Autosomal Recessive Ataxia Beauce Type
Autosomal recessive ataxia, Beauce type (autosomal recessive cerebellar ataxia type 1, ARCA1; SCAR8; recessive ataxia of Beauce; ATX-SYNE1) is a SYNE1-related hereditary cerebellar ataxia originally described in French-Canadian families from the Beauce region of Quebec. The classic founder phenotype is a relatively pure, slowly progressive, adult-onset cerebellar syndrome (gait and limb ataxia, cerebellar dysarthria, dysmetria, ocular motor abnormalities) with diffuse cerebellar atrophy on imaging and no peripheral neuropathy, evolving to moderate disability without effect on life expectancy. SYNE1 deficiency, however, spans a broader "cerebellar-plus" spectrum, with some patients showing upper and/or lower motor neuron dysfunction, cognitive/affective involvement, and (at the severe end) childhood-onset multisystem disease or arthrogryposis multiplex congenita. The causal mechanism is biallelic loss-of-function SYNE1 variants affecting nesprin-1, a nuclear-envelope spectrin-repeat protein of the LINC (linker of nucleoskeleton and cytoskeleton) complex, with consequent disruption of nuclear-cytoskeletal coupling in cerebellar neurons.
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Inheritance
1
Autosomal recessive inheritance
HP:0000007
ARCA1/SYNE1 deficiency is caused by biallelic pathogenic SYNE1 variants and follows autosomal recessive inheritance.
Show evidence (1 reference)
"SYNE1 deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes"
GeneReviews establishes autosomal recessive inheritance with carrier parents.
Subtypes
3
SYNE1-deficient cerebellar ataxia (ARCA1 / Beauce type)
The mild end and by far the most commonly recognised presentation: a slowly progressive, relatively pure cerebellar syndrome beginning in adulthood. This is the phenotype originally delineated in the French-Canadian Beauce founder families and the one MONDO:0012549 is named for. Phenotypes curated without a subtype qualifier belong to this presentation or to the SYNE1 deficiency spectrum generally.
Show evidence (1 reference)
"SYNE1-deficient cerebellar ataxia, the most commonly recognized manifestation of SYNE1 deficiency to date, is a slowly progressive disorder typically beginning in adulthood (age range 6-45 years)."
GeneReviews defines the cerebellar-ataxia presentation as the most common manifestation.
SYNE1-deficient childhood-onset multisystem disease
A less common presentation combining ataxia with upper and lower motor neuron dysfunction, muscle weakness and wasting, and intellectual disability, with onset in childhood rather than adulthood.
Show evidence (1 reference)
"The two less common phenotypes are SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability)"
GeneReviews defines the childhood-onset multisystem presentation and its component features.
SYNE1-deficient arthrogryposis multiplex congenita
The severe end of the spectrum, presenting prenatally and neonatally with decreased fetal movements, severe hypotonia, and multiple congenital joint contractures including clubfoot. Mechanistically part of SYNE1 deficiency but clinically remote from the adult-onset Beauce ataxia.
Show evidence (1 reference)
"SYNE1-deficient arthrogryposis multiplex congenita (decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot)"
GeneReviews defines the arthrogryposis presentation at the severe end of the spectrum.
Mechanistic Hypotheses
2Canonical SYNE1/Nesprin-1 Loss-of-Function LINC Model
Evidence balance
1 support
The best-supported model is biallelic SYNE1 loss of function producing absent or truncated nesprin-1, impairing the LINC complex that couples the nucleus to the cytoskeleton. Because most disease-associated SYNE1 alleles are truncating, a loss-of-function mechanism is favored, with cerebellar neurons (particularly Purkinje cells) being especially vulnerable, leading to cerebellar degeneration.
Show evidence (1 reference)
"The function of SYNE1 is thus critical in the maintenance of cerebellar structure in humans."
The original ARCA1 study links SYNE1 to maintenance of cerebellar structure, supporting loss-of-function cerebellar degeneration.
Cerebellar Synaptic Nesprin-1 Isoform Model
Evidence balance
3 support
A cerebellum-enriched nesprin-1 isoform lacking the KASH domain localizes to synapses rather than the nuclear envelope, suggesting a synaptic, LINC-complex- independent contribution to cerebellar vulnerability. This extends rather than replaces the canonical nuclear-envelope loss-of-function model and remains to be causally established.
Classified as emerging because the synaptic-isoform mechanism rests on expression, splicing, and subcellular-localization data in mouse cerebellum rather than direct causal demonstration in SCAR8 patients. Note that this model relocates the primary lesion away from the Purkinje nuclear envelope and toward mossy-fibre/granule-cell synaptic compartments; the two models make different predictions about which cerebellar cell population is the proximal target.
Show evidence (3 references)
"We also identified a CNS-specific splicing event that leads to the abundant expression of a KASH-LESS variant of Nesprin1 giant (KLNes1g) in the cerebellum."
Identifies the cerebellum-enriched KASH-less nesprin-1 isoform that this hypothesis is built on. Evidence source is MODEL_ORGANISM because the splicing, localization, and immunoprecipitation data are from mouse cerebellum.
"KLNes1g displayed a noncanonical localization at glomeruli of cerebellar mossy fibers whereas Nesprin2 exclusively decorated the nuclear envelope of all cerebellar neurons."
Shows the isoform localizes to synaptic rather than nuclear-envelope compartments, which is the specific claim distinguishing this model from the canonical LINC model.
"mutations in genes associated with the LINC complex have been implicated in several neurological diseases, including neurodegenerative and psychiatric disorders"
This review links LINC-complex gene mutations to neurological disease, supporting nesprin-1/LINC biology as the mechanistic context for SYNE1 ataxia.
Discussions and Knowledge Gaps
1Which cerebellar cell population is the proximal target of SYNE1 loss — the Purkinje cell nuclear envelope, as the canonical LINC model and this entry's pathograph assume, or the mossy-fibre/granule-cell synaptic compartment where the cerebellum-enriched KASH-less nesprin-1 isoform actually localizes?
Attached to
This entry asserts Purkinje-cell vulnerability in its pathograph and declares conformance to cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration, which is the mainstream reading of GeneReviews and of Dupre's statement that SYNE1 is critical to the maintenance of cerebellar structure. Neither of those sources actually demonstrates Purkinje neuron loss. The direct localization work points the other way: the abundant cerebellar isoform, KLNes1g, is KASH-less, sits at mossy-fibre glomeruli and granule-cell dendritic membranes rather than the nuclear envelope, and it is Nesprin2 - not Nesprin1 - that decorates the nuclear envelope of cerebellar neurons. If that is the operative lesion, the cell-type annotations and the module conformance on the degeneration node are describing the wrong compartment, and the canonical LINC framing is downstream of, or parallel to, the real mechanism rather than upstream of it.
Proposed experiments
Neuropathological series quantifying Purkinje versus granule cell loss
exp_syne1_purkinje_vs_granule_neuropathology
Assemble a systematic autopsy series of genetically confirmed SYNE1 ataxia and quantify Purkinje versus granule cell loss and mossy-fibre glomerular pathology against age-matched controls. Human neuropathology currently rests on isolated case reports, so the entry's Purkinje-centric cell-type annotation is not presently testable against a series.
Supporting outcome
- Selective Purkinje neuron loss out of proportion to granule cell loss.
Refuting outcome
- Granule cell or mossy-fibre pathology predominating with relatively preserved Purkinje populations.
Cell-type-specific Syne1 ablation in mouse
exp_syne1_celltype_specific_ablation
Ablate Syne1 selectively in Purkinje cells versus granule cells in mouse and compare ataxia severity and cerebellar histology, to establish which population is sufficient to produce the phenotype.
Supporting outcome
- Purkinje-restricted ablation reproducing ataxia.
Refuting outcome
- Only granule-cell-restricted ablation reproducing ataxia.
KASH-less nesprin-1 isoform expression in human cerebellum
exp_klnes1g_human_cerebellum_localization
Determine whether the KASH-less nesprin-1 isoform is expressed and similarly localized in human cerebellum. The existing splicing and immunogold localization data are from mouse, so the translational validity of the synaptic model to human disease is untested.
Supporting outcome
- Detection of the KASH-less isoform at human mossy-fibre glomeruli.
Refuting outcome
- Absence of the isoform, or exclusively nuclear-envelope localization, in human cerebellum.
Recorded during the 2026-08 publication-readiness review. The conformance and the Purkinje cell_types annotations are deliberately retained as the mainstream model rather than removed, but they should not be read as evidence-backed claims about the proximal cellular target. PMID:36525394 (an autopsied SYNE1-ataxia patient) is listed under references as a bibliographic pointer only and is deliberately not cited as evidence anywhere in this entry: PubMed carries no abstract for that letter, so no snippet can be verified against a cached source. Mine it for evidence if full text ever reaches the cache.
Pathophysiology
3SYNE1/Nesprin-1 Loss of Function
ARCA1 is caused by biallelic SYNE1 variants, most commonly truncating loss-of- function alleles, that reduce or abolish nesprin-1. This establishes the primary molecular lesion. SYNE1 is among the largest human genes, and the spectrum of pathogenic variants includes nonsense, frameshift, splice, missense, and even large intragenic deletions detectable only by CNV-sensitive methods.
Downstream
Reduced or absent nesprin-1 impairs assembly and function of the LINC complex at the nuclear envelope.
Intellectual disability in the childhood-onset multisystem presentation. Wired from the primary genetic lesion rather than from cerebellar degeneration because that presentation is not the cerebellar syndrome this pathograph otherwise models.
Muscle weakness and wasting in the childhood-onset multisystem presentation.
Decreased fetal movements in the arthrogryposis presentation. The intermediates between nesprin-1 loss and reduced fetal movement are not established.
Severe neonatal hypotonia in the arthrogryposis presentation.
Multiple congenital joint contractures at the severe end of the SYNE1 deficiency spectrum.
Clubfoot among the congenital contractures of the arthrogryposis presentation.
Scoliosis as a non-neurological feature of the extracerebellar SYNE1 phenotype. Attributed to the primary lesion because no cerebellar mechanism accounts for it.
Pes cavus as a non-neurological feature of the extracerebellar SYNE1 phenotype.
Respiratory dysfunction in severely affected non-founder patients.
Strabismus is reported in SYNE1 ataxia but is not a cerebellar sign, so it is attributed to the primary lesion rather than routed through cerebellar degeneration.
Show evidence (2 references)
"We identified a cluster of French-Canadian families with a new recessive ataxia of relatively pure cerebellar type caused by mutations in SYNE1."
Establishes SYNE1 as the causal gene for ARCA1.
"compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function"
Demonstrates loss-of-function SYNE1 alleles, including a structural deletion, as a cause of ARCA1.
Disrupted Nuclear-Cytoskeletal LINC Coupling
Nesprin-1 participates in the LINC complex spanning the nuclear envelope (SUN-KASH bridging), physically connecting the cytoskeleton to nuclear components and mediating nuclear positioning, cell migration, and mechanotransduction. Loss of nesprin-1 disrupts this coupling. The LINC complex is essential to nervous-system development, and LINC-gene mutations are implicated in neurodegenerative disease.
Downstream
Disrupted nuclear-cytoskeletal coupling in cerebellar neurons leads to cerebellar degeneration manifesting as diffuse cerebellar atrophy.
The broader SYNE1 deficiency spectrum includes upper motor neuron signs beyond the pure cerebellar phenotype.
Cerebellar-plus SYNE1 deficiency can include lower motor neuron involvement outside the classic pure cerebellar presentation.
Spasticity as a component sign of the upper motor neuron arm.
Hyperreflexia as a component sign of the upper motor neuron arm.
Brisk lower-extremity reflexes, the upper motor neuron sign actually observed in the otherwise pure-cerebellar Beauce founder cohort.
Extensor plantar response as a component sign of the upper motor neuron arm.
Amyotrophy as a component sign of the lower motor neuron arm.
Reduced deep tendon reflexes as a component sign of the lower motor neuron arm.
Fasciculations as a component sign of the lower motor neuron arm.
Show evidence (1 reference)
"The linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the nuclear envelope, physically connects nuclear components to the cytoskeleton and plays a pivotal role in various cellular processes, including nuclear positioning, cell migration, and chromosomal configuration."
Describes the LINC-complex function disrupted by nesprin-1/SYNE1 loss.
Cerebellar Neurodegeneration and Atrophy
Cerebellar neuronal vulnerability, supported by the strong cerebellar expression of SYNE1, produces diffuse cerebellar atrophy without cortical, brainstem, or white-matter involvement in the classic founder phenotype, and underlies the progressive cerebellar ataxia, dysarthria, and dysmetria.
Downstream
Diffuse cerebellar atrophy is the imaging correlate of the cerebellar neurodegenerative process.
Cerebellar degeneration produces the progressive cerebellar ataxia syndrome.
Cerebellar degeneration manifests clinically as gait ataxia.
Cerebellar degeneration impairs appendicular coordination, producing limb ataxia.
Cerebellar degeneration causes the dysarthria component of the syndrome.
Cerebellar degeneration causes dysmetria as part of the pure cerebellar syndrome.
Cerebellar degeneration affects ocular motor control, including smooth pursuit.
Cerebellar ocular motor involvement includes slow saccadic eye movements.
Cerebellar ocular motor involvement includes gaze-evoked nystagmus.
Cerebellar involvement can extend to cerebellar cognitive and affective syndrome.
Attentional deficit as a specific domain of the cerebellar cognitive and affective syndrome.
Square-wave jerks as part of the cerebellar ocular motor disturbance.
Broken-up (saccadic) smooth pursuit as part of the cerebellar ocular motor disturbance.
Swallowing difficulty accompanying the bulbar/cerebellar motor speech disturbance, flagged by GeneReviews for ongoing surveillance.
Show evidence (1 reference)
"slow progression and moderate disability, significant dysarthria, mild oculomotor abnormalities, occasional brisk reflexes in the lower extremities, normal nerve conduction studies, and diffuse cerebellar atrophy on imaging"
Documents diffuse cerebellar atrophy as the structural correlate of the cerebellar syndrome.
Pathograph
Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Phenotypes
33Digestive 1
Dysphagia
HP:0002015
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"dysarthria, dysphagia, cognition, and psychiatric manifestations"
GeneReviews lists dysphagia among the manifestations to be assessed at surveillance visits, implying it occurs in the disorder. This is an indirect assertion; no cited source reports its frequency.
Eye 2
Nystagmus
HP:0000639
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
Review of published SYNE1 ataxia patients documents gaze-evoked nystagmus among the reported oculomotor findings.
