
      (6/10 = 60%, within the 30-79% HPO range) among formally assessed
      patients in the Australian discovery cohort.
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Unilateral or bilateral vestibular hypofunction and tremor of the upper
      limbs may occur.
    explanation: >-
      GeneReviews independently documents unilateral and bilateral vestibular
      hypofunction as a feature of the disease.

- category: Neurological
  name: Hyperreflexia
  description: >-
    Brisk reflexes were reported as a variable feature in the discovery cohort,
    indicating occasional pyramidal involvement.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals had an adult-onset, slowly progressive cerebellar
      ataxia with variable features including vestibular impairment,
      hyper-reflexia, and autonomic dysfunction.
    explanation: >-
      Documents hyperreflexia as a variable accompanying feature. Frequency is
      omitted because the source calls it "variable" without quantification.

imaging_findings:
- name: Cerebellar atrophy on brain MRI
  modality: MRI
  description: >-
    Brain MRI shows regional cerebellar atrophy in a substantial minority of
    patients, concordant with the anterior-vermis-predominant Purkinje cell
    loss seen at autopsy. Critically, a normal MRI does not exclude the
    diagnosis: in the Australian discovery cohort only five of thirteen
    expansion carriers had visible cerebellar atrophy despite a mean 8.5 years
    of symptoms, so imaging is a poor rule-out test and molecular repeat
    sizing should be pursued regardless.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  frequency: FREQUENT
  located_in:
    preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All displayed a range of clinical ataxic phenomena, with MRI scanning
      revealing cerebellar atrophy in five of the 13
    explanation: >-
      Direct quantitative support for both the finding and the FREQUENT band
      (5/13 = 38%, within the 30-79% HPO range), and for the point that most
      expansion carriers in this cohort had no visible atrophy.
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI scans were assessed visually for regional cerebellar atrophy.
    explanation: >-
      Documents the imaging modality and the visual assessment method behind
      the atrophy figure.

histopathology:
- name: Purkinje cell loss with anterior vermian predominance
  description: >-
    Post-mortem examination of genetically confirmed SCA27B brains shows loss
    of Purkinje neurons, most severe in the vermis and particularly the
    anterior vermis.
  evidence:
  - reference: PMID:39263992
    reference_title: Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The principal finding on post-mortem examination of 4 brain specimens
      was loss of Purkinje neurons that was most severe in the vermis most
      particularly in the anterior vermis.
    explanation: Primary neuropathological description of SCA27B.

progression:
- phase: Episodic prodrome
  age_range: Typically two to four years before progressive ataxia
  notes: >-
    Nearly half of patients first experience discrete episodes of gait and limb
    ataxia, visual disturbance, vertigo/dizziness, or dysarthria, on average
    two to four years before progressive ataxia begins.
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nearly 50% of individuals may first experience episodic manifestations
      including gait and limb ataxia, visual disturbances (diplopia,
      oscillopsia, and blurring), vertigo and/or dizziness, or dysarthria on
      average two to four years before the onset of progressive ataxia.
    explanation: Defines the episodic prodromal phase and its lead time.
- phase: Slowly progressive ataxia with functional plateau
  age_range: Median onset 60 years, reported range 21-87 years
  notes: >-
    Progression is slow, about 0.29 SARA points per year, with severity not
    exceeding a moderate level even in advanced disease and unilateral mobility
    aids required after roughly eight years in half of patients. Serum
    neurofilament light is not elevated relative to controls, consistent with
    limited neuroaxonal degeneration. Concurrent second neurological diseases
    are a major individual aggravator of severity and a confounder for trial
    design.
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Median age at onset is 60 years (range: 21-87 years).
    explanation: Supports the recorded age range for this phase.
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional impairment increased relatively slowly (unilateral mobility
      aids after 8 years in 50% of patients).
    explanation: Quantifies functional progression.
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concurrent second diseases (including progressive supranuclear palsy
      neuropathology) represented major individual aggravators of disease
      severity, constituting important caveats for planning future GAA-FGF14
      trials.
    explanation: Documents comorbid disease as a driver of apparent severity.
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      use of a wheelchair is less necessary than in other common hereditary
      spinocerebellar ataxias (e.g., SCA1, SCA2, and SCA3)
    explanation: Contrasts the milder functional trajectory with the polyglutamine SCAs.

