👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

ARCA1/SYNE1 deficiency is caused by biallelic pathogenic SYNE1 variants and follows autosomal recessive inheritance.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:20301553 SUPPORT Human Clinical

"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.

◈

Mechanistic Hypotheses

2

Canonical SYNE1/Nesprin-1 Loss-of-Function LINC Model

canonical_syne1_loss_linc_model CANONICAL

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)

PMID:17503513 SUPPORT Human Clinical

"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

cerebellar_synaptic_nesprin_isoform_model EMERGING

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 is supported by expression/localization and review-level synthesis rather than direct causal demonstration in SCAR8 patients.

Show evidence (1 reference)

PMID:39519078 SUPPORT Other

"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.

⚙

Pathophysiology

3

SYNE1/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.

SYNE1 hgnc:17089 ↓ DECREASED

SYNE1 hgnc:17089

Downstream

Disrupted Nuclear-Cytoskeletal LINC Coupling Reduced or absent nesprin-1 impairs assembly and function of the LINC complex at the nuclear envelope.

Show evidence (2 references)

PMID:17503513 SUPPORT Human Clinical

"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.

PMID:38136976 SUPPORT Human Clinical

"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.

Cerebellar Purkinje cell CL:0000121 Cerebellar granule cell CL:0001031

Cytoskeleton organization GO:0007010 ⚠ ABNORMAL Nuclear migration / positioning GO:0007097 ⚠ ABNORMAL

Nuclear envelope GO:0005635 Nuclear inner membrane GO:0005637

Downstream

Cerebellar Neurodegeneration and Atrophy Disrupted nuclear-cytoskeletal coupling in cerebellar neurons leads to cerebellar degeneration manifesting as diffuse cerebellar atrophy.

Upper motor neuron dysfunction The broader SYNE1 deficiency spectrum includes upper motor neuron signs beyond the pure cerebellar phenotype.

Lower motor neuron involvement (cerebellar-plus) Cerebellar-plus SYNE1 deficiency can include lower motor neuron involvement outside the classic pure cerebellar presentation.

Show evidence (1 reference)

PMID:39519078 SUPPORT Other

"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.

Cerebellar Purkinje cell CL:0000121

Cerebellum UBERON:0002037 Cerebellar cortex UBERON:0002129

Downstream

Cerebellar atrophy Diffuse cerebellar atrophy is the imaging correlate of the cerebellar neurodegenerative process.

Cerebellar ataxia Cerebellar degeneration produces the progressive cerebellar ataxia syndrome.

Gait ataxia Cerebellar degeneration manifests clinically as gait ataxia.

Limb ataxia Cerebellar degeneration impairs appendicular coordination, producing limb ataxia.

Dysarthria Cerebellar degeneration causes the dysarthria component of the syndrome.

Dysmetria Cerebellar degeneration causes dysmetria as part of the pure cerebellar syndrome.

Abnormal ocular smooth pursuit Cerebellar degeneration affects ocular motor control, including smooth pursuit.

Slow saccades Cerebellar ocular motor involvement includes slow saccadic eye movements.

Nystagmus Cerebellar ocular motor involvement includes gaze-evoked nystagmus.

Cognitive impairment Cerebellar involvement can extend to cerebellar cognitive and affective syndrome.

Show evidence (1 reference)

PMID:17503513 SUPPORT Human Clinical

"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.

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Phenotypes

12

Eye 1

Nystagmus Nystagmus HP:0000639

Show evidence (1 reference)

PMID:33526008 SUPPORT Human Clinical

"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.

Nervous System 5

Cerebellar ataxia Ataxia HP:0001251

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:17503513 SUPPORT Human Clinical

"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 Gait ataxia HP:0002066

Show evidence (1 reference)

PMID:33526008 SUPPORT Human Clinical

"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 Dysarthria HP:0001260

Show evidence (1 reference)

PMID:17503513 SUPPORT Human Clinical

"slow progression and moderate disability, significant dysarthria"

Dupre 2007 describes significant dysarthria as a core feature of the syndrome.

Cerebellar atrophy Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:17503513 SUPPORT Human Clinical

"normal nerve conduction studies, and diffuse cerebellar atrophy on imaging"

Documents diffuse cerebellar atrophy on imaging.

Cognitive impairment Cognitive impairment HP:0100543

Show evidence (1 reference)

PMID:20301553 SUPPORT Human Clinical

"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.

Other 6

Limb ataxia Limb ataxia HP:0002070

Show evidence (1 reference)

PMID:33526008 SUPPORT Human Clinical

"the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria"

Confirms limb ataxia as a characteristic feature.

Dysmetria Dysmetria HP:0001310

Show evidence (1 reference)

PMID:20301553 SUPPORT Human Clinical

"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

Show evidence (1 reference)

PMID:20301553 SUPPORT Human Clinical

"abnormalities in ocular saccades and smooth pursuit"

GeneReviews documents abnormal ocular saccades and smooth pursuit.