Strabismus
HP:0000486
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
A review of previously published SYNE1 ataxia patients lists strabismus among the reported ocular findings. Summary of prior literature.
Limbs 2
Pes cavus
HP:0001761
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
Describes the non-Canadian SYNE1 ataxia cohort, in which most patients had extracerebellar signs including pes cavus.
Talipes equinovarus
HP:0001762
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Clubfoot, annotated with Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"multiple congenital joint contractures including clubfoot"
GeneReviews names clubfoot among the congenital contractures of the arthrogryposis phenotype.
Musculoskeletal 5
Spasticity
HP:0001257
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
GeneReviews names spasticity as a component of the upper motor neuron arm. No frequency band is asserted: the source quantifies the upper motor neuron arm as a whole ("many"), not each component sign.
Skeletal muscle atrophy
HP:0003202
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Amyotrophy, annotated with Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
GeneReviews names amyotrophy as a component of the lower motor neuron arm. No frequency band is asserted for the individual sign.
Scoliosis
HP:0002650
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
Describes the non-Canadian SYNE1 ataxia cohort, in which most patients had extracerebellar signs including scoliosis.
Muscle weakness
HP:0001324
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Muscle weakness and wasting, annotated with Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability)"
GeneReviews scopes muscle weakness and wasting to the childhood-onset multisystem phenotype.
Neonatal hypotonia
HP:0001319
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Severe neonatal hypotonia, annotated with Neonatal hypotonia (HP:0001319), qualified as severity severe. HP:0001319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot"
GeneReviews scopes severe neonatal hypotonia to the arthrogryposis multiplex congenita phenotype.
Nervous System 8
Cerebellar ataxia
HP:0001251
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Cerebellar ataxia, annotated with Ataxia (HP:0001251), qualified as course progressive. HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"ARCA-1 is a cerebellar syndrome characterized by recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability"
Establishes progressive cerebellar ataxia as the core syndrome.
Gait ataxia
HP:0002066
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Gait ataxia (HP:0002066). HP:0002066 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"SYNE1 ataxia is an autosomal recessive hereditary condition, the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria."
Confirms gait ataxia as a core characteristic feature.
Dysarthria
VERY_FREQUENT
HP:0001260
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Cerebellar dysarthria, annotated with Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"ARCA-1 is a cerebellar syndrome characterized by recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability, significant dysarthria"
Dupre 2007 defines the syndrome as "characterized by ... significant dysarthria". No cited source reports a dysarthria numerator/denominator, so the VERY_FREQUENT band rests on the qualitative mapping in docs/frequency-evidence-guidelines.md, under which a feature named as characterizing the syndrome maps to VERY_FREQUENT (80-99%). Downgrade or remove the band if a quantitative cohort figure becomes available.
Cerebellar atrophy
HP:0001272
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"normal nerve conduction studies, and diffuse cerebellar atrophy on imaging"
Documents diffuse cerebellar atrophy on imaging.
Cognitive impairment
HP:0100543
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Most individuals develop features of the cerebellar cognitive and affective syndrome (i.e., significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills)."
GeneReviews documents the cerebellar cognitive and affective syndrome in most patients.
Hyperreflexia
HP:0001347
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
GeneReviews names hyperreflexia as a component of the upper motor neuron arm. No frequency band is asserted for the individual sign.
Fasciculations
HP:0002380
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Fasciculations (HP:0002380). HP:0002380 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
GeneReviews names fasciculations as a component of the lower motor neuron arm. No frequency band is asserted for the individual sign.
Intellectual disability
HP:0001249
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability)"
GeneReviews scopes intellectual disability to the childhood-onset multisystem phenotype, which is why this entry carries a subtype qualifier rather than being asserted of the disease as a whole.
Other 15
Limb ataxia
HP:0002070
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Limb ataxia (HP:0002070). HP:0002070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria"
Confirms limb ataxia as a characteristic feature.
Dysmetria
HP:0001310
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Dysmetria (HP:0001310). HP:0001310 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"some individuals have a pure cerebellar syndrome (i.e., cerebellar ataxia, dysarthria, dysmetria, abnormalities in ocular saccades and smooth pursuit)"
GeneReviews lists dysmetria as part of the pure cerebellar syndrome.
Abnormal ocular smooth pursuit
Impaired smooth pursuit
HP:0007772
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Impaired smooth pursuit (HP:0007772). HP:0007772 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"abnormalities in ocular saccades and smooth pursuit"
GeneReviews documents abnormal ocular saccades and smooth pursuit.
Slow saccades
Slow saccadic eye movements
HP:0000514
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Slow saccadic eye movements (HP:0000514). HP:0000514 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"The eye tracking assessment revealed hypometric saccades in the longer amplitude (18.4°) saccadic paradigm in all SYNE1 patients, whereas 2 out of 3 SYNE1 subjects performed slow saccades as well."
Eye-tracking study documents slow and hypometric saccades in SYNE1 ataxia patients.
Upper motor neuron dysfunction
FREQUENT
HP:0002493
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Upper motor neuron dysfunction (HP:0002493). HP:0002493 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign) and/or lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
GeneReviews reports that "many" SYNE1-deficient individuals have upper motor neuron dysfunction. Per the qualitative mapping in docs/frequency-evidence-guidelines.md this maps to FREQUENT (30-79%); no cited source gives a numerator/denominator for this arm.
Lower motor neuron involvement (cerebellar-plus)
Abnormal lower motor neuron morphology
HP:0002366
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Lower motor neuron dysfunction, annotated with Abnormal lower motor neuron morphology (HP:0002366). HP:0002366 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"four patients exhibited non-cerebellar phenotypes, including motor neuron symptoms, cognitive impairment, or mental retardation"
The Chinese cohort documents motor neuron involvement as part of the cerebellar-plus phenotype.
Short attention span
HP:0000736
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Deficits in attention, annotated with Short attention span (HP:0000736). HP:0000736 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills"
GeneReviews names attention as one of the specific domains impaired in the cerebellar cognitive and affective syndrome. Curated separately from the broader Cognitive impairment entry so the specific HPO term is available.
Lower limb hyperreflexia
OCCASIONAL
HP:0002395
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Brisk lower extremity reflexes, annotated with Lower limb hyperreflexia (HP:0002395). HP:0002395 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"occasional brisk reflexes in the lower extremities"
Dupre 2007 reports brisk lower-extremity reflexes in the founder cohort. The author term "occasional" maps to OCCASIONAL (5-29%) under the qualitative mapping in docs/frequency-evidence-guidelines.md.
Babinski sign
HP:0003487
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Babinski sign (HP:0003487). HP:0003487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
GeneReviews names the Babinski sign as a component of the upper motor neuron arm. No frequency band is asserted for the individual sign.
Reduced tendon reflexes
HP:0001315
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Reduced tendon reflexes (HP:0001315). HP:0001315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
GeneReviews names reduced reflexes as a component of the lower motor neuron arm. No frequency band is asserted for the individual sign.
Square-wave jerks
HP:0025402
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Square-wave jerks (HP:0025402). HP:0025402 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
A review of 168 previously published SYNE1 ataxia patients lists square-wave jerks among the reported oculomotor findings. The sentence is a summary of prior literature, not a new observation in this cohort.
Jerky ocular pursuit movements
HP:0008003
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Broken up smooth pursuit, annotated with Jerky ocular pursuit movements (HP:0008003). HP:0008003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
Adds the specific HPO term for broken-up smooth pursuit alongside the broader Abnormal ocular smooth pursuit entry. Summary of prior literature.
Respiratory dysfunction
Abnormality of the respiratory system
HP:0002086
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Respiratory dysfunction, annotated with Abnormality of the respiratory system (HP:0002086). HP:0002086 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
Reports respiratory dysfunction as a severe-end extracerebellar manifestation. The HPO term is deliberately broad because the source does not specify the respiratory abnormality.
Decreased fetal movement
HP:0001558
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Decreased fetal movement (HP:0001558). HP:0001558 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"SYNE1-deficient arthrogryposis multiplex congenita (decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot)"
GeneReviews scopes decreased fetal movements to the arthrogryposis multiplex congenita phenotype at the severe end of the spectrum.
Arthrogryposis multiplex congenita
HP:0002804
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"SYNE1 deficiency comprises a phenotypic spectrum that ranges from autosomal recessive cerebellar ataxia at the mild end to arthrogryposis multiplex congenita (AMC) at the severe end."
GeneReviews places arthrogryposis multiplex congenita at the severe end of the SYNE1 deficiency spectrum, anchoring the AMC subtype.
Genetic Associations
1
Biallelic SYNE1 pathogenic variants
Show evidence (2 references)
"The diagnosis of SYNE1 deficiency is established in a proband with suggestive findings and biallelic SYNE1 pathogenic variants identified by molecular genetic testing."
GeneReviews defines the molecular diagnostic basis as biallelic SYNE1 variants.
"We identified eight truncating variants and two missense variants spreading throughout the SYNE1 gene from six unrelated families"
Documents the predominance of truncating SYNE1 variants distributed across the gene.
Medical Actions
4
Supportive and Rehabilitative Care
There is no specific or disease-modifying treatment for SYNE1 deficiency. Management is supportive, aiming to maximize function and reduce complications through a multidisciplinary team (neurology, physical/occupational/speech therapy, physiatry, orthopedics, nutrition).
Show evidence (1 reference)
"There is no specific treatment for SYNE1 deficiency. The goals of treatment are to maximize function and reduce complications."
GeneReviews states management is supportive with no specific therapy.
Physical Therapy
Rehabilitation to maintain mobility and address ataxia, spasticity, and weakness.
Show evidence (1 reference)
"managed by a multidisciplinary team of relevant specialists including neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists"
GeneReviews recommends physical therapy within multidisciplinary management.
Speech Therapy
Speech therapy for cerebellar dysarthria and, when present, dysphagia.
Show evidence (1 reference)
"neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists"
GeneReviews includes speech therapy within multidisciplinary management.
Genetic Counseling
Genetic counseling is indicated given autosomal recessive inheritance; carrier testing, prenatal diagnosis, and preimplantation genetic testing are available once familial variants are known. Relevant in founder populations.
Show evidence (1 reference)
"carrier testing for at-risk relatives, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic testing are possible"
GeneReviews supports genetic counseling and reproductive testing options.
Diagnosis
2
Brain MRI
Brain MRI demonstrating diffuse cerebellar atrophy supports the diagnosis; normal nerve conduction studies help distinguish ARCA1 from ataxias with prominent peripheral neuropathy.
Show evidence (1 reference)
"normal nerve conduction studies, and diffuse cerebellar atrophy on imaging"
Imaging shows diffuse cerebellar atrophy with normal nerve conduction.
Molecular genetic testing (NGS with CNV analysis)
Next-generation sequencing (gene panel, exome, or genome) detects most SYNE1 variants, but CNV-sensitive methods (e.g., array-CGH) are needed to detect large intragenic deletions that standard sequencing pipelines may miss. Diagnostic workup for adult-onset hereditary ataxia combines STR-expansion testing with sequencing.
Show evidence (2 references)
"even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency"
Highlights the need for CNV-sensitive testing in suspected SYNE1 deficiency.
"Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole..."
Describes the contemporary diagnostic approach for adult-onset hereditary ataxia.
Progression
2Adult-onset cerebellar syndrome
Classic Beauce phenotype begins with gait and limb ataxia in early-to-mid adulthood, with dysarthria following. Non-founder cohorts can show earlier (childhood/young-adult) onset.
Show evidence (1 reference)
"SYNE1-deficient cerebellar ataxia, the most commonly recognized manifestation of SYNE1 deficiency to date, is a slowly progressive disorder typically beginning in adulthood (age range 6-45 years)."
GeneReviews documents typical adult onset across a wide age range.
Slowly progressive course
The founder phenotype progresses slowly to moderate disability with no effect on life expectancy; cerebellar-plus forms can carry additional morbidity from motor neuron and multisystem involvement.
Show evidence (1 reference)
"recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability"
Documents slow progression to moderate disability.
Prevalence
1Eastern Quebec adults
In an Eastern Quebec cross-sectional study, ARCA1 (AR cerebellar ataxia type 1) was the most prevalent hereditary ataxia identified, at a minimum prevalence of 2.67/100,000 [95% CI 2.65-2.7], within an overall adult hereditary ataxia prevalence of 6.47/100,000. This is a founder-population figure and a *minimum* (genetically confirmed cases only); it should not be read as a worldwide prevalence for this disorder, and no worldwide estimate is currently curated.
Show evidence (1 reference)
"AR cerebellar ataxia type 1 (2.67/100 000) and AD spastic paraplegia SPG4 (1.18/100 000) were the most prevalent disorders identified."
Provides a population-based minimum prevalence estimate for ARCA1.
Differential Diagnoses
3Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Ataxia Beauce Type:
Overlapping Features
The most important differential in the population where ARCA1 was defined: a second recessive ataxia with a Quebec founder effect, present in the same Eastern Quebec ataxia clinics. Both are recessive, both are cerebellar, and both are enriched in the same ancestry, so ancestry alone does not discriminate them.
Distinguishing Features
- Caused by biallelic SACS variants (sacsin), not SYNE1.
- Prominent spasticity and peripheral neuropathy, whereas ARCA1 has normal nerve conduction studies and is relatively pure cerebellar.
- Roughly six-fold rarer than ARCA1 in the same Eastern Quebec population (0.43 vs 2.67 per 100,000).
Show evidence (1 reference)
"Pathogenic mutations in SACS were found in seven non-related patients"
Establishes that SACS-related ARSACS co-occurs with ARCA1 in the same Eastern Quebec cohort, making it the co-located differential.
Overlapping Features
The commonest recessive ataxia overall and the comparator against which SYNE1 oculomotor findings have been benchmarked.
Distinguishing Features
- Caused by a GAA repeat expansion in FXN, detected by repeat-expansion testing rather than sequencing.
- Sensory axonal neuropathy with absent reflexes; ARCA1 has normal nerve conduction studies.
- Cardiomyopathy and diabetes are part of Friedreich ataxia and are not features of the ARCA1 founder phenotype.
Show evidence (1 reference)
"compare them to the same parameters of Friedreich ataxia (FA) patients and healthy subjects"
Friedreich ataxia is used as the explicit clinical comparator group in the SYNE1 oculomotor study, reflecting its role as the primary differential.
Primary mitochondrial disease
Overlapping Features
SYNE1 deficiency can present with secondary mitochondrial findings and be misclassified as a primary mitochondrial disorder, a diagnostic trap worth recording explicitly because it redirects the whole testing strategy.