prevalence:
- population: Patients with unsolved adult-onset cerebellar ataxia
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Not a population prevalence: this is the diagnostic yield of FGF14 repeat
    testing among previously undiagnosed adult-onset ataxia patients, reported
    as 23-31% of unsolved cases. Recorded here because the population-level
    prevalence of SCA27B has not yet been established; the corresponding
    per-cohort case fractions are curated under genetic.case_fractions.
  evidence:
  - reference: PMID:39227614
    reference_title: Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this study suggests that SCA27B is a major overlooked cause of
      adult-onset ataxia, accounting for 23-31% of unsolved patients
    explanation: >-
      Quantifies the diagnostic yield among unsolved adult-onset ataxia
      patients.
- population: Patients with idiopathic downbeat nystagmus
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Diagnostic yield rather than population prevalence: 48% of a 170-patient
    idiopathic downbeat nystagmus cohort carried an FGF14 (GAA)>=250 expansion.
  evidence:
  - reference: PMID:38507876
    reference_title: "GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients
      with idiopathic DBN.
    explanation: Quantifies the diagnostic yield in an idiopathic DBN cohort.

diagnosis:
- name: FGF14 repeat sizing by long-range PCR with long-read confirmation
  description: >-
    Molecular diagnosis rests on sizing the intron 1 (GAA) repeat, usually by
    long-range and repeat-primed PCR. Because pathogenicity depends on the
    length of the longest pure GAA tract rather than total allele size,
    long-read sequencing (Nanopore or PacBio) is needed to resolve interrupting
    motifs accurately; short-read genome data can be screened with tools such
    as ExpansionHunter and STRling using outlier approaches.
  presence: Positive
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of GAA-FGF14-related ataxia is established in a
      symptomatic individual with a compatible phenotype by the identification
      of a heterozygous (GAA)>300 repeat expansion in intron 1 of FGF14 by
      molecular genetic testing.
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:40379261
    reference_title: "FGF14 repeat length and mosaic interruptions: modifiers of spinocerebellar ataxia 27B?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      long-read sequencing is required to detect complex repeat interruptions
      accurately
    explanation: Supports the requirement for long-read confirmation.
  - reference: PMID:39227614
    reference_title: Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      we demonstrate that STRling and ExpansionHunter accurately detect FGF14
      expansions from short-read genome data using outlier approaches
    explanation: >-
      Supports short-read screening as a first-pass detection route. Evidence
      source is COMPUTATIONAL because the claim concerns performance of
      bioinformatic repeat-detection algorithms.

differential_diagnoses:
- name: CANVAS
  description: >-
    RFC1-related CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia
    syndrome) is the closest clinical mimic and the most important
    differential in practice. Both are late-onset ataxias that combine
    cerebellar signs with vestibular hypofunction and sensory/afferent
    deficits, so the two are separated by genotype rather than by phenotype:
    CANVAS is autosomal recessive, caused by a biallelic intronic (AAGGG)n
    expansion in RFC1, whereas SCA27B is autosomal dominant and caused by a
    heterozygous intronic (GAA)n expansion in FGF14. The FGF14 expansion was
    explicitly identified as an alternative genetic cause in patients with
    CANVAS-like syndromes who test negative for biallelic RFC1 expansions, so
    a negative RFC1 result in a CANVAS-like presentation should prompt FGF14
    repeat sizing rather than closing the workup.
  distinguishing_features:
  - Autosomal recessive biallelic RFC1 (AAGGG)n expansion, versus autosomal dominant heterozygous FGF14 (GAA)n expansion
  - Prominent sensory neuronopathy and chronic cough are characteristic of CANVAS but not of SCA27B
  - Episodic ataxia and a marked 4-aminopyridine response point towards SCA27B
  disease_term:
    preferred_term: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome
    term:
      id: MONDO:0044720
      label: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome
  evidence:
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      provides an alternative genetic cause in individuals with CANVAS-like
      syndromes negative for bi-allelic
    explanation: >-
      Establishes SCA27B as the alternative diagnosis to pursue in
      RFC1-negative CANVAS-like presentations, which is exactly why the two
      belong together as differentials. Quoted as an exact substring of the
      cached full text; the sentence continues "RFC1 RE", rendered without
      spacing in the cached PDF extraction.

