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Classifications

Harrison's Part

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic GDAP2 variants in every reported patient: homozygous null variants in a Spanish and a further family, and biallelic gene-disruptive variants in the two patients of the defining series. In the Spanish family the heterozygous mother, brother and nephews were unaffected carriers.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease"

Defining report of a recessive cerebellar ataxia caused by biallelic GDAP2 variants.

PMID:40469082 SUPPORT Human clinical

"It was also detected in the patient's mother and brother, who were heterozygous, and 4 nephews on the paternal side, who were also carriers of the variant."

Segregation with unaffected heterozygous relatives, consistent with recessive inheritance.

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Discussions and Knowledge Gaps

2

What does GDAP2 do in human neurons, and does its loss make them vulnerable to oxidative or metabolic stress?

KNOWLEDGE GAP scar27_gdap2_function

Attached to

pathophysiology#GDAP2 Loss of Function pathophysiology#Impaired Neuronal Stress Response

The stress-susceptibility mechanism rests on one Drosophila RNAi model. GDAP2 has a macro domain and a CRAL-TRIO domain but no demonstrated biochemical activity, and no mammalian loss-of-function model of the ataxia has been reported. Why a protein without known neuron-restricted expression causes adult-onset, cerebellum-predominant degeneration is unexplained.

Show evidence (1 reference)

PMID:30084953 SUPPORT Model organism

"Thus, Gdap2 knockdown in Drosophila and GDAP2 loss-of-function mutations in humans lead to locomotor phenotypes, which may be mediated by altered responses to cellular stress."

The authors frame the stress link as a possibility, not a demonstrated mechanism.

Does the Drosophila Gdap2 knockdown phenotype tell us anything about the Purkinje cell loss seen in patients?

HUMAN MODEL MISMATCH scar27_human_model_mismatch

Attached to

pathophysiology#Cerebellar Purkinje Cell Degeneration

Patients show Purkinje cell loss and progressive cerebellar atrophy, while the only functional model is an invertebrate without a cerebellum in which increased neuronal death was not detected. A neuron-specific or cerebellar mammalian knockout, or patient-derived neurons, would be needed to test whether stress susceptibility causes the human lesion.

Show evidence (1 reference)

PMID:30084953 SUPPORT Model organism

"This suggests that the decreased lifespan of the GDAP2 knockdown models upon stress might, at this stage, be a consequence of neuronal dysfunction instead of neuronal degeneration."

The model did not reproduce neuron loss.

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Pathophysiology

4

GDAP2 Loss of Function

Biallelic nonsense, frameshift or premature-stop variants are expected to abolish GDAP2 protein. GDAP2 carries a macro domain and a CRAL-TRIO (Sec14-like) domain, but its biochemical activity is not known, so no molecular function is bound here.

GDAP2 hgnc:18010

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline null variants, homozygous or compound heterozygous.

Downstream

Impaired Neuronal Stress Response Proposed from the Drosophila knockdown; how GDAP2 protects against stress is unknown.

Show evidence (1 reference)

CGGV:assertion_1126fa6f-92b9-46c9-8967-b11a388e62b0-2024-12-11T170000.000Z SUPPORT Other

"The mechanism of pathogenicity is reported to be loss of function as the probands affected with cerebellar ataxia all have biallelic nonsense or frameshift variants in GDAP2"

ClinGen expert-panel summary that all reported alleles are truncating, supporting loss of function.

Impaired Neuronal Stress Response

In Drosophila, Gdap2 expression changes after stress, and ubiquitous Gdap2 knockdown makes flies die much sooner on paraquat (oxidative stress) and slightly sooner on starvation. The authors propose that defective stress handling contributes to the neurological phenotype. Cleaved-caspase-3 staining did not show increased neurodegeneration in knockdown fly brains, so the authors read the reduced survival as neuronal dysfunction rather than cell loss at that stage. This node rests on invertebrate data only.

neuron CL:0000540

cellular response to oxidative stress GO:0034599 ↓ DECREASED response to starvation GO:0042594 ↓ DECREASED

Animal models

Drosophila Gdap2 knockdown Drosophila melanogaster partially recapitulates Stress hypersensitivity of knockdown flies.

Downstream

Cerebellar Purkinje Cell Degeneration Proposed link from stress susceptibility to the neuron loss seen at autopsy; not demonstrated.

Extracerebellar Neurodegeneration Proposed link to the degeneration of thalamic, nigral and pyramidal tract structures; not demonstrated.

Show evidence (2 references)

PMID:30084953 SUPPORT INDIRECT Model organism

"Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation."

Stress hypersensitivity in Gdap2 knockdown flies, the basis of this node; indirect because it is an invertebrate model.

PMID:30084953 SUPPORT Model organism

"This suggests that the decreased lifespan of the GDAP2 knockdown models upon stress might, at this stage, be a consequence of neuronal dysfunction instead of neuronal degeneration."

The authors' own caveat that the fly phenotype reflects dysfunction rather than demonstrated neuron loss.

Cerebellar Purkinje Cell Degeneration

The one autopsy showed cerebello-olivary atrophy with severe, diffuse Purkinje cell loss, and MRI in patients shows cerebellar atrophy predominating in the superior vermis and hemispheres, worsening on serial scans.

Purkinje cell CL:0000121

cerebellum UBERON:0002037 inferior olivary complex UBERON:0002127

Downstream

Cerebellar Purkinje Layer Atrophy Purkinje cell loss is the histological finding.

Cerebellar Atrophy Cerebellar tissue loss is visible on MRI.

Progressive Cerebellar Ataxia Cerebellar degeneration produces gait and limb ataxia.

Cerebellar Dysarthria Cerebellar degeneration produces ataxic dysarthria.

Dysmetria Limb dysmetria is a cerebellar sign.

Dysdiadochokinesis Dysdiadochokinesis is a cerebellar sign.

Gaze-Evoked Nystagmus A cerebellar oculomotor sign.

Hypermetric Saccades A cerebellar oculomotor sign.

Jerky Smooth Pursuit A cerebellar oculomotor sign.

Dysphagia Dysphagia appears in advanced disease; its substrate has not been studied in SCAR27.

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"First, there was a cerebello-olivar atrophy with a severe and diffuse loss of Purkinje cells"

Neuropathology of the autopsied patient.

PMID:40469082 SUPPORT Human clinical

"Cerebellar atrophy worsened in successive MRI scans, and generalized cerebral atrophy was also evidenced"

Progressive cerebellar atrophy on serial imaging in an independent patient.

Extracerebellar Neurodegeneration

At autopsy, degeneration extended to the thalamus, substantia nigra and pyramidal tracts, which the authors propose underlies the non-cerebellar motor features. Global cerebral atrophy accompanies the cognitive decline on imaging. Tau tangles in the hippocampus and amygdala were classed as primary age-related tauopathy, so they are not attributed to GDAP2 here.

thalamus UBERON:0001897 substantia nigra UBERON:0002038 pyramidal tract UBERON:0002707

Downstream

Lower Limb Spasticity Pyramidal tract degeneration produces spasticity.