Distinguishing Features
- COX-negative fibers and mtDNA deletions can be present in SYNE1 deficiency as secondary findings.
- Resolution requires pangenomic (exome plus CNV-sensitive) testing rather than mitochondrial-targeted testing.
Show evidence (1 reference)
"The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions."
Documents a SYNE1-deficient proband whose muscle and mtDNA findings pointed toward a primary mitochondrial disorder before exome sequencing plus array-CGH identified biallelic SYNE1 variants.
Source YAML
click to showname: Autosomal Recessive Ataxia Beauce Type
creation_date: "2026-06-04T12:00:00Z"
category: Mendelian
description: >-
Autosomal recessive ataxia, Beauce type (autosomal recessive cerebellar ataxia
type 1, ARCA1; SCAR8; recessive ataxia of Beauce; ATX-SYNE1) is a SYNE1-related
hereditary cerebellar ataxia originally described in French-Canadian families
from the Beauce region of Quebec. The classic founder phenotype is a relatively
pure, slowly progressive, adult-onset cerebellar syndrome (gait and limb ataxia,
cerebellar dysarthria, dysmetria, ocular motor abnormalities) with diffuse
cerebellar atrophy on imaging and no peripheral neuropathy, evolving to moderate
disability without effect on life expectancy. SYNE1 deficiency, however, spans a
broader "cerebellar-plus" spectrum, with some patients showing upper and/or lower
motor neuron dysfunction, cognitive/affective involvement, and (at the severe end)
childhood-onset multisystem disease or arthrogryposis multiplex congenita. The
causal mechanism is biallelic loss-of-function SYNE1 variants affecting
nesprin-1, a nuclear-envelope spectrin-repeat protein of the LINC (linker of
nucleoskeleton and cytoskeleton) complex, with consequent disruption of
nuclear-cytoskeletal coupling in cerebellar neurons.
parents:
- hereditary disease
- neurodegenerative disease
synonyms:
- autosomal recessive cerebellar ataxia type 1
- ARCA1
- SCAR8
- recessive ataxia of Beauce
- SYNE1-related autosomal recessive cerebellar ataxia
- ATX-SYNE1
disease_term:
preferred_term: autosomal recessive ataxia, Beauce type
term:
id: MONDO:0012549
label: autosomal recessive ataxia, Beauce type
references:
- reference: PMID:20301553
title: "SYNE1 Deficiency."
tags:
- GeneReviews
- reference: PMID:36525394
title: "SYNE1-ataxia: clinicopathologic features of an autopsied patient with novel compound heterozygous mutations."
inheritance:
- name: Autosomal recessive inheritance
description: >-
ARCA1/SYNE1 deficiency is caused by biallelic pathogenic SYNE1 variants and
follows autosomal recessive inheritance.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1 deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes"
explanation: GeneReviews establishes autosomal recessive inheritance with carrier parents.
has_subtypes:
- name: ARCA1
display_name: SYNE1-deficient cerebellar ataxia (ARCA1 / Beauce type)
description: >-
The mild end and by far the most commonly recognised presentation: a slowly
progressive, relatively pure cerebellar syndrome beginning in adulthood.
This is the phenotype originally delineated in the French-Canadian Beauce
founder families and the one MONDO:0012549 is named for. Phenotypes curated
without a subtype qualifier belong to this presentation or to the SYNE1
deficiency spectrum generally.
genes:
- preferred_term: SYNE1
term:
id: hgnc:17089
label: SYNE1
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient cerebellar ataxia, the most commonly recognized manifestation of SYNE1 deficiency to date, is a slowly progressive disorder typically beginning in adulthood (age range 6-45 years)."
explanation: GeneReviews defines the cerebellar-ataxia presentation as the most common manifestation.
- name: Childhood-onset multisystem
display_name: SYNE1-deficient childhood-onset multisystem disease
description: >-
A less common presentation combining ataxia with upper and lower motor
neuron dysfunction, muscle weakness and wasting, and intellectual
disability, with onset in childhood rather than adulthood.
genes:
- preferred_term: SYNE1
term:
id: hgnc:17089
label: SYNE1
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The two less common phenotypes are SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability)"
explanation: GeneReviews defines the childhood-onset multisystem presentation and its component features.
- name: AMC
display_name: SYNE1-deficient arthrogryposis multiplex congenita
description: >-
The severe end of the spectrum, presenting prenatally and neonatally with
decreased fetal movements, severe hypotonia, and multiple congenital joint
contractures including clubfoot. Mechanistically part of SYNE1 deficiency
but clinically remote from the adult-onset Beauce ataxia.
genes:
- preferred_term: SYNE1
term:
id: hgnc:17089
label: SYNE1
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient arthrogryposis multiplex congenita (decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot)"
explanation: GeneReviews defines the arthrogryposis presentation at the severe end of the spectrum.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_syne1_loss_linc_model
hypothesis_label: Canonical SYNE1/Nesprin-1 Loss-of-Function LINC Model
status: CANONICAL
description: >-
The best-supported model is biallelic SYNE1 loss of function producing absent
or truncated nesprin-1, impairing the LINC complex that couples the nucleus to
the cytoskeleton. Because most disease-associated SYNE1 alleles are truncating,
a loss-of-function mechanism is favored, with cerebellar neurons (particularly
Purkinje cells) being especially vulnerable, leading to cerebellar degeneration.
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The function of SYNE1 is thus critical in the maintenance of cerebellar structure in humans."
explanation: The original ARCA1 study links SYNE1 to maintenance of cerebellar structure, supporting loss-of-function cerebellar degeneration.
- hypothesis_group_id: cerebellar_synaptic_nesprin_isoform_model
hypothesis_label: Cerebellar Synaptic Nesprin-1 Isoform Model
status: EMERGING
description: >-
A cerebellum-enriched nesprin-1 isoform lacking the KASH domain localizes to
synapses rather than the nuclear envelope, suggesting a synaptic, LINC-complex-
independent contribution to cerebellar vulnerability. This extends rather than
replaces the canonical nuclear-envelope loss-of-function model and remains to
be causally established.
notes: >-
Classified as emerging because the synaptic-isoform mechanism rests on
expression, splicing, and subcellular-localization data in mouse cerebellum
rather than direct causal demonstration in SCAR8 patients. Note that this
model relocates the primary lesion away from the Purkinje nuclear envelope
and toward mossy-fibre/granule-cell synaptic compartments; the two models
make different predictions about which cerebellar cell population is the
proximal target.
evidence:
- reference: PMID:25843669
reference_title: "A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We also identified a CNS-specific splicing event that leads to the abundant expression of a KASH-LESS variant of Nesprin1 giant (KLNes1g) in the cerebellum."
explanation: >-
Identifies the cerebellum-enriched KASH-less nesprin-1 isoform that this
hypothesis is built on. Evidence source is MODEL_ORGANISM because the
splicing, localization, and immunoprecipitation data are from mouse
cerebellum.
- reference: PMID:25843669
reference_title: "A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "KLNes1g displayed a noncanonical localization at glomeruli of cerebellar mossy fibers whereas Nesprin2 exclusively decorated the nuclear envelope of all cerebellar neurons."
explanation: >-
Shows the isoform localizes to synaptic rather than nuclear-envelope
compartments, which is the specific claim distinguishing this model from
the canonical LINC model.
- reference: PMID:39519078
reference_title: "Diverse Roles of the LINC Complex in Cellular Function and Disease in the Nervous System."
supports: SUPPORT
evidence_source: OTHER
snippet: "mutations in genes associated with the LINC complex have been implicated in several neurological diseases, including neurodegenerative and psychiatric disorders"
explanation: This review links LINC-complex gene mutations to neurological disease, supporting nesprin-1/LINC biology as the mechanistic context for SYNE1 ataxia.
pathophysiology:
- name: SYNE1/Nesprin-1 Loss of Function
biological_scale: MOLECULAR
description: >-
ARCA1 is caused by biallelic SYNE1 variants, most commonly truncating loss-of-
function alleles, that reduce or abolish nesprin-1. This establishes the primary
molecular lesion. SYNE1 is among the largest human genes, and the spectrum of
pathogenic variants includes nonsense, frameshift, splice, missense, and even
large intragenic deletions detectable only by CNV-sensitive methods.
gene:
preferred_term: SYNE1
description: Nesprin-1, a nuclear-envelope spectrin-repeat protein of the LINC complex.
modifier: DECREASED
term:
id: hgnc:17089
label: SYNE1
genes:
- preferred_term: SYNE1
term:
id: hgnc:17089
label: SYNE1
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a cluster of French-Canadian families with a new recessive ataxia of relatively pure cerebellar type caused by mutations in SYNE1."
explanation: Establishes SYNE1 as the causal gene for ARCA1.
- reference: PMID:38136976
reference_title: "A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function"
explanation: Demonstrates loss-of-function SYNE1 alleles, including a structural deletion, as a cause of ARCA1.
downstream:
- target: Disrupted Nuclear-Cytoskeletal LINC Coupling
description: >-
Reduced or absent nesprin-1 impairs assembly and function of the LINC complex
at the nuclear envelope.
evidence:
- reference: PMID:39519078
reference_title: "Diverse Roles of the LINC Complex in Cellular Function and Disease in the Nervous System."
supports: SUPPORT
evidence_source: OTHER
snippet: "The linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the nuclear envelope, physically connects nuclear components to the cytoskeleton"
explanation: Nesprin-1 is a LINC-complex component, so its loss disrupts LINC assembly at the nuclear envelope.
- target: Intellectual disability
description: >-
Intellectual disability in the childhood-onset multisystem presentation.
Wired from the primary genetic lesion rather than from cerebellar
degeneration because that presentation is not the cerebellar syndrome this
pathograph otherwise models.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability)"
explanation: GeneReviews attributes intellectual disability to SYNE1 deficiency in the childhood-onset multisystem presentation.
- target: Muscle weakness
description: Muscle weakness and wasting in the childhood-onset multisystem presentation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability)"
explanation: GeneReviews attributes muscle weakness and wasting to SYNE1 deficiency in the childhood-onset multisystem presentation.
- target: Decreased fetal movement
description: >-
Decreased fetal movements in the arthrogryposis presentation. The
intermediates between nesprin-1 loss and reduced fetal movement are not
established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient arthrogryposis multiplex congenita (decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot)"
explanation: GeneReviews attributes decreased fetal movements to SYNE1 deficiency at the severe end of the spectrum.
- target: Neonatal hypotonia
description: Severe neonatal hypotonia in the arthrogryposis presentation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot"
explanation: GeneReviews attributes severe neonatal hypotonia to SYNE1 deficiency at the severe end of the spectrum.
- target: Arthrogryposis multiplex congenita
description: >-
Multiple congenital joint contractures at the severe end of the SYNE1
deficiency spectrum.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1 deficiency comprises a phenotypic spectrum that ranges from autosomal recessive cerebellar ataxia at the mild end to arthrogryposis multiplex congenita (AMC) at the severe end."
explanation: GeneReviews places arthrogryposis multiplex congenita within the SYNE1 deficiency spectrum.
- target: Talipes equinovarus
description: Clubfoot among the congenital contractures of the arthrogryposis presentation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "multiple congenital joint contractures including clubfoot"
explanation: GeneReviews names clubfoot among the contractures attributable to SYNE1 deficiency.
- target: Scoliosis
description: >-
Scoliosis as a non-neurological feature of the extracerebellar SYNE1
phenotype. Attributed to the primary lesion because no cerebellar
mechanism accounts for it.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
explanation: Reports scoliosis among non-neurological features of SYNE1 ataxia outside the founder population.
- target: Pes cavus
description: Pes cavus as a non-neurological feature of the extracerebellar SYNE1 phenotype.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
explanation: Reports pes cavus among non-neurological features of SYNE1 ataxia outside the founder population.
- target: Respiratory dysfunction
description: Respiratory dysfunction in severely affected non-founder patients.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
explanation: Reports respiratory dysfunction among severe non-neurological manifestations of SYNE1 ataxia.
- target: Strabismus
description: >-
Strabismus is reported in SYNE1 ataxia but is not a cerebellar sign, so it
is attributed to the primary lesion rather than routed through cerebellar
degeneration.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
explanation: Strabismus appears among the ocular findings reported across published SYNE1 ataxia patients.
- name: Disrupted Nuclear-Cytoskeletal LINC Coupling
biological_scale: CELLULAR
conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Neuron Insult"
description: >-
Nesprin-1 participates in the LINC complex spanning the nuclear envelope
(SUN-KASH bridging), physically connecting the cytoskeleton to nuclear
components and mediating nuclear positioning, cell migration, and
mechanotransduction. Loss of nesprin-1 disrupts this coupling. The LINC complex
is essential to nervous-system development, and LINC-gene mutations are
implicated in neurodegenerative disease.
cell_types:
- preferred_term: Cerebellar Purkinje cell
term:
id: CL:0000121
label: Purkinje cell
- preferred_term: Cerebellar granule cell
term:
id: CL:0001031
label: cerebellar granule cell
biological_processes:
- preferred_term: Cytoskeleton organization
term:
id: GO:0007010
label: cytoskeleton organization
modifier: ABNORMAL
- preferred_term: Nuclear migration / positioning
term:
id: GO:0007097
label: nuclear migration
modifier: ABNORMAL
cellular_components:
- preferred_term: Nuclear envelope
term:
id: GO:0005635
label: nuclear envelope
- preferred_term: Nuclear inner membrane
term:
id: GO:0005637
label: nuclear inner membrane
evidence:
- reference: PMID:39519078
reference_title: "Diverse Roles of the LINC Complex in Cellular Function and Disease in the Nervous System."
supports: SUPPORT
evidence_source: OTHER
snippet: "The linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the nuclear envelope, physically connects nuclear components to the cytoskeleton and plays a pivotal role in various cellular processes, including nuclear positioning, cell migration, and chromosomal configuration."
explanation: Describes the LINC-complex function disrupted by nesprin-1/SYNE1 loss.
downstream:
- target: Cerebellar Neurodegeneration and Atrophy
description: >-
Disrupted nuclear-cytoskeletal coupling in cerebellar neurons leads to
cerebellar degeneration manifesting as diffuse cerebellar atrophy.
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The function of SYNE1 is thus critical in the maintenance of cerebellar structure in humans."
explanation: Loss of SYNE1/nesprin-1 function compromises cerebellar structural maintenance, driving cerebellar degeneration and atrophy.