- name: Spinocerebellar ataxia 27A
  description: >-
    SCA27A (MONDO:0008654, OMIM:609307) is caused by FGF14 coding point
    variants (classically the F145S missense) rather than the intronic repeat.
    It shares the gene and, in some families, the episodic ataxia and downbeat
    nystagmus, but presents in childhood. Distinguishing the two is essential
    because literature about one does not transfer to the other.
  distinguishing_features:
  - Coding point variant in FGF14 rather than an intronic GAA repeat expansion
  - Childhood rather than sixth-decade onset
  disease_term:
    preferred_term: Spinocerebellar ataxia 27A
    term:
      id: MONDO:0008654
      label: spinocerebellar ataxia 27A
  evidence:
  - reference: PMID:39227614
    reference_title: Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      similar to the presentation observed in a family with a previously
      unreported nonsense variant (SCA27A)
    explanation: >-
      Confirms that SCA27A is a separate, coding-variant entity whose
      presentation overlaps SCA27B.
  - reference: PMID:18930825
    reference_title: FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A missense mutation in the fibroblast growth factor 14 (FGF14) gene
      underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans.
    explanation: >-
      Documents the coding missense basis of the originally described SCA27
      (now SCA27A). Evidence source is OTHER because this is background framing
      rather than a result of the reported experiments.

treatments:
- name: 4-Aminopyridine
  description: >-
    4-Aminopyridine (4-AP), a voltage-gated potassium channel blocker, is the
    principal symptomatic therapy for SCA27B and is the mechanistically
    rational choice: it does not increase inhibitory drive onto Purkinje cells
    but restores the precision of Purkinje pacemaking by prolonging the action
    potential and increasing the afterhyperpolarization, counteracting the
    firing failure caused by FGF14 loss. Across cohorts, 75-86% of treated
    patients report clinically meaningful benefit, and placebo-controlled
    video-oculography in a small number of expansion carriers showed a
    significant reduction in downbeat nystagmus slow-phase velocity on 4-AP but
    not placebo. Formal randomised trials in genetically defined SCA27B are
    still awaited.
  therapeutic_modality: SMALL_MOLECULE
  action_category: THERAPEUTIC
  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: Downbeat nystagmus
    term:
      id: HP:0010545
      label: Downbeat nystagmus
  - preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  target_mechanisms:
  - target: Impaired Purkinje Neuron Intrinsic Excitability and Firing
    treatment_effect: RESTORES
    description: >-
      Blockade of Kv1-family potassium channels prolongs the Purkinje action
      potential and deepens the afterhyperpolarization, restoring the precision
      of pacemaking that is degraded when FGF14 loss shifts Nav steady-state
      inactivation.
    evidence:
    - reference: PMID:20505092
      reference_title: The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia.
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        4-AP restores the severely diminished precision of pacemaking in
        Purkinje cells of EA2 mutant mice by prolonging the action potential
        and increasing the action potential afterhyperpolarization
      explanation: >-
        Defines the mechanism of action of 4-AP at the Purkinje pacemaking
        node. Classified PARTIAL because the model is EA2 (a P/Q-type calcium
        channelopathy) rather than FGF14 deficiency, so this supports the
        drug-target mechanism generically rather than demonstrating it in
        FGF14-deficient neurons.
  evidence:
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A treatment response to 4-AP with relevance for everyday living was
      reported by 86% of treated patients.
    explanation: Quantifies real-world treatment response in a genetically defined cohort.
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A series of three prospective n-of-1 treatment experiences with on/off
      design showed marked reduction in daily symptomatic time and symptom
      severity on 4-AP.
    explanation: Provides prospective on/off within-patient evidence of benefit.
  - reference: PMID:38507876
    reference_title: "GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Placebo-controlled video-oculography data, available for four patients
      carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in
      slow phase velocity of DBN with 4-aminopyridine, but not placebo.
    explanation: >-
      The only placebo-controlled objective evidence to date, though in only
      four expansion carriers.
  - reference: PMID:39263992
    reference_title: Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar to European populations, a high percent of patients 21/28 (75%)
      reported a positive treatment response with 4-aminopyridine.
    explanation: Independent replication of the response rate in a US cohort.
  notes: >-
    Response rates are drawn from retrospective and open-label real-world data
    plus a very small placebo-controlled video-oculography subset; they are not
    equivalent to randomised trial efficacy. 4-AP at higher concentrations
    blocks a broad range of potassium channels and is proconvulsant.