Brisk Reflexes Pyramidal tract degeneration produces brisk tendon reflexes.

Global Brain Atrophy Cerebral tissue loss is visible on MRI.

Cognitive Decline Cognitive decline parallels cerebral atrophy; which structures are responsible is not established.

Cervical Dystonia Dystonic neck posture is reported but its substrate has not been studied; nigral and thalamic involvement are candidates.

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"Neuropathological investigations confirmed clear degenerative changes in the cerebellum, but also involvement of the thalamus, substantia nigra, and pyramidal tracts that may underlie the other motor features."

Extracerebellar degeneration at autopsy and its proposed link to the pyramidal signs.

PMID:30084953 SUPPORT Human clinical

"This cognitive phenotype was paralleled by global cerebral atrophy accompanying the cerebellar atrophy on brain imaging."

Links the cognitive decline to cerebral atrophy on imaging.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

16

Digestive 1

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:42633453 SUPPORT Human clinical

"His brother exhibited similar but advanced symptoms, including dysphagia and severe gait impairment, leading to wheelchair dependence."

Dysphagia in an affected brother with advanced disease.

Eye 3

Gaze-Evoked Nystagmus HP:0000640

Show evidence (1 reference)

PMID:30084953 SUPPORT Human clinical

"gaze-evoked nystagmus, jerky pursuit, hypermetric saccades; cerebellar dysarthria"

Oculomotor findings at examination.

Hypermetric Saccades HP:0007338

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"gaze-evoked nystagmus, jerky pursuit, hypermetric saccades; cerebellar dysarthria"

Hypermetric saccades at examination.

PMID:40469082 SUPPORT Human clinical

"neurologic examinations revealed the presence of jerky pursuit and hypermetric saccades"

Hypermetric saccades in an independent patient.

Jerky Smooth Pursuit Saccadic smooth pursuit interruptions HP:0001152

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"gaze-evoked nystagmus, jerky pursuit, hypermetric saccades; cerebellar dysarthria"

Jerky pursuit at examination.

PMID:40469082 SUPPORT Human clinical

"neurologic examinations revealed the presence of jerky pursuit and hypermetric saccades"

Jerky pursuit in an independent patient.

Head and Neck 1

Cervical Dystonia Torticollis HP:0000473

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"mild leftward torticollis; ataxia on finger chase and heel-shin slide"

Torticollis in a patient of the defining series.

PMID:40469082 SUPPORT Human clinical

"On evolution, spasticity, cervical dystonia, and cognitive impairment were observed."

Cervical dystonia in an independent patient (retrocollis on examination).

Musculoskeletal 1

Lower Limb Spasticity HP:0002061

Course: PROGRESSIVE

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"Other features included progressive spasticity and dementia."

Progressive spasticity in the defining series.

PMID:30084953 SUPPORT Human clinical

"At that point, clear spasticity in the legs was evident."

Leg spasticity specifically.

Nervous System 10

Progressive Cerebellar Ataxia VERY_FREQUENT HP:0002073

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"Both patients had onset of ataxia in the fourth decade."

Adult-onset ataxia in both patients of the defining series.

PMID:40469082 SUPPORT Human clinical

"The patient is a man who started at age 32 years with dysarthria soon followed by cerebellar ataxia."

Cerebellar ataxia following dysarthria in an independent patient.

Cerebellar Dysarthria VERY_FREQUENT HP:0001260

Show evidence (2 references)

PMID:40469082 SUPPORT Human clinical

"The patient is a man who started at age 32 years with dysarthria soon followed by cerebellar ataxia."

Dysarthria as the presenting feature.

PMID:42633453 SUPPORT Human clinical

"A 47-year-old man with diabetes mellitus and dyslipidemia developed progressive slurred speech over four years."

Progressive dysarthria as the dominant presentation.

Dysmetria HP:0001310

Show evidence (1 reference)

PMID:40469082 SUPPORT Human clinical

"neurologic examination displayed normal cognition, cerebellar dysarthria, dysmetria and dysdiadochokinesia of limbs, and ataxic gait"

Limb dysmetria on examination.

Dysdiadochokinesis HP:0002075

Show evidence (1 reference)

PMID:40469082 SUPPORT Human clinical

"neurologic examination displayed normal cognition, cerebellar dysarthria, dysmetria and dysdiadochokinesia of limbs, and ataxic gait"

Limb dysdiadochokinesia on examination.

Brisk Reflexes HP:0001348

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"very brisk tendon reflexes, but downgoing plantar responses"

Brisk reflexes at examination.

PMID:40469082 SUPPORT Human clinical

"spasticity with brisk tendon reflexes without Babinski sign"

Brisk reflexes in an independent patient.

Cognitive Decline Cognitive impairment HP:0100543

Course: PROGRESSIVE

Show evidence (3 references)

PMID:30084953 SUPPORT Human clinical

"They also developed spasticity, and dementia emerged in the patient with long follow-up time and eventual early death (Patient AW)."

Dementia in the patient with long follow-up.

PMID:30084953 SUPPORT Human clinical

"disturbances of short-term memory and mild behavioural changes, with a Mini-Mental State Examination (MMSE) of 25/30"

Short-term memory impairment in the second patient.

PMID:40469082 SUPPORT Human clinical

"At age 48 years, he started with short-term memory disturbances and mild behavioral changes."

Later-onset memory impairment in an independent patient.

Cerebellar Atrophy HP:0001272

Show evidence (3 references)

PMID:30084953 SUPPORT Human clinical

"Brain MRI at age 53 years revealed severe atrophy of the cerebellum, both vermian and hemispheric, mainly of the superior aspect"

Superior-predominant cerebellar atrophy on MRI.

PMID:40469082 SUPPORT Human clinical

"On cranial MRI, cerebellar atrophy mainly in superior vermis was already visible."

Superior vermian atrophy in an independent patient.

PMID:42633453 REFUTE Human clinical

"MRI revealed no cerebellar atrophy, and routine laboratory and neurophysiological investigations were unremarkable."

Cerebellar atrophy was absent in one patient with four years of dysarthria, so it is not universal.

Cerebellar Purkinje Layer Atrophy HP:0012082

Show evidence (1 reference)

PMID:30084953 SUPPORT Human clinical

"First, there was a cerebello-olivar atrophy with a severe and diffuse loss of Purkinje cells"

Autopsy finding.

Global Brain Atrophy HP:0002283

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"Brain MRI at age 53 years revealed severe atrophy of the cerebellum, both vermian and hemispheric, mainly of the superior aspect, and also global cerebral atrophy (cortical and central)."

Global cerebral atrophy on MRI.

PMID:40469082 SUPPORT Human clinical

"Cerebellar atrophy worsened in successive MRI scans, and generalized cerebral atrophy was also evidenced"

Generalized cerebral atrophy in an independent patient.

Loss of Independent Ambulation Inability to walk HP:0002540

Show evidence (2 references)

PMID:30084953 SUPPORT Human clinical

"A clear progression was noted in the following years with further worsening of gait resulting in the use of a walker and later wheelchair (at age 54 years)."