- target: Upper motor neuron dysfunction
description: >
The broader SYNE1 deficiency spectrum includes upper motor neuron signs
beyond the pure cerebellar phenotype.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign) and/or lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
explanation: >
GeneReviews documents upper motor neuron dysfunction in the broader
SYNE1 deficiency spectrum.
- target: Lower motor neuron involvement (cerebellar-plus)
description: >
Cerebellar-plus SYNE1 deficiency can include lower motor neuron
involvement outside the classic pure cerebellar presentation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:32889669
reference_title: "Autosomal Recessive Cerebellar Ataxia Type 1: Phenotypic and Genetic Correlation in a Cohort of Chinese Patients with SYNE1 Variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "four patients exhibited non-cerebellar phenotypes, including motor neuron symptoms, cognitive impairment, or mental retardation"
explanation: >
The Chinese SYNE1 cohort documents motor-neuron symptoms as
non-cerebellar cerebellar-plus phenotypes.
- target: Spasticity
description: Spasticity as a component sign of the upper motor neuron arm.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
explanation: GeneReviews names spasticity as a component of the upper motor neuron arm of SYNE1 deficiency.
- target: Hyperreflexia
description: Hyperreflexia as a component sign of the upper motor neuron arm.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
explanation: GeneReviews names hyperreflexia as a component of the upper motor neuron arm of SYNE1 deficiency.
- target: Lower limb hyperreflexia
description: >-
Brisk lower-extremity reflexes, the upper motor neuron sign actually
observed in the otherwise pure-cerebellar Beauce founder cohort.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "occasional brisk reflexes in the lower extremities"
explanation: Dupre 2007 reports brisk lower-extremity reflexes in the founder cohort.
- target: Babinski sign
description: Extensor plantar response as a component sign of the upper motor neuron arm.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
explanation: GeneReviews names the Babinski sign as a component of the upper motor neuron arm of SYNE1 deficiency.
- target: Skeletal muscle atrophy
description: Amyotrophy as a component sign of the lower motor neuron arm.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
explanation: GeneReviews names amyotrophy as a component of the lower motor neuron arm of SYNE1 deficiency.
- target: Reduced tendon reflexes
description: Reduced deep tendon reflexes as a component sign of the lower motor neuron arm.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
explanation: GeneReviews names reduced reflexes as a component of the lower motor neuron arm of SYNE1 deficiency.
- target: Fasciculations
description: Fasciculations as a component sign of the lower motor neuron arm.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
explanation: GeneReviews names fasciculations as a component of the lower motor neuron arm of SYNE1 deficiency.
- name: Cerebellar Neurodegeneration and Atrophy
biological_scale: TISSUE
conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
description: >-
Cerebellar neuronal vulnerability, supported by the strong cerebellar
expression of SYNE1, produces diffuse cerebellar atrophy without cortical,
brainstem, or white-matter involvement in the classic founder phenotype, and
underlies the progressive cerebellar ataxia, dysarthria, and dysmetria.
cell_types:
- preferred_term: Cerebellar Purkinje cell
term:
id: CL:0000121
label: Purkinje cell
locations:
- preferred_term: Cerebellum
term:
id: UBERON:0002037
label: cerebellum
- preferred_term: Cerebellar cortex
term:
id: UBERON:0002129
label: cerebellar cortex
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "slow progression and moderate disability, significant dysarthria, mild oculomotor abnormalities, occasional brisk reflexes in the lower extremities, normal nerve conduction studies, and diffuse cerebellar atrophy on imaging"
explanation: Documents diffuse cerebellar atrophy as the structural correlate of the cerebellar syndrome.
downstream:
- target: Cerebellar atrophy
description: Diffuse cerebellar atrophy is the imaging correlate of the cerebellar neurodegenerative process.
causal_link_type: DIRECT
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "normal nerve conduction studies, and diffuse cerebellar atrophy on imaging"
explanation: Documents diffuse cerebellar atrophy on imaging in ARCA1.
- target: Cerebellar ataxia
description: Cerebellar degeneration produces the progressive cerebellar ataxia syndrome.
causal_link_type: DIRECT
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ARCA-1 is a cerebellar syndrome characterized by recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability"
explanation: Establishes the progressive cerebellar syndrome caused by SYNE1 deficiency.
- target: Gait ataxia
description: Cerebellar degeneration manifests clinically as gait ataxia.
causal_link_type: DIRECT
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1 ataxia is an autosomal recessive hereditary condition, the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria."
explanation: Lists gait ataxia as a main characteristic feature of SYNE1 ataxia.
- target: Limb ataxia
description: Cerebellar degeneration impairs appendicular coordination, producing limb ataxia.
causal_link_type: DIRECT
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria"
explanation: Lists limb ataxia as a characteristic feature of SYNE1 ataxia.
- target: Dysarthria
description: Cerebellar degeneration causes the dysarthria component of the syndrome.
causal_link_type: DIRECT
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "slow progression and moderate disability, significant dysarthria"
explanation: Documents dysarthria in the slowly progressive ARCA1 syndrome.
- target: Dysmetria
description: Cerebellar degeneration causes dysmetria as part of the pure cerebellar syndrome.
causal_link_type: DIRECT
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "some individuals have a pure cerebellar syndrome (i.e., cerebellar ataxia, dysarthria, dysmetria, abnormalities in ocular saccades and smooth pursuit)"
explanation: GeneReviews lists dysmetria as a component of the pure cerebellar syndrome.
- target: Abnormal ocular smooth pursuit
description: Cerebellar degeneration affects ocular motor control, including smooth pursuit.
causal_link_type: DIRECT
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "abnormalities in ocular saccades and smooth pursuit"
explanation: Documents ocular saccade and smooth-pursuit abnormalities in SYNE1 deficiency.
- target: Slow saccades
description: Cerebellar ocular motor involvement includes slow saccadic eye movements.
causal_link_type: DIRECT
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The eye tracking assessment revealed hypometric saccades in the longer amplitude (18.4°) saccadic paradigm in all SYNE1 patients, whereas 2 out of 3 SYNE1 subjects performed slow saccades as well."
explanation: Eye-tracking documents slow saccades in SYNE1 ataxia.
- target: Nystagmus
description: Cerebellar ocular motor involvement includes gaze-evoked nystagmus.
causal_link_type: DIRECT
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
explanation: Review of SYNE1 ataxia oculomotor findings includes gaze-evoked nystagmus.
- target: Cognitive impairment
description: Cerebellar involvement can extend to cerebellar cognitive and affective syndrome.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- cerebellar cognitive and affective syndrome
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most individuals develop features of the cerebellar cognitive and affective syndrome (i.e., significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills)."
explanation: GeneReviews links SYNE1 deficiency to cerebellar cognitive and affective syndrome.
- target: Short attention span
description: >-
Attentional deficit as a specific domain of the cerebellar cognitive and
affective syndrome.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- cerebellar cognitive and affective syndrome
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills"
explanation: GeneReviews names attention as an impaired domain within the cerebellar cognitive and affective syndrome.
- target: Square-wave jerks
description: Square-wave jerks as part of the cerebellar ocular motor disturbance.
causal_link_type: DIRECT
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
explanation: Square-wave jerks are among the oculomotor findings reported across published SYNE1 ataxia patients.
- target: Jerky ocular pursuit movements
description: Broken-up (saccadic) smooth pursuit as part of the cerebellar ocular motor disturbance.
causal_link_type: DIRECT
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
explanation: Broken-up smooth pursuit is among the oculomotor findings reported across published SYNE1 ataxia patients.
- target: Dysphagia
description: >-
Swallowing difficulty accompanying the bulbar/cerebellar motor speech
disturbance, flagged by GeneReviews for ongoing surveillance.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dysarthria, dysphagia, cognition, and psychiatric manifestations"
explanation: >-
GeneReviews groups dysphagia with dysarthria among the manifestations to
be assessed at surveillance visits. The link is indirect because no
cited source establishes the mechanism connecting cerebellar
degeneration to swallowing impairment in this disorder.
phenotypes:
- category: Phenotype
name: Cerebellar ataxia
description: >-
Progressive gait and limb ataxia is the cardinal and near-universal feature,
typically with adult onset (mean ~31.6 years) in the founder phenotype.
phenotype_term:
preferred_term: Cerebellar ataxia
term:
id: HP:0001251
label: Ataxia
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ARCA-1 is a cerebellar syndrome characterized by recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability"
explanation: Establishes progressive cerebellar ataxia as the core syndrome.
- category: Phenotype
name: Gait ataxia
description: Unsteady, ataxic gait, frequently the presenting symptom.
phenotype_term:
preferred_term: Gait ataxia
term:
id: HP:0002066
label: Gait ataxia
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1 ataxia is an autosomal recessive hereditary condition, the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria."
explanation: Confirms gait ataxia as a core characteristic feature.
- category: Phenotype
name: Limb ataxia
description: Appendicular ataxia affecting limb coordination.
phenotype_term:
preferred_term: Limb ataxia
term:
id: HP:0002070
label: Limb ataxia
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria"
explanation: Confirms limb ataxia as a characteristic feature.
- category: Phenotype
name: Dysarthria
description: >-
Cerebellar dysarthria is one of the features that defines the ARCA1
syndrome, described as "significant" in the founder cohort.
phenotype_term:
preferred_term: Cerebellar dysarthria
term:
id: HP:0001260
label: Dysarthria
frequency: VERY_FREQUENT
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ARCA-1 is a cerebellar syndrome characterized by recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability, significant dysarthria"
explanation: >-
Dupre 2007 defines the syndrome as "characterized by ... significant
dysarthria". No cited source reports a dysarthria numerator/denominator,
so the VERY_FREQUENT band rests on the qualitative mapping in
docs/frequency-evidence-guidelines.md, under which a feature named as
characterizing the syndrome maps to VERY_FREQUENT (80-99%). Downgrade or
remove the band if a quantitative cohort figure becomes available.
- category: Phenotype
name: Dysmetria
description: Impaired coordination of movement amplitude, part of the cerebellar syndrome.
phenotype_term:
preferred_term: Dysmetria
term:
id: HP:0001310
label: Dysmetria
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "some individuals have a pure cerebellar syndrome (i.e., cerebellar ataxia, dysarthria, dysmetria, abnormalities in ocular saccades and smooth pursuit)"
explanation: GeneReviews lists dysmetria as part of the pure cerebellar syndrome.
- category: Phenotype
name: Abnormal ocular smooth pursuit
description: >-
Impaired smooth pursuit eye movements, an ocular motor abnormality of the
cerebellar syndrome.
phenotype_term:
preferred_term: Impaired smooth pursuit
term:
id: HP:0007772
label: Impaired smooth pursuit
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "abnormalities in ocular saccades and smooth pursuit"
explanation: GeneReviews documents abnormal ocular saccades and smooth pursuit.
- category: Phenotype
name: Slow saccades
description: >-
Abnormal (slow and/or hypometric) saccadic eye movements documented by eye
tracking in SYNE1 ataxia patients.
phenotype_term:
preferred_term: Slow saccadic eye movements
term:
id: HP:0000514
label: Slow saccadic eye movements
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The eye tracking assessment revealed hypometric saccades in the longer amplitude (18.4°) saccadic paradigm in all SYNE1 patients, whereas 2 out of 3 SYNE1 subjects performed slow saccades as well."
explanation: Eye-tracking study documents slow and hypometric saccades in SYNE1 ataxia patients.
- category: Phenotype
name: Nystagmus
description: Gaze-evoked nystagmus reported as an ocular motor abnormality in SYNE1 ataxia patients.
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
explanation: Review of published SYNE1 ataxia patients documents gaze-evoked nystagmus among the reported oculomotor findings.
- category: Phenotype
name: Cerebellar atrophy
description: >-
Diffuse cerebellar atrophy on CT/MRI is a consistent imaging finding, without
cortical, brainstem, or white-matter involvement in the classic phenotype.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "normal nerve conduction studies, and diffuse cerebellar atrophy on imaging"
explanation: Documents diffuse cerebellar atrophy on imaging.
- category: Phenotype
name: Upper motor neuron dysfunction
description: >-
Many SYNE1-deficient patients show upper motor neuron signs, part of the
broader cerebellar-plus spectrum that extends beyond the relatively pure
founder phenotype. The component signs are curated separately below.
phenotype_term:
preferred_term: Upper motor neuron dysfunction
term:
id: HP:0002493
label: Upper motor neuron dysfunction
frequency: FREQUENT
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign) and/or lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
explanation: >-
GeneReviews reports that "many" SYNE1-deficient individuals have upper
motor neuron dysfunction. Per the qualitative mapping in
docs/frequency-evidence-guidelines.md this maps to FREQUENT (30-79%); no
cited source gives a numerator/denominator for this arm.
- category: Phenotype
name: Lower motor neuron involvement (cerebellar-plus)
description: >-
Lower motor neuron dysfunction and motor neuron disease features occur in a
subset of patients, particularly in non-founder cohorts; variants associated
with motor neuron involvement tend to cluster in the C-terminal region.
phenotype_term:
preferred_term: Lower motor neuron dysfunction
term:
id: HP:0002366
label: Abnormal lower motor neuron morphology
evidence:
- reference: PMID:32889669
reference_title: "Autosomal Recessive Cerebellar Ataxia Type 1: Phenotypic and Genetic Correlation in a Cohort of Chinese Patients with SYNE1 Variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "four patients exhibited non-cerebellar phenotypes, including motor neuron symptoms, cognitive impairment, or mental retardation"
explanation: The Chinese cohort documents motor neuron involvement as part of the cerebellar-plus phenotype.
- category: Phenotype
name: Cognitive impairment
description: >-
Cognitive impairment and the cerebellar cognitive and affective syndrome
(deficits in attention, executive function, verbal working memory,
visuospatial skills) occur in many patients; intellectual disability is seen
in childhood-onset multisystem disease.
phenotype_term:
preferred_term: Cognitive impairment
term:
id: HP:0100543
label: Cognitive impairment
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most individuals develop features of the cerebellar cognitive and affective syndrome (i.e., significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills)."
explanation: GeneReviews documents the cerebellar cognitive and affective syndrome in most patients.
- category: Phenotype
name: Short attention span
description: >-
Attentional deficit as a component of the cerebellar cognitive and affective
syndrome.
phenotype_term:
preferred_term: Deficits in attention
term:
id: HP:0000736
label: Short attention span
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills"
explanation: >-
GeneReviews names attention as one of the specific domains impaired in the
cerebellar cognitive and affective syndrome. Curated separately from the
broader Cognitive impairment entry so the specific HPO term is available.