- name: Avoidance of episode triggers
  description: >-
    Patients should be informed that alcohol intake and strenuous physical
    activity may precipitate episodes of ataxia and worsen incoordination, and
    that medications with known cerebellar or vestibular toxicity should be
    avoided.
  therapeutic_modality: BEHAVIORAL
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inform affected individuals that alcohol intake and strenuous physical
      activity may precipitate episodes of ataxia and may exacerbate
      incoordination. Avoid medications with known toxicity to the cerebellum
      and the vestibular system.
    explanation: >-
      GeneReviews "Agents/circumstances to avoid" guidance, quoted verbatim.

- name: Multidisciplinary rehabilitation
  description: >-
    There is no cure or disease-modifying therapy. Management aims to improve
    quality of life, maximise function, and reduce complications through
    multidisciplinary care including physical therapy, occupational therapy,
    and speech-language therapy.
  therapeutic_modality: BEHAVIORAL
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This ideally involves multidisciplinary care by specialists in relevant
      fields, such as neurologists, ophthalmologists, orthoptists, physical
      therapists, occupational therapists, speech-language therapists, and
      psychologists.
    explanation: GeneReviews management recommendation.

- name: Genetic counseling
  description: >-
    Counseling should cover the autosomal dominant 50% transmission risk, the
    age-dependent and incomplete penetrance of shorter expansions, and the
    intergenerational instability of the repeat (expansion on maternal, and
    contraction on paternal, transmission). Predictive and prenatal testing are
    technically possible but prognostically limited: clinical manifestations
    cannot be predicted from a fetal repeat size, and prenatal somatic
    instability is not characterised.
  therapeutic_modality: OTHER
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38271551
    reference_title: GAA-FGF14-Related Ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      accurate prediction of future possible clinical manifestations in a
      fetus found to have an FGF14 GAA repeat expansion is not possible, and
      the current lack of knowledge regarding somatic instability of the repeat
      prenatally makes the interpretation of prenatal genetic test results
      challenging
    explanation: >-
      GeneReviews statement of the counseling limitations around predictive and
      prenatal testing.