Wheelchair dependence at 54 years.

PMID:40469082 SUPPORT Human clinical

"At the age of 50 years, the patient could no longer walk independently and required a wheelchair."

Wheelchair dependence at 50 years.

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Genetic Associations

1

GDAP2 (Biallelic GDAP2 loss-of-function variants: nonsense and frameshift variants in the defining series, a homozygous premature stop (c.57_59delinsACCCCAGCT, p.Trp19*) in a Spanish patient, and a homozygous nonsense variant in two brothers with dysarthria-predominant disease.)

Gene: GDAP2 hgnc:18010 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:30084953 SUPPORT Human clinical

"we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease"

Establishes GDAP2 as the causal gene.

PMID:40469082 SUPPORT Human clinical

"A premature stop codon variant was detected in homozygosity in exon 2 of the GDAP2 gene"

Independent family with a homozygous null GDAP2 allele.

PMID:42633453 SUPPORT Human clinical

"Whole-exome sequencing identified a likely pathogenic homozygous nonsense mutation in the GDAP2 gene, confirming a diagnosis of autosomal recessive spinocerebellar ataxia type 27 (SCAR27)."

A further family with a homozygous nonsense GDAP2 variant.

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Diagnosis

1

Molecular genetic testing

Diagnosis rests on biallelic GDAP2 variants found by exome sequencing or an adult-onset hereditary ataxia gene panel, after repeat-expansion ataxias have been excluded. A normal MRI does not exclude it.

Show evidence (2 references)

PMID:40469082 SUPPORT Human clinical

"We studied the virtual gene panel of hereditary ataxia with onset in adulthood (version 4.15) of PanelApp by means of whole exome sequencing."

Diagnostic route used in the Spanish patient.

PMID:42633453 SUPPORT Human clinical

"This report emphasizes the importance of considering hereditary ataxias in the differential diagnosis of progressive dysarthria, even in the absence of striking ataxic signs or neuroimaging abnormalities."

Diagnosis can require genetic testing when MRI is normal.

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Animal Models

1

Drosophila Gdap2 knockdown

Ubiquitous knockdown of the fly GDAP2 orthologue shortens lifespan, impairs righting, walking and flight, and greatly increases mortality on paraquat and slightly on starvation.

Species

Drosophila melanogaster

Genotype

Ubiquitous Gdap2 RNAi (two independent lines)

Publication

PMID:30084953

Pathograph links

Impaired Neuronal Stress Response partially recapitulates fidelity: low observes: organism Stress hypersensitivity of knockdown flies.

Limitations: Ubiquitous RNAi knockdown in an invertebrate rather than a null allele in neurons; survival was measured at the whole-organism level and increased neuronal apoptosis was not shown, so the neuronal locus of the stress defect is inferred.

Show evidence (1 reference)

PMID:30084953 SUPPORT Model organism

"Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation."

Supports the model as informative for the stress-response node.