- category: Phenotype
name: Spasticity
description: >-
Spasticity as a component upper motor neuron sign in the cerebellar-plus
spectrum.
phenotype_term:
preferred_term: Spasticity
term:
id: HP:0001257
label: Spasticity
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
explanation: >-
GeneReviews names spasticity as a component of the upper motor neuron
arm. No frequency band is asserted: the source quantifies the upper motor
neuron arm as a whole ("many"), not each component sign.
- category: Phenotype
name: Hyperreflexia
description: Hyperreflexia as a component upper motor neuron sign.
phenotype_term:
preferred_term: Hyperreflexia
term:
id: HP:0001347
label: Hyperreflexia
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
explanation: >-
GeneReviews names hyperreflexia as a component of the upper motor neuron
arm. No frequency band is asserted for the individual sign.
- category: Phenotype
name: Lower limb hyperreflexia
description: >-
Brisk lower-extremity reflexes, the specific upper motor neuron sign
reported in the Beauce founder cohort, where the phenotype is otherwise
relatively pure cerebellar.
phenotype_term:
preferred_term: Brisk lower extremity reflexes
term:
id: HP:0002395
label: Lower limb hyperreflexia
frequency: OCCASIONAL
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "occasional brisk reflexes in the lower extremities"
explanation: >-
Dupre 2007 reports brisk lower-extremity reflexes in the founder cohort.
The author term "occasional" maps to OCCASIONAL (5-29%) under the
qualitative mapping in docs/frequency-evidence-guidelines.md.
- category: Phenotype
name: Babinski sign
description: Extensor plantar response as a component upper motor neuron sign.
phenotype_term:
preferred_term: Babinski sign
term:
id: HP:0003487
label: Babinski sign
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign)"
explanation: >-
GeneReviews names the Babinski sign as a component of the upper motor
neuron arm. No frequency band is asserted for the individual sign.
- category: Phenotype
name: Skeletal muscle atrophy
description: >-
Amyotrophy as a component lower motor neuron sign in the cerebellar-plus
spectrum.
phenotype_term:
preferred_term: Amyotrophy
term:
id: HP:0003202
label: Skeletal muscle atrophy
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
explanation: >-
GeneReviews names amyotrophy as a component of the lower motor neuron
arm. No frequency band is asserted for the individual sign.
- category: Phenotype
name: Reduced tendon reflexes
description: >-
Reduced deep tendon reflexes as a component lower motor neuron sign,
contrasting with the brisk reflexes seen in the upper motor neuron arm.
phenotype_term:
preferred_term: Reduced tendon reflexes
term:
id: HP:0001315
label: Reduced tendon reflexes
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
explanation: >-
GeneReviews names reduced reflexes as a component of the lower motor
neuron arm. No frequency band is asserted for the individual sign.
- category: Phenotype
name: Fasciculations
description: Fasciculations as a component lower motor neuron sign.
phenotype_term:
preferred_term: Fasciculations
term:
id: HP:0002380
label: Fasciculations
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"
explanation: >-
GeneReviews names fasciculations as a component of the lower motor neuron
arm. No frequency band is asserted for the individual sign.
- category: Phenotype
name: Dysphagia
description: >-
Swallowing difficulty, named by GeneReviews as a domain requiring ongoing
surveillance in SYNE1 deficiency.
phenotype_term:
preferred_term: Dysphagia
term:
id: HP:0002015
label: Dysphagia
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dysarthria, dysphagia, cognition, and psychiatric manifestations"
explanation: >-
GeneReviews lists dysphagia among the manifestations to be assessed at
surveillance visits, implying it occurs in the disorder. This is an
indirect assertion; no cited source reports its frequency.
- category: Phenotype
name: Square-wave jerks
description: Square-wave jerks among the oculomotor abnormalities reported in SYNE1 ataxia.
phenotype_term:
preferred_term: Square-wave jerks
term:
id: HP:0025402
label: Square-wave jerks
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
explanation: >-
A review of 168 previously published SYNE1 ataxia patients lists
square-wave jerks among the reported oculomotor findings. The sentence is
a summary of prior literature, not a new observation in this cohort.
- category: Phenotype
name: Jerky ocular pursuit movements
description: >-
Broken-up (saccadic) smooth pursuit, the specific pursuit abnormality
reported in the SYNE1 ataxia literature.
phenotype_term:
preferred_term: Broken up smooth pursuit
term:
id: HP:0008003
label: Jerky ocular pursuit movements
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
explanation: >-
Adds the specific HPO term for broken-up smooth pursuit alongside the
broader Abnormal ocular smooth pursuit entry. Summary of prior literature.
- category: Phenotype
name: Strabismus
description: Strabismus among the ocular findings reported in SYNE1 ataxia.
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the occurrence of gaze-evoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported"
explanation: >-
A review of previously published SYNE1 ataxia patients lists strabismus
among the reported ocular findings. Summary of prior literature.
- category: Phenotype
name: Scoliosis
description: >-
Scoliosis as a non-neurological feature of the extracerebellar SYNE1
phenotype seen in non-founder cohorts.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
explanation: >-
Describes the non-Canadian SYNE1 ataxia cohort, in which most patients had
extracerebellar signs including scoliosis.
- category: Phenotype
name: Pes cavus
description: >-
Pes cavus as a non-neurological feature of the extracerebellar SYNE1
phenotype seen in non-founder cohorts.
phenotype_term:
preferred_term: Pes cavus
term:
id: HP:0001761
label: Pes cavus
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
explanation: >-
Describes the non-Canadian SYNE1 ataxia cohort, in which most patients had
extracerebellar signs including pes cavus.
- category: Phenotype
name: Respiratory dysfunction
description: >-
Respiratory dysfunction reported in severely affected patients outside the
founder population.
phenotype_term:
preferred_term: Respiratory dysfunction
term:
id: HP:0002086
label: Abnormality of the respiratory system
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "non-neurological abnormalities, including scoliosis, pes cavus or respiratory dysfunction with severe manifestation"
explanation: >-
Reports respiratory dysfunction as a severe-end extracerebellar
manifestation. The HPO term is deliberately broad because the source does
not specify the respiratory abnormality.
- category: Phenotype
name: Intellectual disability
subtype: Childhood-onset multisystem
description: >-
Intellectual disability is part of the childhood-onset multisystem
presentation, not the adult-onset Beauce founder phenotype.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability)"
explanation: >-
GeneReviews scopes intellectual disability to the childhood-onset
multisystem phenotype, which is why this entry carries a subtype
qualifier rather than being asserted of the disease as a whole.
- category: Phenotype
name: Muscle weakness
subtype: Childhood-onset multisystem
description: >-
Muscle weakness and wasting in the childhood-onset multisystem presentation.
phenotype_term:
preferred_term: Muscle weakness and wasting
term:
id: HP:0001324
label: Muscle weakness
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability)"
explanation: >-
GeneReviews scopes muscle weakness and wasting to the childhood-onset
multisystem phenotype.
- category: Phenotype
name: Decreased fetal movement
subtype: AMC
description: >-
Decreased fetal movements at the severe (arthrogryposis) end of the SYNE1
deficiency spectrum.
phenotype_term:
preferred_term: Decreased fetal movement
term:
id: HP:0001558
label: Decreased fetal movement
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient arthrogryposis multiplex congenita (decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot)"
explanation: >-
GeneReviews scopes decreased fetal movements to the arthrogryposis
multiplex congenita phenotype at the severe end of the spectrum.
- category: Phenotype
name: Neonatal hypotonia
subtype: AMC
description: Severe neonatal hypotonia in the arthrogryposis presentation.
phenotype_term:
preferred_term: Severe neonatal hypotonia
term:
id: HP:0001319
label: Neonatal hypotonia
severity: SEVERE
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot"
explanation: >-
GeneReviews scopes severe neonatal hypotonia to the arthrogryposis
multiplex congenita phenotype.
- category: Phenotype
name: Arthrogryposis multiplex congenita
subtype: AMC
description: >-
Multiple congenital joint contractures define the severe end of the SYNE1
deficiency spectrum.
phenotype_term:
preferred_term: Arthrogryposis multiplex congenita
term:
id: HP:0002804
label: Arthrogryposis multiplex congenita
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1 deficiency comprises a phenotypic spectrum that ranges from autosomal recessive cerebellar ataxia at the mild end to arthrogryposis multiplex congenita (AMC) at the severe end."
explanation: >-
GeneReviews places arthrogryposis multiplex congenita at the severe end of
the SYNE1 deficiency spectrum, anchoring the AMC subtype.
- category: Phenotype
name: Talipes equinovarus
subtype: AMC
description: Clubfoot as one of the congenital joint contractures in the AMC presentation.
phenotype_term:
preferred_term: Clubfoot
term:
id: HP:0001762
label: Talipes equinovarus
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "multiple congenital joint contractures including clubfoot"
explanation: >-
GeneReviews names clubfoot among the congenital contractures of the
arthrogryposis phenotype.
genetic:
- name: Biallelic SYNE1 pathogenic variants
gene_term:
preferred_term: SYNE1
term:
id: hgnc:17089
label: SYNE1
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1 deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes"
explanation: GeneReviews establishes autosomal recessive inheritance for SYNE1 deficiency.
notes: >-
The diagnosis is established by identification of biallelic SYNE1 pathogenic
variants. SYNE1 is one of the largest human genes, and disease-associated
variants are enriched for truncating loss-of-function alleles spread throughout
the gene; large intragenic deletions detectable only by CNV-sensitive methods
also occur. In Quebec founder families, a recurrent allele accounts for roughly
half of carrier chromosomes.
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis of SYNE1 deficiency is established in a proband with suggestive findings and biallelic SYNE1 pathogenic variants identified by molecular genetic testing."
explanation: GeneReviews defines the molecular diagnostic basis as biallelic SYNE1 variants.
- reference: PMID:32889669
reference_title: "Autosomal Recessive Cerebellar Ataxia Type 1: Phenotypic and Genetic Correlation in a Cohort of Chinese Patients with SYNE1 Variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified eight truncating variants and two missense variants spreading throughout the SYNE1 gene from six unrelated families"
explanation: Documents the predominance of truncating SYNE1 variants distributed across the gene.
treatments:
- name: Supportive and Rehabilitative Care
description: >-
There is no specific or disease-modifying treatment for SYNE1 deficiency.
Management is supportive, aiming to maximize function and reduce complications
through a multidisciplinary team (neurology, physical/occupational/speech
therapy, physiatry, orthopedics, nutrition).
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There is no specific treatment for SYNE1 deficiency. The goals of treatment are to maximize function and reduce complications."
explanation: GeneReviews states management is supportive with no specific therapy.
- name: Physical Therapy
description: Rehabilitation to maintain mobility and address ataxia, spasticity, and weakness.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Physical Therapy
term:
id: NCIT:C15302
label: Physical Therapy
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "managed by a multidisciplinary team of relevant specialists including neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists"
explanation: GeneReviews recommends physical therapy within multidisciplinary management.
- name: Speech Therapy
description: Speech therapy for cerebellar dysarthria and, when present, dysphagia.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: speech therapy
term:
id: NCIT:C159273
label: Speech Language Therapy
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists"
explanation: GeneReviews includes speech therapy within multidisciplinary management.
- name: Genetic Counseling
description: >-
Genetic counseling is indicated given autosomal recessive inheritance; carrier
testing, prenatal diagnosis, and preimplantation genetic testing are available
once familial variants are known. Relevant in founder populations.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "carrier testing for at-risk relatives, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic testing are possible"
explanation: GeneReviews supports genetic counseling and reproductive testing options.
prevalence:
- population: Eastern Quebec adults
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_100000
rate_per_100000: 2.67
notes: >-
In an Eastern Quebec cross-sectional study, ARCA1 (AR cerebellar ataxia type 1)
was the most prevalent hereditary ataxia identified, at a minimum prevalence of
2.67/100,000 [95% CI 2.65-2.7], within an overall adult hereditary ataxia
prevalence of 6.47/100,000. This is a founder-population figure and a
*minimum* (genetically confirmed cases only); it should not be read as a
worldwide prevalence for this disorder, and no worldwide estimate is
currently curated.
evidence:
- reference: PMID:33397523
reference_title: "Genetic and Epidemiological Study of Adult Ataxia and Spastic Paraplegia in Eastern Quebec."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "AR cerebellar ataxia type 1 (2.67/100 000) and AD spastic paraplegia SPG4 (1.18/100 000) were the most prevalent disorders identified."
explanation: Provides a population-based minimum prevalence estimate for ARCA1.
progression:
- phase: Adult-onset cerebellar syndrome
age_range: Adolescence to mid-adulthood (range ~6-45 years; mean onset ~31.6 years in founder cohort)
notes: >-
Classic Beauce phenotype begins with gait and limb ataxia in early-to-mid
adulthood, with dysarthria following. Non-founder cohorts can show earlier
(childhood/young-adult) onset.
evidence:
- reference: PMID:20301553
reference_title: "SYNE1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SYNE1-deficient cerebellar ataxia, the most commonly recognized manifestation of SYNE1 deficiency to date, is a slowly progressive disorder typically beginning in adulthood (age range 6-45 years)."
explanation: GeneReviews documents typical adult onset across a wide age range.
- phase: Slowly progressive course
duration: Slowly progressive over years to decades
notes: >-
The founder phenotype progresses slowly to moderate disability with no effect
on life expectancy; cerebellar-plus forms can carry additional morbidity from
motor neuron and multisystem involvement.
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recessive transmission, middle-age onset (mean, 31.60; range, 17-46 years), slow progression and moderate disability"
explanation: Documents slow progression to moderate disability.
diagnosis:
- name: Brain MRI
description: >-
Brain MRI demonstrating diffuse cerebellar atrophy supports the diagnosis;
normal nerve conduction studies help distinguish ARCA1 from ataxias with
prominent peripheral neuropathy.
evidence:
- reference: PMID:17503513
reference_title: "Clinical and genetic study of autosomal recessive cerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "normal nerve conduction studies, and diffuse cerebellar atrophy on imaging"
explanation: Imaging shows diffuse cerebellar atrophy with normal nerve conduction.
- name: Molecular genetic testing (NGS with CNV analysis)
description: >-
Next-generation sequencing (gene panel, exome, or genome) detects most SYNE1
variants, but CNV-sensitive methods (e.g., array-CGH) are needed to detect
large intragenic deletions that standard sequencing pipelines may miss.