discussions:
- discussion_id: sca27b_pathogenic_threshold
  prompt: >-
    What is the true pathogenic threshold for the FGF14 intronic GAA
    expansion, and how should length and motif purity be combined into a
    single interpretive rule?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#FGF14 Intronic GAA Repeat Expansion
  rationale: >-
    Every major cohort has proposed a different cut-off. The discovery study
    supported (GAA)>=250 from family cosegregation; an independent
    Australian/German cohort concluded (GAA)>335 is fully penetrant with
    (GAA)>250 likely pathogenic at reduced penetrance; GeneReviews adopts
    (GAA)>300 for a definitive diagnosis with a 250-300 reduced-penetrance
    zone; a downbeat-nystagmus cohort found (GAA)200-249 alleles enriched
    15-fold over controls with an indistinguishable phenotype; and long-read
    work argues that once the repeat is known to be uninterrupted, enrichment
    begins at 180-200 repeats. The disagreement is not merely statistical: it
    reflects that total allele length is the wrong variable. The pathogenically
    relevant quantity appears to be the longest pure GAA tract, since
    GAAGGA/AAGGAG hexameric expansions are equally common in patients and
    controls, and mosaic interruptions that shorten the pure tract are enriched
    in unaffected carriers. No consensus interpretive rule combining these
    dimensions exists, so laboratories currently report the same allele
    differently.
  proposed_experiments:
  - experiment_id: exp_sca27b_motif_aware_threshold
    name: Motif-aware case-control threshold derivation by long-read sequencing
    description: >-
      Long-read resequencing of a large multi-ancestry case-control set,
      reporting the longest pure GAA tract rather than total allele size, to
      derive a motif-aware pathogenic threshold with calibrated penetrance
      estimates.
    decision_criterion: >-
      A motif-aware rule is preferable to a length-only rule if pure-tract
      length separates cases from controls with materially higher accuracy than
      total allele length in held-out cohorts.
  - experiment_id: exp_sca27b_carrier_penetrance_cohort
    name: Prospective penetrance follow-up of intermediate-range carriers
    description: >-
      Prospective longitudinal follow-up of asymptomatic carriers of
      200-300-repeat alleles to measure age-dependent penetrance directly
      rather than inferring it from cross-sectional case-control enrichment.
    decision_criterion: >-
      Age-stratified conversion rates would establish whether the 200-300 zone
      is genuinely reduced-penetrance pathogenic or simply a common
      non-pathogenic polymorphism enriched by ascertainment.
  - experiment_id: exp_sca27b_somatic_mosaicism_tissue
    name: Cerebellum-versus-blood somatic repeat mosaicism
    description: >-
      Systematic assay of somatic repeat mosaicism in cerebellum versus blood
      from the same individuals, since a blood-derived repeat size may not
      represent the size present in the pathogenically relevant tissue.
    decision_criterion: >-
      Substantial cerebellum-specific somatic expansion would explain why
      blood-based thresholds disagree across cohorts and would argue for
      tissue-adjusted interpretation.
  evidence:
  - reference: PMID:36493768
    reference_title: An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      while (GAA)>250 is likely pathogenic with reduced penetrance
    explanation: One of the several competing threshold definitions in the literature.
  - reference: PMID:38507876
    reference_title: "GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It provides preliminary evidence that (GAA)200-249 alleles might be
      pathogenic.
    explanation: >-
      Extends candidate pathogenicity below the previously accepted cut-off,
      widening rather than resolving the uncertainty.
  - reference: PMID:39227614
    reference_title: Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We strongly recommend re-evaluating pathogenic thresholds and
      integrating expansion sequencing into the molecular diagnostic process.
    explanation: >-
      The authors themselves call the current thresholds into question and ask
      for motif-aware reinterpretation.
  - reference: PMID:40379261
    reference_title: "FGF14 repeat length and mosaic interruptions: modifiers of spinocerebellar ataxia 27B?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five ataxia patients with interruptions still had a remaining pure GAA
      expansion <200.
    explanation: >-
      Shows that even a motif-purity-corrected rule does not cleanly separate
      patients from unaffected carriers, so the gap remains open.