Slow saccades Slow saccadic eye movements HP:0000514

Show evidence (1 reference)

PMID:33526008 SUPPORT Human Clinical

"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 Upper motor neuron dysfunction HP:0002493

Show evidence (1 reference)

PMID:20301553 SUPPORT Human Clinical

"many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign) and/or lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations)"

GeneReviews documents upper motor neuron dysfunction in many SYNE1-deficient patients.

Lower motor neuron involvement (cerebellar-plus) Abnormal lower motor neuron morphology HP:0002366

Show evidence (1 reference)

PMID:32889669 SUPPORT Human Clinical

"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.

🧬

Genetic Associations

1

Biallelic SYNE1 pathogenic variants

Gene: SYNE1 hgnc:17089

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20301553 SUPPORT Human Clinical

"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.

PMID:32889669 SUPPORT Human Clinical

"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

Action: supportive care MAXO:0000950

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)

PMID:20301553 SUPPORT Human Clinical

"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

Action: Physical Therapy NCIT:C15302

Rehabilitation to maintain mobility and address ataxia, spasticity, and weakness.

Show evidence (1 reference)

PMID:20301553 SUPPORT Human Clinical

"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

Action: speech therapy MAXO:0000930

Speech therapy for cerebellar dysarthria and, when present, dysphagia.

Show evidence (1 reference)

PMID:20301553 SUPPORT Human Clinical

"neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists"

GeneReviews includes speech therapy within multidisciplinary management.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

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)

PMID:20301553 SUPPORT Human Clinical

"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.

{ }

Source YAML

click to show

name: 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
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.
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 is supported by
    expression/localization and review-level synthesis rather than direct causal
    demonstration in SCAR8 patients.
  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: "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
  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.
- name: Disrupted Nuclear-Cytoskeletal LINC Coupling
  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.
- name: Cerebellar Neurodegeneration and Atrophy
  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.
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 (scanning) dysarthria, present in essentially all patients 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: "slow progression and moderate disability, significant dysarthria"
    explanation: Dupre 2007 describes significant dysarthria as a core feature of the syndrome.
- 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: >-
    A subset of SYNE1-deficient patients show upper motor neuron signs (spasticity,
    hyperreflexia, Babinski sign), part of the broader cerebellar-plus spectrum.
  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 documents upper motor neuron dysfunction in many SYNE1-deficient patients.
- 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.
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: MAXO:0000950
      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.
  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.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech 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)
  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, within an overall adult hereditary ataxia prevalence of
    6.47/100,000.
  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: "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.
datasets: []

📚

References & Deep Research

References

1

PMID:20301553

SYNE1 Deficiency.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Autosomal Recessive Ataxia Beauce Type (ARCA1 / SCAR8 / ATX‑SYNE1): Comprehensive Disease Characteristics Report

Edison Scientific Literature 27 citations 2026-06-04T11:45:34.278886

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

(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(dupre2008étudecliniqueeta pages 23-29): N Dupré. Étude clinique et génétique de l'ataxie récessive de la beauce. Unknown journal, 2008.
(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.
(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.
(dupre2008étudecliniqueeta pages 29-34): N Dupré. Étude clinique et génétique de l'ataxie récessive de la beauce. Unknown journal, 2008.
(dupre2008étudecliniqueeta pages 34-39): N Dupré. Étude clinique et génétique de l'ataxie récessive de la beauce. Unknown journal, 2008.
(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.
(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.
(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.
(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.
(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.
(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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## Context ID: pqac-00000045 Figure 2 on page 11 provides a comprehensive flowchart for the genetic diagnosis of adult-onset hereditary cerebellar ataxia. It ou

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Autosomal Recessive Ataxia Beauce Type (ARCA1 / SCAR8 / ATX‑SYNE1): Comprehensive Disease Characteristics Report

Executive summary

1. Disease information

1.1 Overview / definition

1.2 Key identifiers (available from retrieved evidence)

1.3 Synonyms / alternative names

1.4 Resource provenance

1.5 Identifiers not confirmed in the retrieved corpus

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors / gene–environment interactions

3. Phenotypes (clinical spectrum)

3.1 Core cerebellar phenotype (Quebec founder phenotype)

3.2 Broader “cerebellar-plus” phenotype (non-founder cohorts)

3.3 HPO term suggestions (non-exhaustive)

4. Genetic / molecular information

4.1 Causal gene

4.2 Variant classes and examples

4.3 Variant distribution/interpretation (expert synthesis)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Current mechanistic model

6.2 Synaptic/cerebellar isoform hypothesis (2024 review evidence)

6.3 Model organism evidence (supporting LINC relevance to ataxia)

6.4 Suggested ontology terms

7. Anatomical structures affected

7.1 Primary systems/organs

7.2 Tissue/cell populations

7.3 UBERON suggestions

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology (statistics)

10. Diagnostics

10.1 Clinical evaluation

10.2 Genetic testing (current practice and recent advances)

10.3 Differential diagnosis

11. Outcome / prognosis

12. Treatment

12.1 Disease-modifying therapy

12.2 Supportive and rehabilitative care (current real-world implementation)

12.3 Clinical trials landscape (not disease-specific)

13. Prevention

14. Other species / natural disease

15. Model organisms

Notes on evidence gaps and 2023–2024 prioritization

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