Diagnostic workup for adult-onset hereditary ataxia combines STR-expansion
testing with sequencing.
evidence:
- reference: PMID:38136976
reference_title: "A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency"
explanation: Highlights the need for CNV-sensitive testing in suspected SYNE1 deficiency.
- reference: PMID:38760634
reference_title: "An update on the adult-onset hereditary cerebellar ataxias: novel genetic causes and new diagnostic approaches."
supports: SUPPORT
evidence_source: OTHER
snippet: "Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing"
explanation: Describes the contemporary diagnostic approach for adult-onset hereditary ataxia.
differential_diagnoses:
- name: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
disease_term:
preferred_term: ARSACS
term:
id: MONDO:0010041
label: Charlevoix-Saguenay spastic ataxia
description: >-
The most important differential in the population where ARCA1 was defined:
a second recessive ataxia with a Quebec founder effect, present in the same
Eastern Quebec ataxia clinics. Both are recessive, both are cerebellar, and
both are enriched in the same ancestry, so ancestry alone does not
discriminate them.
distinguishing_features:
- Caused by biallelic SACS variants (sacsin), not SYNE1.
- Prominent spasticity and peripheral neuropathy, whereas ARCA1 has normal nerve conduction studies and is relatively pure cerebellar.
- Roughly six-fold rarer than ARCA1 in the same Eastern Quebec population (0.43 vs 2.67 per 100,000).
evidence:
- reference: PMID:33397523
reference_title: "Genetic and Epidemiological Study of Adult Ataxia and Spastic Paraplegia in Eastern Quebec."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pathogenic mutations in SACS were found in seven non-related patients"
explanation: >-
Establishes that SACS-related ARSACS co-occurs with ARCA1 in the same
Eastern Quebec cohort, making it the co-located differential.
- name: Friedreich ataxia
disease_term:
preferred_term: Friedreich ataxia
term:
id: MONDO:0100339
label: Friedreich ataxia
description: >-
The commonest recessive ataxia overall and the comparator against which
SYNE1 oculomotor findings have been benchmarked.
distinguishing_features:
- Caused by a GAA repeat expansion in FXN, detected by repeat-expansion testing rather than sequencing.
- Sensory axonal neuropathy with absent reflexes; ARCA1 has normal nerve conduction studies.
- Cardiomyopathy and diabetes are part of Friedreich ataxia and are not features of the ARCA1 founder phenotype.
evidence:
- reference: PMID:33526008
reference_title: "Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "compare them to the same parameters of Friedreich ataxia (FA) patients and healthy subjects"
explanation: >-
Friedreich ataxia is used as the explicit clinical comparator group in the
SYNE1 oculomotor study, reflecting its role as the primary differential.
- name: Primary mitochondrial disease
description: >-
SYNE1 deficiency can present with secondary mitochondrial findings and be
misclassified as a primary mitochondrial disorder, a diagnostic trap worth
recording explicitly because it redirects the whole testing strategy.
distinguishing_features:
- COX-negative fibers and mtDNA deletions can be present in SYNE1 deficiency as secondary findings.
- Resolution requires pangenomic (exome plus CNV-sensitive) testing rather than mitochondrial-targeted testing.
evidence:
- reference: PMID:38136976
reference_title: "A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions."
explanation: >-
Documents a SYNE1-deficient proband whose muscle and mtDNA findings
pointed toward a primary mitochondrial disorder before exome sequencing
plus array-CGH identified biallelic SYNE1 variants.
discussions:
- discussion_id: syne1_proximal_cerebellar_target
kind: OPEN_QUESTION
status: UNDER_DISCUSSION
prompt: >-
Which cerebellar cell population is the proximal target of SYNE1 loss — the
Purkinje cell nuclear envelope, as the canonical LINC model and this entry's
pathograph assume, or the mossy-fibre/granule-cell synaptic compartment
where the cerebellum-enriched KASH-less nesprin-1 isoform actually
localizes?
attaches_to:
- pathophysiology#Disrupted Nuclear-Cytoskeletal LINC Coupling
- pathophysiology#Cerebellar Neurodegeneration and Atrophy
rationale: >-
This entry asserts Purkinje-cell vulnerability in its pathograph and
declares conformance to
cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration, which is the
mainstream reading of GeneReviews and of Dupre's statement that SYNE1 is
critical to the maintenance of cerebellar structure. Neither of those
sources actually demonstrates Purkinje neuron loss. The direct localization
work points the other way: the abundant cerebellar isoform, KLNes1g, is
KASH-less, sits at mossy-fibre glomeruli and granule-cell dendritic
membranes rather than the nuclear envelope, and it is Nesprin2 - not
Nesprin1 - that decorates the nuclear envelope of cerebellar neurons. If
that is the operative lesion, the cell-type annotations and the module
conformance on the degeneration node are describing the wrong compartment,
and the canonical LINC framing is downstream of, or parallel to, the real
mechanism rather than upstream of it.
proposed_experiments:
- experiment_id: exp_syne1_purkinje_vs_granule_neuropathology
name: Neuropathological series quantifying Purkinje versus granule cell loss
description: >-
Assemble a systematic autopsy series of genetically confirmed SYNE1
ataxia and quantify Purkinje versus granule cell loss and mossy-fibre
glomerular pathology against age-matched controls. Human neuropathology
currently rests on isolated case reports, so the entry's Purkinje-centric
cell-type annotation is not presently testable against a series.
supporting_outcome:
- Selective Purkinje neuron loss out of proportion to granule cell loss.
refuting_outcome:
- Granule cell or mossy-fibre pathology predominating with relatively preserved Purkinje populations.
- experiment_id: exp_syne1_celltype_specific_ablation
name: Cell-type-specific Syne1 ablation in mouse
description: >-
Ablate Syne1 selectively in Purkinje cells versus granule cells in mouse
and compare ataxia severity and cerebellar histology, to establish which
population is sufficient to produce the phenotype.
supporting_outcome:
- Purkinje-restricted ablation reproducing ataxia.
refuting_outcome:
- Only granule-cell-restricted ablation reproducing ataxia.
- experiment_id: exp_klnes1g_human_cerebellum_localization
name: KASH-less nesprin-1 isoform expression in human cerebellum
description: >-
Determine whether the KASH-less nesprin-1 isoform is expressed and
similarly localized in human cerebellum. The existing splicing and
immunogold localization data are from mouse, so the translational
validity of the synaptic model to human disease is untested.
supporting_outcome:
- Detection of the KASH-less isoform at human mossy-fibre glomeruli.
refuting_outcome:
- Absence of the isoform, or exclusively nuclear-envelope localization, in human cerebellum.
notes: >-
Recorded during the 2026-08 publication-readiness review. The conformance
and the Purkinje cell_types annotations are deliberately retained as the
mainstream model rather than removed, but they should not be read as
evidence-backed claims about the proximal cellular target. PMID:36525394
(an autopsied SYNE1-ataxia patient) is listed under references as a
bibliographic pointer only and is deliberately not cited as evidence
anywhere in this entry: PubMed carries no abstract for that letter, so no
snippet can be verified against a cached source. Mine it for evidence if
full text ever reaches the cache.
review_notes: >-
Publication-readiness review, August 2026. Baseline was already schema-valid
with 100% recommended-field compliance and 46/46 verified snippets, so this
pass targeted content completeness and claim-evidence alignment rather than
structure. Changes: added the three GeneReviews-defined presentations as
has_subtypes so severe-end features can be curated without leaking into the
adult-onset Beauce founder phenotype; added 21 source-backed phenotypes and
wired every one of them into the pathograph; declared conformance to
cerebellar_purkinje_degeneration; tagged biological_scale; converted the
free-text prevalence record to the structured measure_type/prevalence_class/
rate_per_100000 slots; and added differential diagnoses. Snippet count went
46 -> 96, all verified.
Claim-evidence alignment fixes. (1) The EMERGING synaptic-isoform hypothesis
was supported only by a generic LINC-complex review whose quoted sentence
never mentions an isoform; it now cites the primary source (PMID:25843669)
for both the KASH-less cerebellar isoform and its synaptic localization.
(2) Dysarthria claimed "present in essentially all patients in the founder
cohort" and a VERY_FREQUENT band that no source quantified; the description
now tracks what Dupre actually wrote and the band is explicitly justified as
a qualitative mapping. (3) The FREQUENT band on upper motor neuron
dysfunction is likewise now tied to the source word "many". (4) Component
motor-neuron signs are curated WITHOUT frequency bands, because the source
quantifies the UMN and LMN arms as wholes and not the individual signs.
(5) The prevalence record now states that 2.67/100,000 is a minimum
founder-population figure and not a worldwide rate.
Dispositions for the 19 remaining D2P recommendations, none of which are
adopted in this pass:
- Peripheral-neuropathy cluster (HP:0003477 peripheral axonal neuropathy,
HP:0003390 sensory axonal neuropathy, HP:0007267 chronic axonal
neuropathy, HP:0007178 motor polyneuropathy, HP:0001271 polyneuropathy,
HP:0003445 EMG neuropathic changes, HP:0002495 impaired vibratory
sensation). NOT ADDED, deliberately. The ARCA1 founder phenotype is
defined in part by normal nerve conduction studies, and normal NCS is what
separates it from Friedreich ataxia and ARSACS in the differential above.
OMIM/Orphanet carry these at Very rare/Occasional, presumably from
non-founder SYNE1 cohorts. Adding them unqualified would contradict the
entry's own definition; adding them qualified needs a cohort source that
reports neuropathy in genetically confirmed SYNE1 patients, which is not
in the cache. Revisit with such a source.
- Skeletal/ocular items (HP:0002808 kyphosis, HP:0000508 ptosis, HP:0000597
ophthalmoparesis, HP:0031960 arm dystonia, HP:0000020 urinary
incontinence, HP:0002312 clumsiness, HP:0007366 brainstem atrophy,
HP:0002500 abnormal cerebral white matter, HP:0001270 motor delay). NOT
ADDED: no cached source supports any of them with a quotable snippet, and
HP:0002500 and HP:0007366 additionally sit against this entry's curated
claim that the classic phenotype shows cerebellar atrophy without
brainstem or white-matter involvement. Fetch primary sources before
adopting.
- Broader-term flags (HP:0002061 lower limb spasticity vs curated HP:0001257
spasticity; HP:0007340 lower limb muscle weakness vs curated HP:0001324
muscle weakness; HP:0011448 ankle clonus under HP:0002493). NOT
NARROWED: GeneReviews names spasticity and muscle weakness without limb
localization, so the broader terms are what the evidence actually supports.
Narrowing would assert a distribution no cited source states. Ankle clonus
is not named in any cached source.
Also unresolved and worth flagging beyond this entry: `just refresh-orphadata`
currently fails a checksum check against the pinned manifest (upstream
Orphadata has drifted), so ORPHA:88644 could not be cached and Orphanet
frequency rows were unavailable as evidence for this review. That blocks
Orphanet-backed frequency curation repo-wide, not just here.
datasets: []
References & Deep Research
References
2SYNE1 Deficiency.
No top-level findings curated for this source.
SYNE1-ataxia: clinicopathologic features of an autopsied patient with novel compound heterozygous mutations.
No top-level findings curated for this source.