{ }

Source YAML

click to show

name: Spinocerebellar Ataxia, Autosomal Recessive 27
creation_date: "2026-11-07T11:30:26Z"
category: Mendelian
synonyms:
- SCAR27
- autosomal recessive cerebellar ataxia 27
- GDAP2-related cerebellar ataxia
description: >-
  Spinocerebellar ataxia, autosomal recessive 27 (SCAR27) is an ultra-rare,
  adult-onset, slowly progressive cerebellar ataxia caused by biallelic
  loss-of-function variants in GDAP2 (ganglioside-induced
  differentiation-associated protein 2). Every reported disease allele is a
  nonsense, frameshift or premature-stop variant, homozygous or compound
  heterozygous. Ataxia and cerebellar dysarthria begin in the fourth or fifth
  decade, and dysarthria can be the presenting sign. Gaze-evoked nystagmus,
  jerky pursuit and hypermetric saccades, limb dysmetria, lower-limb
  spasticity with brisk reflexes, mild cervical dystonia and later cognitive
  decline follow; several patients have become wheelchair-dependent in their
  fifties. MRI shows superior-predominant cerebellar atrophy and later global
  cerebral atrophy, although it was normal in one patient after four years of
  dysarthria. In the one autopsied patient, degeneration involved the
  cerebellum (with severe diffuse Purkinje cell loss), the inferior olive,
  thalamus, substantia nigra and pyramidal tracts. GDAP2 function is poorly
  understood. The only functional model, Drosophila Gdap2 knockdown, shows
  shortened lifespan, motor deficits and heightened sensitivity to oxidative
  stress and starvation, which has led to the proposal that neurons lacking
  GDAP2 handle cellular stress poorly; that link has not been tested in human
  or mammalian neurons.
disease_term:
  preferred_term: spinocerebellar ataxia, autosomal recessive 27
  term:
    id: MONDO:0032706
    label: spinocerebellar ataxia, autosomal recessive 27
parents:
- Autosomal recessive cerebellar ataxia
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Presents and is managed as a progressive adult-onset cerebellar ataxia
      with pyramidal and cognitive features.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian recessive disorder diagnosed by exome sequencing or a
      hereditary ataxia gene panel.
references:
- reference: PMID:30084953
  title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
- reference: PMID:40469082
  title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
- reference: PMID:42633453
  title: "Progressive Slurred Speech as an Atypical Presentation of GDAP2-Related Spinocerebellar Ataxia: A Case Report."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic GDAP2 variants in every reported patient: homozygous null
    variants in a Spanish and a further family, and biallelic gene-disruptive
    variants in the two patients of the defining series. In the Spanish family
    the heterozygous mother, brother and nephews were unaffected carriers.
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease"
    explanation: Defining report of a recessive cerebellar ataxia caused by biallelic GDAP2 variants.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was also detected in the patient's mother and brother, who were heterozygous, and 4 nephews on the paternal side, who were also carriers of the variant."
    explanation: Segregation with unaffected heterozygous relatives, consistent with recessive inheritance.
genetic:
- name: GDAP2
  gene_term:
    preferred_term: GDAP2
    term:
      id: hgnc:18010
      label: GDAP2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Biallelic GDAP2 loss-of-function variants: nonsense and frameshift
    variants in the defining series, a homozygous premature stop
    (c.57_59delinsACCCCAGCT, p.Trp19*) in a Spanish patient, and a homozygous
    nonsense variant in two brothers with dysarthria-predominant disease.
  notes: >-
    ClinGen's evidence summary counts at least four probands in three
    publications up to 2024 (PMID:30084953, PMID:32437512, PMID:32428220);
    the two 2020 Brain letters have no abstract in the reference cache and are
    not cited here as evidence. Two later case reports are cited directly.
  gene_disease_validity:
  - validity_classification: STRONG
    classified_by: CLINGEN
    external_id: CGGV:assertion_1126fa6f-92b9-46c9-8967-b11a388e62b0-2024-12-11T170000.000Z
    evidence:
    - reference: CGGV:assertion_1126fa6f-92b9-46c9-8967-b11a388e62b0-2024-12-11T170000.000Z
      reference_title: "GDAP2 / spinocerebellar ataxia, autosomal recessive 27 (Strong)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "GDAP2 | HGNC:18010 | spinocerebellar ataxia, autosomal recessive 27 | MONDO:0032706 | AR | Strong"
      explanation: ClinGen gene-disease validity record classifying this pair as Strong.
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease"
    explanation: Establishes GDAP2 as the causal gene.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A premature stop codon variant was detected in homozygosity in exon 2 of the GDAP2 gene"
    explanation: Independent family with a homozygous null GDAP2 allele.
  - reference: PMID:42633453
    reference_title: "Progressive Slurred Speech as an Atypical Presentation of GDAP2-Related Spinocerebellar Ataxia: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified a likely pathogenic homozygous nonsense mutation in the GDAP2 gene, confirming a diagnosis of autosomal recessive spinocerebellar ataxia type 27 (SCAR27)."
    explanation: A further family with a homozygous nonsense GDAP2 variant.
pathophysiology:
- name: GDAP2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic nonsense, frameshift or premature-stop variants are expected to
    abolish GDAP2 protein. GDAP2 carries a macro domain and a CRAL-TRIO
    (Sec14-like) domain, but its biochemical activity is not known, so no
    molecular function is bound here.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline null variants, homozygous or compound heterozygous.
  genes:
  - preferred_term: GDAP2
    term:
      id: hgnc:18010
      label: GDAP2
  evidence:
  - reference: CGGV:assertion_1126fa6f-92b9-46c9-8967-b11a388e62b0-2024-12-11T170000.000Z
    reference_title: "GDAP2 / spinocerebellar ataxia, autosomal recessive 27 (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is reported to be loss of function as the probands affected with cerebellar ataxia all have biallelic nonsense or frameshift variants in GDAP2"
    explanation: ClinGen expert-panel summary that all reported alleles are truncating, supporting loss of function.
  downstream:
  - target: Impaired Neuronal Stress Response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed from the Drosophila knockdown; how GDAP2 protects against
      stress is unknown.
- name: Impaired Neuronal Stress Response
  biological_scale: CELLULAR
  description: >-
    In Drosophila, Gdap2 expression changes after stress, and ubiquitous Gdap2
    knockdown makes flies die much sooner on paraquat (oxidative stress) and
    slightly sooner on starvation. The authors propose that defective stress
    handling contributes to the neurological phenotype. Cleaved-caspase-3
    staining did not show increased neurodegeneration in knockdown fly
    brains, so the authors read the reduced survival as neuronal dysfunction
    rather than cell loss at that stage. This node rests on invertebrate data
    only.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: DECREASED
  - preferred_term: response to starvation
    term:
      id: GO:0042594
      label: response to starvation
    modifier: DECREASED
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation."
    explanation: Stress hypersensitivity in Gdap2 knockdown flies, the basis of this node; indirect because it is an invertebrate model.
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This suggests that the decreased lifespan of the GDAP2 knockdown models upon stress might, at this stage, be a consequence of neuronal dysfunction instead of neuronal degeneration."
    explanation: The authors' own caveat that the fly phenotype reflects dysfunction rather than demonstrated neuron loss.
  downstream:
  - target: Cerebellar Purkinje Cell Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed link from stress susceptibility to the neuron loss seen at
      autopsy; not demonstrated.
  - target: Extracerebellar Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed link to the degeneration of thalamic, nigral and pyramidal
      tract structures; not demonstrated.
- name: Cerebellar Purkinje Cell Degeneration
  biological_scale: TISSUE
  description: >-
    The one autopsy showed cerebello-olivary atrophy with severe, diffuse
    Purkinje cell loss, and MRI in patients shows cerebellar atrophy
    predominating in the superior vermis and hemispheres, worsening on serial
    scans.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  - preferred_term: inferior olivary complex
    term:
      id: UBERON:0002127
      label: inferior olivary complex
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "First, there was a cerebello-olivar atrophy with a severe and diffuse loss of Purkinje cells"
    explanation: Neuropathology of the autopsied patient.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar atrophy worsened in successive MRI scans, and generalized cerebral atrophy was also evidenced"
    explanation: Progressive cerebellar atrophy on serial imaging in an independent patient.
  downstream:
  - target: Cerebellar Purkinje Layer Atrophy
    causal_link_type: DIRECT
    description: Purkinje cell loss is the histological finding.
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