- discussion_id: sca27b_intronic_repeat_to_expression_route
  prompt: >-
    By what molecular route does the intronic GAA expansion reduce FGF14
    expression - transcriptional elongation blockade, R-loop formation,
    repressive chromatin, or another mechanism?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#FGF14 Intronic GAA Repeat Expansion
  - pathophysiology#Reduced FGF14 Expression in Cerebellar Neurons
  rationale: >-
    Reduced FGF14 RNA and protein have been demonstrated in patient postmortem
    cerebellum and patient-derived neurons, and the pathogenic tract is a GAA
    repeat in the first intron - the same sequence and genomic context as the
    FXN intron 1 expansion in Friedreich ataxia, where heterochromatin
    formation and transcriptional silencing are established. Whether SCA27B
    uses the same machinery, however, has not been shown. Until it is, the
    causal edge from expansion to reduced expression carries unknown
    intermediates, and a whole class of candidate therapeutic strategies
    (transcriptional de-repression, HDAC inhibition, R-loop modulation) cannot
    be rationally prioritised.
  proposed_experiments:
  - experiment_id: exp_sca27b_fgf14_locus_chromatin
    name: Chromatin and methylation profiling of the FGF14 locus
    description: >-
      Chromatin state and DNA methylation profiling across the FGF14 locus in
      expansion-carrier versus control cerebellum and in iPSC-derived
      Purkinje-like neurons.
    decision_criterion: >-
      Repressive chromatin marks or hypermethylation spreading from the repeat
      in carriers would implicate the Friedreich-ataxia-like silencing
      mechanism.
  - experiment_id: exp_sca27b_nascent_transcription
    name: Nascent-transcription analysis for elongation stalling at the repeat
    description: >-
      PRO-seq or TT-seq analysis of expansion-carrier versus control neurons to
      test whether RNA polymerase II stalls within FGF14 intron 1 at the GAA
      tract.
    decision_criterion: >-
      A carrier-specific drop in nascent transcription immediately downstream
      of the repeat would establish elongation blockade as the route.
  - experiment_id: exp_sca27b_rloop_drip
    name: R-loop mapping at the FGF14 intron 1 tract
    description: >-
      DRIP-seq for R-loop accumulation at the FGF14 intron 1 GAA tract in
      carrier versus control cells.
    decision_criterion: >-
      Carrier-specific R-loop enrichment at the repeat would implicate
      co-transcriptional R-loop formation and nominate R-loop-directed
      therapeutics.
  - experiment_id: exp_sca27b_derepression_rescue
    name: Test of transcriptional de-repression agents on FGF14 expression
    description: >-
      Test whether transcriptional de-repression agents with efficacy in
      Friedreich ataxia models (for example HDAC inhibitors) restore FGF14 RNA
      and protein in patient-derived neurons.
    decision_criterion: >-
      Restoration of FGF14 expression would both confirm a silencing mechanism
      and identify a repurposable therapeutic class.
  evidence:
  - reference: PMID:36516086
    reference_title: Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postmortem cerebellum specimens and iPSC-derived motor neurons from
      patients showed reduced expression of FGF14 RNA and protein.
    explanation: >-
      Establishes the endpoint (reduced expression) without establishing the
      route, which is precisely the gap.