Deep Research
1
Falcon
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Autosomal Recessive Ataxia Beauce Type (ARCA1 / SCAR8 / ATX‑SYNE1): Comprehensive Disease Characteristics Report
Executive summary
Autosomal recessive ataxia Beauce type is a SYNE1-related, autosomal recessive hereditary cerebellar ataxia originally described in French-Canadian families from the Beauce and Bas–St‑Laurent regions of Quebec and now recognized worldwide with a broader “cerebellar-plus” spectrum. It is classically an adult-onset, slowly progressive, predominantly cerebellar syndrome with diffuse cerebellar atrophy and minimal extracerebellar involvement in the Quebec founder phenotype, but other cohorts (e.g., China) show earlier onset and frequent motor-neuron/cognitive involvement. The causal mechanism is typically biallelic loss-of-function SYNE1 variants affecting nesprin‑1/LINC (linker of nucleoskeleton to cytoskeleton) biology and potentially cerebellum-specific synaptic isoforms. (dupre2007clinicalandgenetic pages 2-3, duan2021autosomalrecessivecerebellar pages 1-2, kuwako2024diverserolesof pages 11-12)
1. Disease information
1.1 Overview / definition
- Disease concept: SYNE1-related autosomal recessive cerebellar ataxia characterized by progressive gait and limb ataxia and cerebellar dysarthria, with cerebellar atrophy on neuroimaging; originally described as a cluster in the Beauce region (Quebec) and mapped to SYNE1 at 6q. (dupre2007clinicalandgenetic pages 1-2, dupre2007clinicalandgenetic pages 2-3)
- Current understanding: SYNE1-related ataxia can present as “pure” cerebellar ataxia or as a multisystem disorder with upper and/or lower motor neuron dysfunction and cognitive impairment, among others. (serag2023acasereport pages 1-2, duan2021autosomalrecessivecerebellar pages 2-4)
1.2 Key identifiers (available from retrieved evidence)
- OMIM / MIM (disease): 610743 (ARCA1/SCAR8/recessive ataxia of Beauce). (rudaks2024anupdateon pages 7-8, duan2021autosomalrecessivecerebellar pages 1-2, thiffault2009caractérisationcliniqueet pages 39-43)
- OMIM (gene SYNE1): 608441. (duan2021autosomalrecessivecerebellar pages 1-2, szpisjak2021eyetrackingaidedcharacterizationof pages 1-2, thiffault2009caractérisationcliniqueet pages 39-43)
- Chromosomal locus: 6q25.2 (gene-based nomenclature table). (rudaks2024anupdateon pages 7-8)
1.3 Synonyms / alternative names
- Autosomal recessive cerebellar ataxia type 1 (ARCA1) (duan2021autosomalrecessivecerebellar pages 1-2, thiffault2009caractérisationcliniqueet pages 39-43)
- Spinocerebellar ataxia, autosomal recessive 8 (SCAR8) (duan2021autosomalrecessivecerebellar pages 1-2, szpisjak2021eyetrackingaidedcharacterizationof pages 1-2)
- Recessive ataxia of Beauce / Beauce ataxia (rudaks2024anupdateon pages 7-8, szpisjak2021eyetrackingaidedcharacterizationof pages 1-2)
- ATX‑SYNE1 (proposed gene-based nomenclature in adult-onset HCA review) (rudaks2024anupdateon pages 7-8)
1.4 Resource provenance
The evidence summarized here is derived primarily from: - Aggregated disease-level research cohorts (Eastern Quebec epidemiology; Chinese cohort). (salem2021geneticandepidemiological pages 1-2, duan2021autosomalrecessivecerebellar pages 1-2) - Founder/cohort clinical-genetic characterization in Quebec families. (dupre2007clinicalandgenetic pages 2-3, dupre2008étudecliniqueeta pages 23-29) - Recent single-family genomic diagnostic case report. (serag2023acasereport pages 1-2)
1.5 Identifiers not confirmed in the retrieved corpus
- MONDO ID, Orphanet ID, MeSH term, ICD‑10/ICD‑11 codes: not found in the retrieved full texts; these typically require direct lookup in ontology/databases rather than primary papers. (rudaks2024anupdateon pages 7-8, szpisjak2021eyetrackingaidedcharacterizationof pages 1-2)
2. Etiology
2.1 Disease causal factors
- Primary cause: biallelic pathogenic variants in SYNE1 (nesprin‑1), most commonly truncating loss-of-function variants, cause ARCA1/SCAR8. (dupre2007clinicalandgenetic pages 2-3, duan2021autosomalrecessivecerebellar pages 1-2)
- Recent development (2023): first report of a large intragenic deletion in SYNE1 causing ARCA1 (compound heterozygous with a nonsense allele), highlighting structural variants as an etiologic class that may be missed by standard WES pipelines. (serag2023acasereport pages 4-5, serag2023acasereport pages 1-2)
Direct abstract quote (2023 case report): “Whole exome sequencing (WES), supplemented by a high-resolution array… allowed us to identify two pathogenic variants in the non-mitochondrial SYNE1 gene… To our knowledge, this is the first report of a large intragenic deletion of SYNE1 in patients with cerebellar ataxia (ARCA1).” (Published 29 Nov 2023; URL: https://doi.org/10.3390/genes14122154) (serag2023acasereport pages 1-2)
2.2 Risk factors
- Genetic: autosomal recessive inheritance; founder variants in Quebec/Eastern Quebec significantly contribute to regional burden. (dupre2007clinicalandgenetic pages 2-3, salem2021geneticandepidemiological pages 3-4)
- Environmental: no established environmental risk factors were identified in the retrieved evidence; current understanding supports a primarily genetic etiology. (dupre2007clinicalandgenetic pages 2-3, serag2023acasereport pages 1-2)
2.3 Protective factors / gene–environment interactions
No specific protective genetic variants or gene–environment interactions were found in the retrieved evidence corpus. (dupre2007clinicalandgenetic pages 2-3, serag2023acasereport pages 1-2)
3. Phenotypes (clinical spectrum)
3.1 Core cerebellar phenotype (Quebec founder phenotype)
From the 64-subject Beauce cohort: - Age at onset: ataxia mean 31.60 years (range 17–45); dysarthria mean 34.79 years (range 17–50). (dupre2008étudecliniqueeta pages 23-29) - First symptom: ataxia 62.5%, dysarthria 12.5%, both 25%. (dupre2008étudecliniqueeta pages 23-29) - Symptom frequencies: dysarthria 100%, ataxia 98.4%, dysmetria ~90.6%; abnormal pursuit 43.8%, slow saccades 31.2%, nystagmus 9.4%; brisk lower-limb reflexes 32.8%, Babinski/clonus 6.2%. (dupre2008étudecliniqueeta pages 23-29) - Imaging: CT/MRI in 50 subjects “invariably showed marked diffuse cerebellar atrophy” with no cortical/brainstem/white-matter involvement. (dupre2008étudecliniqueeta pages 23-29) - Neurophysiology: nerve conduction studies normal in 22/22 (no peripheral neuropathy). (dupre2008étudecliniqueeta pages 23-29) - Natural history: slowly progressive to moderate disability with “no effect on life expectancy.” (dupre2007clinicalandgenetic pages 2-3, dupre2008étudecliniqueeta pages 23-29)
3.2 Broader “cerebellar-plus” phenotype (non-founder cohorts)
From the Chinese cohort (8 affected individuals): - Onset: 10–27 years (median 18). (duan2021autosomalrecessivecerebellar pages 2-4) - Phenotypic categories at last follow-up: pure cerebellar ataxia 2/8; ataxia + motor neuron disease 3/8; ataxia + cognitive impairment 2/8; ataxia + motor neuron disease + mental retardation 1/8. (duan2021autosomalrecessivecerebellar pages 2-4) - Severity metrics: SARA 12.88 ± 3.56; ICARS 33.63 ± 6.44. (duan2021autosomalrecessivecerebellar pages 2-4) - Reported extracerebellar features (compiled by authors): motor neuron disease, cognitive impairment/intellectual disability, brainstem dysfunction, musculoskeletal deformities, and others. (duan2021autosomalrecessivecerebellar pages 2-4)
Direct abstract quote (2020 accepted; published in 2021 issue): “Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause autosomal recessive cerebellar ataxia (ARCA) type 1 with highly variable clinical phenotypes.” (URL: https://doi.org/10.1007/s12311-020-01186-8) (duan2021autosomalrecessivecerebellar pages 1-2)
3.3 HPO term suggestions (non-exhaustive)
Core neurologic: - Cerebellar ataxia (HP:0001251) (dupre2008étudecliniqueeta pages 23-29) - Gait ataxia (HP:0002066) (dupre2008étudecliniqueeta pages 23-29) - Limb ataxia (HP:0002060) (dupre2008étudecliniqueeta pages 23-29) - Cerebellar dysarthria / Dysarthria (HP:0001260) (dupre2008étudecliniqueeta pages 23-29) - Dysmetria (HP:0001310) (dupre2008étudecliniqueeta pages 23-29) - Abnormal smooth pursuit (HP:0000658) (dupre2008étudecliniqueeta pages 23-29) - Slow saccades (HP:0000644) (dupre2008étudecliniqueeta pages 23-29) - Nystagmus (HP:0000639) (dupre2008étudecliniqueeta pages 23-29)
Cerebellar-plus (variable): - Upper motor neuron signs / Spasticity (HP:0001257), Hyperreflexia (HP:0001347), Babinski sign (HP:0003487) (serag2023acasereport pages 1-2) - Motor neuron disease (HP:0007354) (duan2021autosomalrecessivecerebellar pages 2-4) - Cognitive impairment (HP:0100543) / Intellectual disability (HP:0001249) (duan2021autosomalrecessivecerebellar pages 2-4)
Imaging: - Cerebellar atrophy (HP:0001272) (dupre2008étudecliniqueeta pages 23-29)
4. Genetic / molecular information
4.1 Causal gene
- SYNE1 encodes nesprin‑1, a very large nuclear envelope spectrin-repeat protein involved in LINC complexes; SYNE1 is among the largest human genes (longest isoform 147 exons; ~8797 aa protein). (duan2021autosomalrecessivecerebellar pages 1-2)
4.2 Variant classes and examples
- Quebec founder cohort shows multiple truncating alleles, with a major recurrent allele representing ~50.8% of carrier chromosomes in the patient series. (dupre2008étudecliniqueeta pages 29-34)
- 2023 case report identifies compound heterozygosity including a large intragenic deletion (exon 122 deletion) plus a nonsense variant c.13258C>T p.(Arg4420Ter). (serag2023acasereport pages 4-5)
4.3 Variant distribution/interpretation (expert synthesis)
- Review of LINC-complex disease genetics notes the majority of disease-associated SYNE1 variants are coding and enriched for truncating loss-of-function, consistent with a loss-of-function mechanism, and that SCAR8 accounts for the bulk of reported SYNE1 disease associations. (kuwako2024diverserolesof pages 11-12)
4.4 Modifier genes / epigenetics / chromosomal abnormalities
No specific modifier genes or epigenetic signatures for ARCA1 were identified in the retrieved evidence corpus. (kuwako2024diverserolesof pages 11-12, serag2023acasereport pages 1-2)
5. Environmental information
No validated non-genetic environmental contributors were identified in the retrieved evidence corpus. (dupre2007clinicalandgenetic pages 2-3, serag2023acasereport pages 1-2)
6. Mechanism / pathophysiology
6.1 Current mechanistic model
- Nesprin‑1 (SYNE1) participates in the LINC complex (SUN–KASH bridging across the nuclear envelope), physically coupling cytoskeletal forces to nuclear structure and positioning; ARCA1 is believed to arise predominantly from loss-of-function leading to absent or truncated nesprin‑1. (duan2021autosomalrecessivecerebellar pages 1-2, kuwako2024diverserolesof pages 11-12)
- A Quebec founder analysis hypothesized impaired spectrin interactions and altered nuclear structure in cerebellar neurons (particularly Purkinje cells) as a proximate cause of cerebellar degeneration. (dupre2008étudecliniqueeta pages 34-39)
6.2 Synaptic/cerebellar isoform hypothesis (2024 review evidence)
- A cerebellum-enriched SYNE1 isoform (KLNes1g) lacking the KASH domain localizes to mossy-fiber synapses and binds clathrin on synaptic vesicles, suggesting a synaptic mechanism contributing to cerebellar vulnerability, although direct causation remains unresolved. (kuwako2024diverserolesof pages 11-12, kuwako2024diverserolesof pages 12-14)
6.3 Model organism evidence (supporting LINC relevance to ataxia)
- SUN1 knockout mice develop cerebellar ataxia with Purkinje cell migration/dendritic/synaptic abnormalities and mislocalization of nesprin proteins, supporting LINC-complex necessity for cerebellar motor function, even though nesprin‑1 knockout models may not fully recapitulate human SCAR8. (kuwako2024diverserolesof pages 12-14, litster2026duplicationwithin14q32.13 pages 20-23)
6.4 Suggested ontology terms
- GO Biological Process (suggestions): nuclear migration; nuclear anchoring; cytoskeleton organization; synaptic vesicle endocytosis; mechanotransduction.
- GO Cellular Component (suggestions): nuclear envelope; outer nuclear membrane; LINC complex; synapse.
- CL Cell types (suggestions): Purkinje cell (cerebellar cortex), cerebellar granule neuron.
(These ontology suggestions are consistent with the described LINC/nesprin/synaptic localization evidence but were not explicitly enumerated as ontology IDs in the retrieved texts.) (kuwako2024diverserolesof pages 11-12, kuwako2024diverserolesof pages 12-14)
7. Anatomical structures affected
7.1 Primary systems/organs
- Central nervous system, cerebellum with diffuse cerebellar atrophy is the dominant structural correlate in classic Beauce phenotype. (dupre2008étudecliniqueeta pages 23-29)
7.2 Tissue/cell populations
- Cerebellar neuronal vulnerability is supported by the strong cerebellar expression of SYNE1 and atrophy pattern. (duan2021autosomalrecessivecerebellar pages 1-2, dupre2008étudecliniqueeta pages 23-29)
7.3 UBERON suggestions
- Cerebellum (UBERON:0002037)
- Cerebellar cortex (UBERON:0004720)
- Cerebellar Purkinje cell layer (UBERON term varies by ontology release)
8. Temporal development
- Onset: typically early-to-mid adulthood in Quebec founder cohorts (~30s), but can be childhood/young-adult in other populations. (dupre2008étudecliniqueeta pages 23-29, duan2021autosomalrecessivecerebellar pages 2-4)
- Course: slowly progressive with moderate disability in classic Beauce phenotype; multisystem progression occurs in cerebellar-plus forms. (dupre2008étudecliniqueeta pages 23-29, duan2021autosomalrecessivecerebellar pages 2-4)
9. Inheritance and population
9.1 Inheritance
- Autosomal recessive inheritance is consistently reported. (dupre2007clinicalandgenetic pages 2-3, serag2023acasereport pages 1-2)
9.2 Epidemiology (statistics)
Eastern Quebec regional study (published 2021; URL: https://doi.org/10.1017/cjn.2020.277): - Minimum prevalence of adult hereditary ataxias: 6.47/100,000; AR ataxias: 3.73/100,000. (salem2021geneticandepidemiological pages 1-2) - ARCA1 prevalence: 2.67/100,000. (salem2021geneticandepidemiological pages 1-2, salem2021geneticandepidemiological pages 3-4) - 52.4% of patients had a confirmed genetic diagnosis. (salem2021geneticandepidemiological pages 1-2)
Direct abstract quote (2021): “The minimum prevalence of HA in Eastern Quebec was estimated at 6.47/100 000… In total, 52.4% of patients had a confirmed genetic diagnosis. AR cerebellar ataxia type 1 (2.67/100 000)… were the most prevalent disorders identified.” (salem2021geneticandepidemiological pages 1-2)
Variant-specific minimum carrier frequencies (Eastern Quebec): examples include c.15705–12 A>G 1/134 and p.Arg2906Ter 1/200. (salem2021geneticandepidemiological pages 6-7)
Quebec prevalence estimate in Beauce-focused thesis text: ~1/1,000,000 in the Quebec population (estimate; not a modern province-wide registry-based statistic). (thiffault2009caractérisationcliniqueet pages 39-43)
10. Diagnostics
10.1 Clinical evaluation
- Imaging: brain MRI demonstrating diffuse cerebellar atrophy is a consistent finding in classic Beauce phenotype. (dupre2008étudecliniqueeta pages 23-29)
- Neurophysiology: normal nerve conduction studies in founder phenotype can help distinguish from ataxias with prominent neuropathy. (dupre2008étudecliniqueeta pages 23-29)
- Quantitative ataxia scales: SARA and ICARS were used in the Chinese cohort. (duan2021autosomalrecessivecerebellar pages 2-4)
10.2 Genetic testing (current practice and recent advances)
Key recent development (2023): CNV/structural variant detection matters in SYNE1. - WES may identify one allele but miss a second pathogenic structural variant; the 2023 case required high-resolution array-CGH to detect an intragenic SYNE1 deletion. (serag2023acasereport pages 1-2, serag2023acasereport pages 4-5)
2024 diagnostic approach review (adult-onset hereditary ataxia): - Testing often requires a combination of STR expansion testing plus sequencing for conventional variants (panel/WES/WGS), and long-read sequencing is highlighted as a future unifying modality. (rudaks2024anupdateon pages 1-2)
Direct abstract quote (2024): “Testing methods include targeted evaluation of STR expansions… next generation sequencing for conventional variants… Implementing long-read sequencing has the potential to transform the diagnostic approach…” (Accepted 7 May 2024; URL: https://doi.org/10.1007/s12311-024-01703-z) (rudaks2024anupdateon pages 1-2)
Visual evidence (diagnostic algorithm): Figure 2 provides a flowchart for genetic diagnosis of adult-onset hereditary cerebellar ataxia (STR expansion testing → NGS → long-read sequencing as later option). (rudaks2024anupdateon media daaff5ba)
10.3 Differential diagnosis
- Mitochondrial disease can be a diagnostic mimic in progressive ataxia; 2023 case report emphasizes that “more than 50% of patients with suspected mitochondrial disease could have a non-mitochondrial disorder” and shows SYNE1 can be one such cause. (serag2023acasereport pages 1-2)
- Other hereditary ataxias (repeat-expansion SCAs, FRDA, RFC1-related disease, etc.) must be excluded depending on phenotype/inheritance per adult-onset HCA diagnostic algorithms. (rudaks2024anupdateon pages 10-12, rudaks2024anupdateon media daaff5ba)
11. Outcome / prognosis
- In the Beauce founder phenotype, progression is slow, with evolution to moderate disability and “no effect on life expectancy.” (dupre2007clinicalandgenetic pages 2-3, dupre2008étudecliniqueeta pages 23-29)
- Broader multisystem phenotypes may have additional morbidity (e.g., motor neuron involvement), but survival statistics were not identified in the retrieved evidence corpus. (duan2021autosomalrecessivecerebellar pages 2-4)
12. Treatment
12.1 Disease-modifying therapy
No disease-modifying or gene-targeted therapy specific to SYNE1-related ARCA1/SCAR8 was identified in the retrieved sources. (serag2023acasereport pages 1-2, rudaks2024anupdateon pages 1-2)
12.2 Supportive and rehabilitative care (current real-world implementation)
While disease-specific protocols were not provided in the retrieved papers, clinical management is typically supportive (mobility aids; PT/OT; speech therapy for dysarthria; fall prevention; management of spasticity if present) based on the dominant cerebellar syndrome and any cerebellar-plus complications. The need for structured clinical evaluation and monitoring (SARA/ICARS; cognitive testing; MRI; EMG/NCS; ECG) is explicitly described in the Chinese cohort methods. (duan2021autosomalrecessivecerebellar pages 2-4)
12.3 Clinical trials landscape (not disease-specific)
Clinical trial searches retrieved rehabilitation-focused interventional studies in neurodegenerative ataxia (e.g., cerebello-spinal tDCS; supervised rehabilitation in spastic ataxias) but none specifically targeting SYNE1/ARCA1 at the time of retrieval. Examples include NCT04153110 and NCT03120013 (tDCS in neurodegenerative ataxia) and NCT06261424 (rehabilitation program in spastic ataxias). (serag2023acasereport pages 1-2)
MAXO suggestions (supportive actions): physical therapy; occupational therapy; speech therapy; assistive device use; genetic counseling.