    description: Cerebellar tissue loss is visible on MRI.
  - target: Progressive Cerebellar Ataxia
    causal_link_type: DIRECT
    description: Cerebellar degeneration produces gait and limb ataxia.
  - target: Cerebellar Dysarthria
    causal_link_type: DIRECT
    description: Cerebellar degeneration produces ataxic dysarthria.
  - target: Dysmetria
    causal_link_type: DIRECT
    description: Limb dysmetria is a cerebellar sign.
  - target: Dysdiadochokinesis
    causal_link_type: DIRECT
    description: Dysdiadochokinesis is a cerebellar sign.
  - target: Gaze-Evoked Nystagmus
    causal_link_type: DIRECT
    description: A cerebellar oculomotor sign.
  - target: Hypermetric Saccades
    causal_link_type: DIRECT
    description: A cerebellar oculomotor sign.
  - target: Jerky Smooth Pursuit
    causal_link_type: DIRECT
    description: A cerebellar oculomotor sign.
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dysphagia appears in advanced disease; its substrate has not been
      studied in SCAR27.
- name: Extracerebellar Neurodegeneration
  biological_scale: TISSUE
  description: >-
    At autopsy, degeneration extended to the thalamus, substantia nigra and
    pyramidal tracts, which the authors propose underlies the non-cerebellar
    motor features. Global cerebral atrophy accompanies the cognitive decline
    on imaging. Tau tangles in the hippocampus and amygdala were classed as
    primary age-related tauopathy, so they are not attributed to GDAP2 here.
  locations:
  - preferred_term: thalamus
    term:
      id: UBERON:0001897
      label: dorsal plus ventral thalamus
  - preferred_term: substantia nigra
    term:
      id: UBERON:0002038
      label: substantia nigra
  - preferred_term: pyramidal tract
    term:
      id: UBERON:0002707
      label: corticospinal tract
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuropathological investigations confirmed clear degenerative changes in the cerebellum, but also involvement of the thalamus, substantia nigra, and pyramidal tracts that may underlie the other motor features."
    explanation: Extracerebellar degeneration at autopsy and its proposed link to the pyramidal signs.
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This cognitive phenotype was paralleled by global cerebral atrophy accompanying the cerebellar atrophy on brain imaging."
    explanation: Links the cognitive decline to cerebral atrophy on imaging.
  downstream:
  - target: Lower Limb Spasticity
    causal_link_type: DIRECT
    description: Pyramidal tract degeneration produces spasticity.
  - target: Brisk Reflexes
    causal_link_type: DIRECT
    description: Pyramidal tract degeneration produces brisk tendon reflexes.
  - target: Global Brain Atrophy
    causal_link_type: DIRECT
    description: Cerebral tissue loss is visible on MRI.
  - target: Cognitive Decline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cognitive decline parallels cerebral atrophy; which structures are
      responsible is not established.
  - target: Cervical Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dystonic neck posture is reported but its substrate has not been
      studied; nigral and thalamic involvement are candidates.
phenotypes:
- name: Progressive Cerebellar Ataxia
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Gait and limb ataxia beginning in the fourth or fifth decade and slowly
    progressing; mild in one patient whose disease was dominated by
    dysarthria.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients had onset of ataxia in the fourth decade."
    explanation: Adult-onset ataxia in both patients of the defining series.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is a man who started at age 32 years with dysarthria soon followed by cerebellar ataxia."
    explanation: Cerebellar ataxia following dysarthria in an independent patient.
- name: Cerebellar Dysarthria
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Cerebellar dysarthria in all reported patients, and the presenting
    feature in at least two, including one with normal MRI.
  phenotype_term:
    preferred_term: Cerebellar dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is a man who started at age 32 years with dysarthria soon followed by cerebellar ataxia."
    explanation: Dysarthria as the presenting feature.
  - reference: PMID:42633453
    reference_title: "Progressive Slurred Speech as an Atypical Presentation of GDAP2-Related Spinocerebellar Ataxia: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 47-year-old man with diabetes mellitus and dyslipidemia developed progressive slurred speech over four years."
    explanation: Progressive dysarthria as the dominant presentation.
- name: Dysmetria
  category: Neurological
  description: Limb dysmetria on examination.
  phenotype_term:
    preferred_term: Dysmetria
    term:
      id: HP:0001310
      label: Dysmetria
  evidence:
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic examination displayed normal cognition, cerebellar dysarthria, dysmetria and dysdiadochokinesia of limbs, and ataxic gait"
    explanation: Limb dysmetria on examination.
- name: Dysdiadochokinesis
  category: Neurological
  description: Dysdiadochokinesis of the limbs on examination.
  phenotype_term:
    preferred_term: Dysdiadochokinesis
    term:
      id: HP:0002075
      label: Dysdiadochokinesis
  evidence:
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic examination displayed normal cognition, cerebellar dysarthria, dysmetria and dysdiadochokinesia of limbs, and ataxic gait"
    explanation: Limb dysdiadochokinesia on examination.
- name: Gaze-Evoked Nystagmus
  category: Neurological
  description: Gaze-evoked nystagmus in one patient of the defining series.
  phenotype_term:
    preferred_term: Gaze-evoked nystagmus
    term:
      id: HP:0000640
      label: Gaze-evoked nystagmus
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gaze-evoked nystagmus, jerky pursuit, hypermetric saccades; cerebellar dysarthria"
    explanation: Oculomotor findings at examination.
- name: Hypermetric Saccades
  category: Neurological
  description: Hypermetric saccades in two independent patients.
  phenotype_term:
    preferred_term: Hypermetric saccades
    term:
      id: HP:0007338
      label: Hypermetric saccades
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gaze-evoked nystagmus, jerky pursuit, hypermetric saccades; cerebellar dysarthria"
    explanation: Hypermetric saccades at examination.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic examinations revealed the presence of jerky pursuit and hypermetric saccades"
    explanation: Hypermetric saccades in an independent patient.
- name: Jerky Smooth Pursuit
  category: Neurological
  description: Jerky (saccadic) smooth pursuit in two independent patients.
  phenotype_term:
    preferred_term: Jerky smooth pursuit
    term:
      id: HP:0001152
      label: Saccadic smooth pursuit interruptions
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gaze-evoked nystagmus, jerky pursuit, hypermetric saccades; cerebellar dysarthria"
    explanation: Jerky pursuit at examination.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurologic examinations revealed the presence of jerky pursuit and hypermetric saccades"
    explanation: Jerky pursuit in an independent patient.
- name: Lower Limb Spasticity
  category: Neurological
  description: >-
    Progressive lower-limb spasticity with a spastic-ataxic gait, without
    extensor plantar responses in the patients described in detail.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features included progressive spasticity and dementia."
    explanation: Progressive spasticity in the defining series.
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At that point, clear spasticity in the legs was evident."
    explanation: Leg spasticity specifically.
- name: Brisk Reflexes
  category: Neurological
  description: Very brisk tendon reflexes with downgoing plantar responses.
  phenotype_term:
    preferred_term: Brisk reflexes
    term:
      id: HP:0001348
      label: Brisk reflexes
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "very brisk tendon reflexes, but downgoing plantar responses"
    explanation: Brisk reflexes at examination.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spasticity with brisk tendon reflexes without Babinski sign"
    explanation: Brisk reflexes in an independent patient.
- name: Cervical Dystonia
  category: Neurological
  description: >-
    Mild cervical dystonia, as torticollis in one patient and retrocollis in
    another.
  phenotype_term:
    preferred_term: Cervical dystonia
    term:
      id: HP:0000473
      label: Torticollis
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild leftward torticollis; ataxia on finger chase and heel-shin slide"
    explanation: Torticollis in a patient of the defining series.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On evolution, spasticity, cervical dystonia, and cognitive impairment were observed."
    explanation: Cervical dystonia in an independent patient (retrocollis on examination).
- name: Cognitive Decline
  category: Neurological
  description: >-
    Later-onset memory impairment progressing to dementia in some patients;
    cognition was normal at early examinations.
  phenotype_term:
    preferred_term: Cognitive decline
    term:
      id: HP:0100543
      label: Cognitive impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They also developed spasticity, and dementia emerged in the patient with long follow-up time and eventual early death (Patient AW)."