- discussion_id: sca27b_firing_failure_versus_cell_loss
  prompt: >-
    Is the clinical deficit in SCA27B driven primarily by reversible Purkinje
    firing failure or by irreversible Purkinje neuron loss, and does that
    balance shift over the disease course?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Purkinje Neuron Intrinsic Excitability and Firing
  - pathophysiology#Purkinje Neuron Degeneration and Cerebellar Atrophy
  rationale: >-
    Several observations point towards a functional rather than degenerative
    dominant mechanism: the striking episodic phase, the rapid and substantial
    response to 4-aminopyridine, the mild SARA progression rate with a plateau
    at moderate severity, and serum neurofilament light that is not elevated
    relative to controls. Against that, autopsy in genetically confirmed cases
    shows definite Purkinje neuron loss. If the deficit is largely a reversible
    channel-availability problem for much of the disease course, that has
    direct consequences for trial endpoint choice (symptomatic versus
    disease-modifying), for the therapeutic window, and for whether restoring
    FGF14 expression late in disease could help.
  proposed_experiments:
  - experiment_id: exp_sca27b_longitudinal_nfl_volumetry
    name: Longitudinal neurofilament light and cerebellar volumetry
    description: >-
      Longitudinal serum and CSF neurofilament light measurement plus
      cerebellar volumetry in a genetically defined SCA27B cohort, testing
      whether a degenerative signal emerges at a definable disease stage.
    decision_criterion: >-
      A stage-dependent rise in neurofilament light with accelerating volume
      loss would mark the transition from functional to degenerative
      pathophysiology and define the therapeutic window.
  - experiment_id: exp_sca27b_purkinje_counts_duration
    name: Quantitative Purkinje cell counts stratified by disease duration
    description: >-
      Quantitative Purkinje cell counts correlated with disease duration across
      a larger SCA27B autopsy series than the four brains reported to date.
    decision_criterion: >-
      Substantial Purkinje loss in short-duration cases would favour early
      degeneration; preserved counts in short-duration cases would favour a
      primarily functional early phase.
  - experiment_id: exp_sca27b_ipsc_purkinje_rescue
    name: Rescue electrophysiology in patient-derived Purkinje-like neurons
    description: >-
      Electrophysiological characterisation of iPSC-derived Purkinje-like
      neurons from expansion carriers, testing whether restoring FGF14
      expression or applying 4-aminopyridine rescues firing independently of
      any effect on survival.
    decision_criterion: >-
      Full firing rescue without a survival effect would establish the deficit
      as functional and reversible at the cellular level.
  evidence:
  - reference: PMID:37165652
    reference_title: "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corresponding to slow progression and low extra-cerebellar involvement,
      sNfL was not increased relative to controls.
    explanation: >-
      Absence of a neuroaxonal damage biomarker signal argues for a largely
      functional deficit.
  - reference: PMID:39263992
    reference_title: Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The principal finding on post-mortem examination of 4 brain specimens
      was loss of Purkinje neurons that was most severe in the vermis most
      particularly in the anterior vermis.
    explanation: >-
      Establishes that genuine neuron loss does occur, counterbalancing the
      purely functional interpretation; PARTIAL because four brains without
      quantitative counts or duration stratification cannot settle the balance.

references:
- reference: PMID:38271551
  title: GAA-FGF14-Related Ataxia.
  tags:
  - GeneReviews

notes: >-
  Module conformance: four pathophysiology nodes declare conformance to
  cerebellar_purkinje_degeneration (Cerebellar Neuron Insult, Purkinje Neuron
  Degeneration, Loss of Cerebellar Cortical Output, Cerebellar Ataxia). The
  module's "Purkinje Cell Calcium and Proteostasis Dysregulation" amplifier node
  is deliberately NOT claimed: SCA27B's amplifying lesion is sodium-channel
  gating and intrinsic excitability failure, not calcium dysregulation or
  proteotoxicity, so the entry substitutes its own "Impaired Purkinje Neuron
  Intrinsic Excitability and Firing" node at that position in the chain.

  Nomenclature: the same disease appears in the literature as SCA27B,
  GAA-FGF14 ataxia/disease, SCA50, and ATX-FGF14. The SCA50 designation was
  assigned independently by the Australian discovery group before the entities
  were recognised as identical. This entry is scoped strictly to the intronic
  repeat-expansion disease (MONDO:0859340, OMIM:620174) and excludes SCA27A
  (MONDO:0008654, OMIM:609307), the childhood-onset FGF14 coding-variant
  disorder.

  Repeat orientation: reports differ in whether the tract is written as (GAA)n
  or (AAG)n depending on the strand and register used; these refer to the same
  repeat. Snippets in this entry preserve whichever form the source used.

  Deliberately omitted: prevalence is
  recorded as diagnostic yield with measure_type UNKNOWN rather than a
  population rate, because no population-based prevalence estimate for SCA27B
  has been published. Age at onset is captured as an OnsetDescriptor on the
  gait-ataxia phenotype and in the progression phases rather than as a separate
  HP:0003584 phenotype, since onset modifiers are not members of the
  PhenotypeTerm enum. Snippets avoid square-bracketed source text (e.g. the
  "[0.29 SARA points/year]" interval), which the reference validator strips
  before substring matching.

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References & Deep Research

References

1

PMID:38271551

GAA-FGF14-Related Ataxia.

No top-level findings curated for this source.

Spinocerebellar ataxia 27B

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References