13. Prevention
- Primary prevention: not applicable for established Mendelian disease except through reproductive options.
- Genetic counseling: indicated due to autosomal recessive inheritance; carrier testing/cascade screening is relevant in families and potentially in founder populations. (dupre2007clinicalandgenetic pages 2-3, salem2021geneticandepidemiological pages 6-7)
- Secondary prevention: early molecular diagnosis can prevent misdiagnosis and inappropriate workups (e.g., mitochondrial disease) and enables appropriate surveillance for cerebellar-plus features. (serag2023acasereport pages 1-2)
14. Other species / natural disease
No naturally occurring veterinary analogs were identified in the retrieved evidence corpus.
15. Model organisms
- Evidence implicating LINC biology in cerebellar motor function includes SUN1 knockout mice with cerebellar ataxia phenotypes and Purkinje cell abnormalities; nesprin-1 knockout models may not fully recapitulate human SCAR8. (kuwako2024diverserolesof pages 12-14, litster2026duplicationwithin14q32.13 pages 20-23)
Notes on evidence gaps and 2023–2024 prioritization
- Key 2023–2024 advances captured here include: (i) recognition of SYNE1 CNVs (first large intragenic deletion reported) and the need for CNV-sensitive/pangenomic diagnostics (2023), and (ii) updated adult-onset hereditary ataxia diagnostic algorithms and the expected role of long-read sequencing (2024). (serag2023acasereport pages 1-2, rudaks2024anupdateon media daaff5ba, rudaks2024anupdateon pages 1-2)
- Disease identifiers beyond OMIM (MONDO/Orphanet/MeSH/ICD) were not present in the retrieved texts and require direct database lookup to complete a knowledge base entry. (rudaks2024anupdateon pages 7-8, szpisjak2021eyetrackingaidedcharacterizationof pages 1-2)
References
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(dupre2007clinicalandgenetic pages 2-3): Nicolas Dupré, François Gros‐Louis, Nicolas Chrestian, Steve Verreault, Denis Brunet, Danielle de Verteuil, Bernard Brais, Jean‐Pierre Bouchard, and Guy A. Rouleau. Clinical and genetic study of autosomal recessive cerebellar ataxia type 1. Annals of Neurology, 62:93-98, Jul 2007. URL: https://doi.org/10.1002/ana.21143, doi:10.1002/ana.21143. This article has 101 citations and is from a highest quality peer-reviewed journal.
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(duan2021autosomalrecessivecerebellar pages 1-2): Xiaohui Duan, Ying Hao, Zhenhua Cao, Chao Zhou, Jin Zhang, Renbin Wang, Shaojie Sun, and Weihong Gu. Autosomal recessive cerebellar ataxia type 1: phenotypic and genetic correlation in a cohort of chinese patients with syne1 variants. The Cerebellum, 20:74-82, Sep 2021. URL: https://doi.org/10.1007/s12311-020-01186-8, doi:10.1007/s12311-020-01186-8. This article has 16 citations.
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(kuwako2024diverserolesof pages 11-12): Ken-ichiro Kuwako and Sadafumi Suzuki. Diverse roles of the linc complex in cellular function and disease in the nervous system. International Journal of Molecular Sciences, 25:11525, Oct 2024. URL: https://doi.org/10.3390/ijms252111525, doi:10.3390/ijms252111525. This article has 4 citations.
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(dupre2007clinicalandgenetic pages 1-2): Nicolas Dupré, François Gros‐Louis, Nicolas Chrestian, Steve Verreault, Denis Brunet, Danielle de Verteuil, Bernard Brais, Jean‐Pierre Bouchard, and Guy A. Rouleau. Clinical and genetic study of autosomal recessive cerebellar ataxia type 1. Annals of Neurology, 62:93-98, Jul 2007. URL: https://doi.org/10.1002/ana.21143, doi:10.1002/ana.21143. This article has 101 citations and is from a highest quality peer-reviewed journal.
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(serag2023acasereport pages 1-2): Mounir Serag, Morgane Plutino, Perrine Charles, Jean-Philippe Azulay, Annabelle Chaussenot, Véronique Paquis-Flucklinger, Samira Ait-El-Mkadem Saadi, and Cécile Rouzier. A case report of syne1 deficiency-mimicking mitochondrial disease and the value of pangenomic investigations. Genes, 14:2154, Nov 2023. URL: https://doi.org/10.3390/genes14122154, doi:10.3390/genes14122154. This article has 1 citations.
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(duan2021autosomalrecessivecerebellar pages 2-4): Xiaohui Duan, Ying Hao, Zhenhua Cao, Chao Zhou, Jin Zhang, Renbin Wang, Shaojie Sun, and Weihong Gu. Autosomal recessive cerebellar ataxia type 1: phenotypic and genetic correlation in a cohort of chinese patients with syne1 variants. The Cerebellum, 20:74-82, Sep 2021. URL: https://doi.org/10.1007/s12311-020-01186-8, doi:10.1007/s12311-020-01186-8. This article has 16 citations.
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(rudaks2024anupdateon pages 7-8): Laura Ivete Rudaks, Dennis Yeow, Karl Ng, Ira W. Deveson, Marina L. Kennerson, and Kishore Raj Kumar. An update on the adult-onset hereditary cerebellar ataxias: novel genetic causes and new diagnostic approaches. Cerebellum (London, England), 23:2152-2168, May 2024. URL: https://doi.org/10.1007/s12311-024-01703-z, doi:10.1007/s12311-024-01703-z. This article has 54 citations.
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(thiffault2009caractérisationcliniqueet pages 39-43): I Thiffault. Caractérisation clinique et génétique d'une nouvelle forme d'ataxie autosomique récessive dans la population québécoise. Unknown journal, 2009.
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(szpisjak2021eyetrackingaidedcharacterizationof pages 1-2): Laszlo Szpisjak, Gabor Szaraz, Andras Salamon, Viola L. Nemeth, Noemi Szepfalusi, Gabor Veres, Balint Kincses, Zoltan Maroti, Tibor Kalmar, Malgorzata Rydzanicz, Rafal Ploski, Peter Klivenyi, and Denes Zadori. Eye-tracking-aided characterization of saccades and antisaccades in syne1 ataxia patients: a pilot study. BMC Neuroscience, Feb 2021. URL: https://doi.org/10.1186/s12868-021-00612-9, doi:10.1186/s12868-021-00612-9. This article has 7 citations and is from a peer-reviewed journal.
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(salem2021geneticandepidemiological pages 1-2): Ikhlass Haj Salem, Marie Beaudin, Monica Stumpf, Mehrdad A. Estiar, Pierre-Olivier Côté, Francis Brunet, Pierre-Luc Gamache, Guy A. Rouleau, Karim Mourabit-Amari, Ziv Gan-Or, and Nicolas Dupré. Genetic and epidemiological study of adult ataxia and spastic paraplegia in eastern quebec. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 48:655-665, Jan 2021. URL: https://doi.org/10.1017/cjn.2020.277, doi:10.1017/cjn.2020.277. This article has 12 citations.
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(dupre2008étudecliniqueeta pages 23-29): N Dupré. Étude clinique et génétique de l'ataxie récessive de la beauce. Unknown journal, 2008.
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(serag2023acasereport pages 4-5): Mounir Serag, Morgane Plutino, Perrine Charles, Jean-Philippe Azulay, Annabelle Chaussenot, Véronique Paquis-Flucklinger, Samira Ait-El-Mkadem Saadi, and Cécile Rouzier. A case report of syne1 deficiency-mimicking mitochondrial disease and the value of pangenomic investigations. Genes, 14:2154, Nov 2023. URL: https://doi.org/10.3390/genes14122154, doi:10.3390/genes14122154. This article has 1 citations.
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(salem2021geneticandepidemiological pages 3-4): Ikhlass Haj Salem, Marie Beaudin, Monica Stumpf, Mehrdad A. Estiar, Pierre-Olivier Côté, Francis Brunet, Pierre-Luc Gamache, Guy A. Rouleau, Karim Mourabit-Amari, Ziv Gan-Or, and Nicolas Dupré. Genetic and epidemiological study of adult ataxia and spastic paraplegia in eastern quebec. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 48:655-665, Jan 2021. URL: https://doi.org/10.1017/cjn.2020.277, doi:10.1017/cjn.2020.277. This article has 12 citations.
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(dupre2008étudecliniqueeta pages 29-34): N Dupré. Étude clinique et génétique de l'ataxie récessive de la beauce. Unknown journal, 2008.
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(dupre2008étudecliniqueeta pages 34-39): N Dupré. Étude clinique et génétique de l'ataxie récessive de la beauce. Unknown journal, 2008.
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(kuwako2024diverserolesof pages 12-14): Ken-ichiro Kuwako and Sadafumi Suzuki. Diverse roles of the linc complex in cellular function and disease in the nervous system. International Journal of Molecular Sciences, 25:11525, Oct 2024. URL: https://doi.org/10.3390/ijms252111525, doi:10.3390/ijms252111525. This article has 4 citations.
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(litster2026duplicationwithin14q32.13 pages 20-23): Thomas M Litster, Robert A Wilcox, Renée Carroll, Alison E Gardner, Nazzmer M Nazri, Cheryl A Shoubridge, Martin B Delatycki, Katja Lohmann, Marc Agzarian, Rafaela Turella Divani, Haloom Rafehi, Liam Scott, Gavin Monahan, Phillipa J Lamont, Catherine Ashton, Nigel G Laing, Gianina Ravenscroft, Melanie Bahlo, Eric Haan, Paul J Lockhart, Kathryn L Friend, Mark A Corbett, and Jozef Gecz. Duplication within 14q32.13 implicates a chimeric clmn :: syne3 rna transcript in cerebellar ataxia. Unknown journal, Apr 2026. URL: https://doi.org/10.64898/2026.04.23.26350376, doi:10.64898/2026.04.23.26350376.
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(salem2021geneticandepidemiological pages 6-7): Ikhlass Haj Salem, Marie Beaudin, Monica Stumpf, Mehrdad A. Estiar, Pierre-Olivier Côté, Francis Brunet, Pierre-Luc Gamache, Guy A. Rouleau, Karim Mourabit-Amari, Ziv Gan-Or, and Nicolas Dupré. Genetic and epidemiological study of adult ataxia and spastic paraplegia in eastern quebec. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 48:655-665, Jan 2021. URL: https://doi.org/10.1017/cjn.2020.277, doi:10.1017/cjn.2020.277. This article has 12 citations.
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(rudaks2024anupdateon pages 1-2): Laura Ivete Rudaks, Dennis Yeow, Karl Ng, Ira W. Deveson, Marina L. Kennerson, and Kishore Raj Kumar. An update on the adult-onset hereditary cerebellar ataxias: novel genetic causes and new diagnostic approaches. Cerebellum (London, England), 23:2152-2168, May 2024. URL: https://doi.org/10.1007/s12311-024-01703-z, doi:10.1007/s12311-024-01703-z. This article has 54 citations.
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(rudaks2024anupdateon media daaff5ba): Laura Ivete Rudaks, Dennis Yeow, Karl Ng, Ira W. Deveson, Marina L. Kennerson, and Kishore Raj Kumar. An update on the adult-onset hereditary cerebellar ataxias: novel genetic causes and new diagnostic approaches. Cerebellum (London, England), 23:2152-2168, May 2024. URL: https://doi.org/10.1007/s12311-024-01703-z, doi:10.1007/s12311-024-01703-z. This article has 54 citations.
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(rudaks2024anupdateon pages 10-12): Laura Ivete Rudaks, Dennis Yeow, Karl Ng, Ira W. Deveson, Marina L. Kennerson, and Kishore Raj Kumar. An update on the adult-onset hereditary cerebellar ataxias: novel genetic causes and new diagnostic approaches. Cerebellum (London, England), 23:2152-2168, May 2024. URL: https://doi.org/10.1007/s12311-024-01703-z, doi:10.1007/s12311-024-01703-z. This article has 54 citations.
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