    explanation: Dementia in the patient with long follow-up.
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "disturbances of short-term memory and mild behavioural changes, with a Mini-Mental State Examination (MMSE) of 25/30"
    explanation: Short-term memory impairment in the second patient.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 48 years, he started with short-term memory disturbances and mild behavioral changes."
    explanation: Later-onset memory impairment in an independent patient.
- name: Cerebellar Atrophy
  category: Neurological
  description: >-
    Cerebellar atrophy, predominantly superior and vermian, worsening on
    serial MRI; MRI was normal early in one patient and after four years of
    dysarthria in another.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI at age 53 years revealed severe atrophy of the cerebellum, both vermian and hemispheric, mainly of the superior aspect"
    explanation: Superior-predominant cerebellar atrophy on MRI.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On cranial MRI, cerebellar atrophy mainly in superior vermis was already visible."
    explanation: Superior vermian atrophy in an independent patient.
  - reference: PMID:42633453
    reference_title: "Progressive Slurred Speech as an Atypical Presentation of GDAP2-Related Spinocerebellar Ataxia: A Case Report."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI revealed no cerebellar atrophy, and routine laboratory and neurophysiological investigations were unremarkable."
    explanation: Cerebellar atrophy was absent in one patient with four years of dysarthria, so it is not universal.
- name: Cerebellar Purkinje Layer Atrophy
  category: Neurological
  description: Severe, diffuse Purkinje cell loss at autopsy.
  phenotype_term:
    preferred_term: Cerebellar Purkinje layer atrophy
    term:
      id: HP:0012082
      label: Cerebellar Purkinje layer atrophy
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "First, there was a cerebello-olivar atrophy with a severe and diffuse loss of Purkinje cells"
    explanation: Autopsy finding.
- name: Global Brain Atrophy
  category: Neurological
  description: Global cerebral (cortical and central) atrophy on later MRI.
  phenotype_term:
    preferred_term: Global brain atrophy
    term:
      id: HP:0002283
      label: Global brain atrophy
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI at age 53 years revealed severe atrophy of the cerebellum, both vermian and hemispheric, mainly of the superior aspect, and also global cerebral atrophy (cortical and central)."
    explanation: Global cerebral atrophy on MRI.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar atrophy worsened in successive MRI scans, and generalized cerebral atrophy was also evidenced"
    explanation: Generalized cerebral atrophy in an independent patient.
- name: Loss of Independent Ambulation
  category: Neurological
  description: >-
    Progression to walker use and then wheelchair dependence in the fifth or
    sixth decade.
  phenotype_term:
    preferred_term: Wheelchair dependence
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A clear progression was noted in the following years with further worsening of gait resulting in the use of a walker and later wheelchair (at age 54 years)."
    explanation: Wheelchair dependence at 54 years.
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 50 years, the patient could no longer walk independently and required a wheelchair."
    explanation: Wheelchair dependence at 50 years.
- name: Dysphagia
  category: Neurological
  description: Dysphagia in advanced disease.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:42633453
    reference_title: "Progressive Slurred Speech as an Atypical Presentation of GDAP2-Related Spinocerebellar Ataxia: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His brother exhibited similar but advanced symptoms, including dysphagia and severe gait impairment, leading to wheelchair dependence."
    explanation: Dysphagia in an affected brother with advanced disease.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Diagnosis rests on biallelic GDAP2 variants found by exome sequencing or
    an adult-onset hereditary ataxia gene panel, after repeat-expansion
    ataxias have been excluded. A normal MRI does not exclude it.
  evidence:
  - reference: PMID:40469082
    reference_title: "Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied the virtual gene panel of hereditary ataxia with onset in adulthood (version 4.15) of PanelApp by means of whole exome sequencing."
    explanation: Diagnostic route used in the Spanish patient.
  - reference: PMID:42633453
    reference_title: "Progressive Slurred Speech as an Atypical Presentation of GDAP2-Related Spinocerebellar Ataxia: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report emphasizes the importance of considering hereditary ataxias in the differential diagnosis of progressive dysarthria, even in the absence of striking ataxic signs or neuroimaging abnormalities."
    explanation: Diagnosis can require genetic testing when MRI is normal.
animal_models:
- name: Drosophila Gdap2 knockdown
  species: Drosophila melanogaster
  genotype: Ubiquitous Gdap2 RNAi (two independent lines)
  publication: PMID:30084953
  description: >-
    Ubiquitous knockdown of the fly GDAP2 orthologue shortens lifespan,
    impairs righting, walking and flight, and greatly increases mortality on
    paraquat and slightly on starvation.
  modeled_mechanisms:
  - target: Impaired Neuronal Stress Response
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Stress hypersensitivity of knockdown flies.
    limitations: >-
      Ubiquitous RNAi knockdown in an invertebrate rather than a null allele
      in neurons; survival was measured at the whole-organism level and
      increased neuronal apoptosis was not shown, so the neuronal locus of the
      stress defect is inferred.
    evidence:
    - reference: PMID:30084953
      reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation."
      explanation: Supports the model as informative for the stress-response node.
  - target: Progressive Cerebellar Ataxia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Motor deficits (righting, walking, flight) in knockdown flies.
    limitations: >-
      Fly locomotor deficits are not cerebellar ataxia, the fly has no
      cerebellum, and neurodegeneration was not demonstrated in the model.
    evidence:
    - reference: PMID:30084953
      reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ubiquitous knockdown of Drosophila Gdap2 resulted in shortened lifespan and motor behaviour anomalies such as righting defects, reduced and uncoordinated walking behaviour, and compromised flight."
      explanation: Locomotor phenotype in the knockdown model.
discussions:
- discussion_id: scar27_gdap2_function
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#GDAP2 Loss of Function
  - pathophysiology#Impaired Neuronal Stress Response
  prompt: >-
    What does GDAP2 do in human neurons, and does its loss make them
    vulnerable to oxidative or metabolic stress?
  rationale: >-
    The stress-susceptibility mechanism rests on one Drosophila RNAi model.
    GDAP2 has a macro domain and a CRAL-TRIO domain but no demonstrated
    biochemical activity, and no mammalian loss-of-function model of the
    ataxia has been reported. Why a protein without known neuron-restricted
    expression causes adult-onset, cerebellum-predominant degeneration is
    unexplained.
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, Gdap2 knockdown in Drosophila and GDAP2 loss-of-function mutations in humans lead to locomotor phenotypes, which may be mediated by altered responses to cellular stress."
    explanation: The authors frame the stress link as a possibility, not a demonstrated mechanism.
- discussion_id: scar27_human_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Cerebellar Purkinje Cell Degeneration
  prompt: >-
    Does the Drosophila Gdap2 knockdown phenotype tell us anything about the
    Purkinje cell loss seen in patients?
  rationale: >-
    Patients show Purkinje cell loss and progressive cerebellar atrophy,
    while the only functional model is an invertebrate without a cerebellum
    in which increased neuronal death was not detected. A neuron-specific or
    cerebellar mammalian knockout, or patient-derived neurons, would be
    needed to test whether stress susceptibility causes the human lesion.
  evidence:
  - reference: PMID:30084953
    reference_title: "GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This suggests that the decreased lifespan of the GDAP2 knockdown models upon stress might, at this stage, be a consequence of neuronal dysfunction instead of neuronal degeneration."
    explanation: The model did not reproduce neuron loss.
notes: >-
  No GeneReviews chapter or disease-specific treatment exists for SCAR27;
  management is supportive and no treatment is curated. Fewer than ten
  patients had been reported by 2026. Nerve conduction studies were normal
  where tested, so peripheral neuropathy is not part of the reported
  phenotype. A rodent study of GDAP2 overexpression in hippocampal neurons and
  silkworm GDAP2 knockouts are not used here: overexpression is the opposite
  of the patients' loss of function, and the silkworm studies concern
  development and longevity, not neurodegeneration. GDAP2 is annotated to the
  lysosomal membrane only from a high-throughput assay, which is too weak to
  place the mechanism at the lysosome.

📚

References & Deep Research

References

3

PMID:30084953

GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia.

No top-level findings curated for this source.

PMID:40469082

Autosomal Recessive Cerebellar Ataxia-27 Caused by a Novel Loss-of-Function Variant of Ganglioside-Induced Differentiation Associated Protein 2 in a Spanish Family.

No top-level findings curated for this source.

PMID:42633453

Progressive Slurred Speech as an Atypical Presentation of GDAP2-Related Spinocerebellar Ataxia: A Case Report.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Spinocerebellar Ataxia, Autosomal Recessive 27 · 2026-11-07T12:09:59Z · View source

New entry for SCAR27 (GDAP2, MONDO:0032706), claimed in issue 16794. Deep research was run with OpenScientist because the Edison (falcon) provider returned HTTP 403 for this session's API key; the report is committed under research/. The report was used as a lead only: its suggested UBERON identifiers for the pyramidal tract and inferior olive were wrong and were replaced after lookup, and its HP suggestions were checked against the term caches and OLS. Evidence comes from the defining Eidhof 2018 series (full text, including the autopsy), a 2025 Spanish family, a 2025 dysarthria-predominant family and the ClinGen Strong (AR) assertion, whose tier is copied into gene_disease_validity. The two 2020 Brain letters have no abstract in the cache and are not cited. The stress-susceptibility mechanism rests only on Drosophila knockdown data and is marked as indirect, with a knowledge gap and a human-model-mismatch discussion. Validated with just validate, validate-terms, count-verified-snippets (48/48) and the offline whole-repo gates.

OpenScientist ▸

Spinocerebellar Ataxia, Autosomal Recessive 27 (SCAR27) — Comprehensive Disease Report

openscientist-autonomous 8 citations 2026-11-07T11:51:10.387109

Spinocerebellar Ataxia, Autosomal Recessive 27 (SCAR27) — Comprehensive Disease Report

Disease: Spinocerebellar Ataxia, Autosomal Recessive 27 (SCAR27) Causal gene: GDAP2 (ganglioside-induced differentiation-associated protein 2) Identifiers: MONDO:0032706 · phenotype OMIM #618369 · gene OMIM 618128 · HGNC:18010 · Ensembl ENSG00000196505 · UniProt Q9NXN4 Category:* Mendelian, monogenic, autosomal recessive

Summary

Spinocerebellar ataxia, autosomal recessive 27 (SCAR27) is an ultra-rare, adult-onset, slowly progressive neurodegenerative disorder caused by biallelic loss-of-function (LOF) variants in GDAP2, the gene encoding ganglioside-induced differentiation-associated protein 2. The disease was first defined in 2018, when Eidhof and colleagues reported two unrelated patients with gene-disruptive GDAP2 mutations and onset of ataxia in the fourth decade of life; GDAP2 had not previously been implicated in any human disease (PMID: 30084953). Despite its name ("spinocerebellar ataxia"), SCAR27 is unambiguously a GDAP2 disorder — this report follows the MONDO ID (MONDO:0032706) and causal gene provided, and should not be confused with other serially-numbered spinocerebellar ataxias caused by different genes.

Clinically, SCAR27 presents in the third-to-fourth decade with cerebellar ataxia, dysarthria, and gait difficulty, frequently accompanied by eye-movement abnormalities, lower-limb spasticity, difficulty writing (dysgraphia), and cognitive impairment that can progress to dementia. Some patients lose independent ambulation and become wheelchair-dependent. Reported neuropathology extends well beyond the cerebellum to include the inferior olive, thalamus, substantia nigra, and pyramidal tracts, with limbic (hippocampus/amygdala) tau pathology. The molecular mechanism, best characterized in a Drosophila knockdown model, centers on impaired cellular stress handling — GDAP2-deficient cells show heightened vulnerability to oxidative stress (reactive oxygen species) and nutrient deprivation. GDAP2 is a 497-amino-acid protein containing a macro domain and a CRAL-TRIO/Sec14-like domain, and (distinct from its mitochondrial paralog GDAP1) localizes to the lysosomal membrane.

SCAR27 is caused exclusively by loss-of-function alleles: ClinVar's pathogenic/likely-pathogenic GDAP2 variants are uniformly truncating (nonsense, frameshift) or canonical splice-site changes, and population genetic constraint data (gnomAD) are consistent with a recessive LOF mechanism rather than haploinsufficiency. There is no disease-modifying therapy; management is supportive and rehabilitative, and diagnosis rests on whole-exome sequencing or hereditary-ataxia gene panels. No faithful mammalian neurodegeneration model yet exists — all published LOF animal models are invertebrate (Drosophila and silkworm) — representing a major gap for mechanistic and therapeutic research.

Key Findings

Finding 1 — SCAR27 is an adult-onset autosomal recessive cerebellar ataxia caused by biallelic GDAP2 loss-of-function

The defining study established the disease entity in two unrelated patients with biallelic, gene-disruptive GDAP2 mutations, both with onset of ataxia in the fourth decade and additional features of progressive spasticity and dementia. GDAP2 was explicitly described as "a gene previously not implicated in disease." As the authors state: "we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease. Both patients had onset of ataxia in the fourth decade. Other features included progressive spasticity and dementia" (PMID: 30084953).

This finding anchors the disease definition: an autosomal recessive, adult-onset cerebellar ataxia with a monogenic GDAP2 cause. Subsequent reports have reproduced this picture in independent families — a Chinese family (PMID: 32437512), an additional adult-onset case (PMID: 32428220), and a Spanish family with a novel null variant (PMID: 40469082) — confirming the gene-disease relationship across populations.

Finding 2 — GDAP2 links cerebellar ataxia to defective cellular stress responses

Functional work in Drosophila linked GDAP2 loss to impaired stress handling. Ubiquitous knockdown of fly Gdap2 caused shortened lifespan and motor anomalies (righting defects, reduced and uncoordinated walking, compromised flight). Critically, Gdap2 expression itself responded to stress treatments, and knockdown flies were hypersensitive to oxidative and metabolic stress: "Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation" (PMID: 30084953).

On the human side, neuropathological examination demonstrated degeneration extending to the cerebellum, inferior olive, thalamus, substantia nigra, and pyramidal tracts, with tau pathology in the hippocampus and amygdala. Together these data support a model in which GDAP2 normally protects neurons against cellular stress, and its loss renders long-lived post-mitotic neurons progressively vulnerable to oxidative and nutrient stress — a plausible explanation for the adult-onset, slowly progressive neurodegeneration.

Finding 3 — GDAP2 is a 497-aa macro-domain + CRAL-TRIO protein on 1p13.2, with constraint consistent with recessive LOF

GDAP2 (UniProt Q9NXN4) is a 497-amino-acid protein containing a macro domain (residues ~43–223) and a CRAL-TRIO/Sec14-like domain (residues ~333–481), plus a disordered region (~252–273). The gene maps to chromosome 1p13.2 (GRCh38 chr1:117,863,485–117,929,621; HGNC:18010; Ensembl ENSG00000196505). This locus assignment corrects earlier imprecise annotations.

Population constraint metrics from gnomAD v4 are consistent with a recessive, loss-of-function disease mechanism rather than dominant haploinsufficiency: pLI ≈ 0 (1.1×10⁻¹³), LOEUF (oe_lof upper bound) = 0.96, observed/expected LoF = 51/67 (oe_lof = 0.76), LoF Z = 1.66, missense Z = 0.73. In plain terms, heterozygous loss of one GDAP2 allele is tolerated in the general population — as expected for a recessive disorder where disease requires loss of both copies.

The macro domain is a known ADP-ribose/NAD-metabolite-binding module (associated with poly-ADP-ribose signaling and stress responses), while CRAL-TRIO/Sec14 domains bind small hydrophobic ligands (e.g., lipids). These domain assignments provide a biochemical scaffold linking GDAP2 to the stress-response and lipid/membrane biology implicated in the phenotype.

Finding 4 — The SCAR27 clinical spectrum includes eye-movement abnormalities and dysgraphia beyond ataxia/spasticity/cognitive impairment

Curated clinical descriptions (UniProt, derived from primary literature) characterize SCAR27 as a "progressive disease characterized by gait difficulties, eye movement abnormalities, dysarthria, and difficulty writing. Some patients may lose independent ambulation. Additional features include spasticity of the lower limbs and cognitive impairment." This broadens the recognized phenotype to include oculomotor abnormalities and dysgraphia alongside the cardinal cerebellar, pyramidal, and cognitive features.

The phenotypic range continues to expand. A 2025 case report described progressive slurred speech (dysarthria) as an atypical presenting feature in a 47-year-old man — notably without cerebellar atrophy on MRI — whose brother had more advanced disease with dysphagia and wheelchair dependence; whole-exome sequencing identified a homozygous nonsense GDAP2 mutation (PMID: 42633453). This underscores that SCAR27 can present with isolated dysarthria and normal neuroimaging, and should be considered in the differential diagnosis of progressive dysarthria.

Finding 5 — Pathogenic GDAP2 variants are uniformly loss-of-function (truncating/splice), confirming the LOF mechanism

ClinVar (RefSeq NM_017686.4) lists 112 GDAP2 variants, of which 3 are Pathogenic and 6 Likely pathogenic (the remainder largely VUS/benign). Every pathogenic/likely-pathogenic single-nucleotide variant is loss-of-function:

Variant (cDNA)	Protein	Type	Classification
c.757C>T	p.Arg253Ter	Nonsense	Pathogenic
c.677C>A	p.Ser226Ter	Nonsense	Likely pathogenic
c.760C>T	p.Gln254Ter	Nonsense	Likely pathogenic
c.1048C>T	p.Arg350Ter	Nonsense	Likely pathogenic
c.134del	p.Pro45fs	Frameshift	Likely pathogenic
c.1107+1G>T	—	Canonical splice	Likely pathogenic
c.1030+1G>T	—	Canonical splice	Likely pathogenic

Two large multigene 1p13 copy-number variants are also classified Pathogenic in ClinVar but are not SCAR27-specific (they span additional genes). The uniform truncating/splice signature across unrelated families strongly supports loss of function (not gain of function or dominant negative) as the disease mechanism, consistent with the recessive inheritance and the gnomAD constraint profile.

Finding 6 — All GDAP2 loss-of-function animal models are invertebrate; no faithful mammalian neurodegeneration model exists

A model-organism audit found that every published GDAP2 loss-of-function model is an invertebrate:

Drosophila Gdap2 knockdown — the only neuromotor LOF model, showing shortened lifespan, motor defects, and stress hypersensitivity (PMID: 30084953).
Silkworm (Bombyx mori) CRISPR/Cas9 knockout of BmGDAP2 (2025) — extended lifespan, reduced body size, prolonged growth cycle, and 149 differentially expressed genes enriched (KEGG) in peroxidase activity, hormone synthesis, apoptosis, and longevity regulation (PMID: 40332832).
Silkworm systemic GDAP2 knockout — delayed larval development, reduced body weight, and arrest at the 4th-instar stage; GDAP2 is a direct downstream target of the bHLH transcription factor Dimm integrating insulin/IGF and juvenile-hormone signaling (PMID: 40205793).

Importantly, the frequently-cited rodent study used GDAP2 overexpression (gain of dosage) in primary hippocampal neurons and an epileptic mouse — not a knockout — finding increased dendritic complexity, dysregulated excitatory synaptic transmission, and increased seizure frequency (PMID: 35158016). This models a dosage-gain condition, not the recessive LOF of SCAR27. Ortholog gene IDs: human GDAP2 (NCBI 54834), mouse Gdap2 (14547), rat Gdap2 (362004), zebrafish gdap2 (447824), Drosophila Gdap2 (59173), Bombyx mori BmGDAP2 (101738783). The absence of a mammalian knockout that recapitulates adult-onset neurodegeneration is the single largest experimental gap in the field.

Finding 7 — GDAP2 localizes to the lysosomal membrane, distinguishing it from its mitochondrial paralog GDAP1

UniProt (Q9NXN4) records a single experimentally-supported Gene Ontology cellular-component annotation for GDAP2: GO:0005765 "lysosomal membrane" (evidence code HDA, high-throughput direct assay). This is mechanistically important because the better-known paralog GDAP1 (mutated in Charcot-Marie-Tooth disease) localizes to the mitochondrial outer membrane. Thus, despite the shared "GDAP" name and domain architecture, the two paralogs operate at different organelles. A lysosomal localization for GDAP2 reorients mechanistic thinking toward lysosomal/autophagic and membrane-lipid biology (consistent with the CRAL-TRIO/Sec14 lipid-binding domain), rather than assuming a mitochondrial role by analogy to GDAP1.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic loss-of-function variant in GDAP2 (nonsense, frameshift, or canonical splice-site) results in absent or non-functional GDAP2 protein in all tissues. (Demonstrated — ClinVar LOF alleles; recessive inheritance.)
Loss of GDAP2 leads to deficient cellular stress-response capacity — the protein's macro domain (ADP-ribose/NAD metabolite binding) and CRAL-TRIO/Sec14 (lipid-binding) domains normally support stress handling at the lysosomal membrane. (Inferred from domain architecture + GO:0005765 lysosomal localization.)
Deficient stress handling results in heightened vulnerability of cells to oxidative stress (reactive oxygen species) and nutrient deprivation. (Demonstrated in Drosophila knockdown — PMID 30084953.)
In long-lived post-mitotic neurons, chronic exposure to oxidative/metabolic stress over decades leads to progressive neuronal dysfunction and death. (Inferred — explains adult onset and slow progression.)
Neurodegeneration manifests in the cerebellum, inferior olive, thalamus, substantia nigra, and pyramidal tracts, with limbic tau pathology. (Demonstrated — human neuropathology, PMID 30084953.)
Regional degeneration produces the clinical phenotype:
Cerebellar + olivary degeneration → ataxia, dysarthria, oculomotor abnormalities, dysgraphia
Pyramidal tract involvement → lower-limb spasticity
Cortical/thalamic/limbic + tau pathology → cognitive impairment / dementia
Progressive cerebellar/brainstem loss → loss of independent ambulation, dysphagia

Branch point

 Biallelic GDAP2 LOF
         |
 (lysosomal-membrane stress-response deficit)
         |
  Heightened vulnerability to ROS + nutrient stress
         |
+----------------+---------------------+
   Cerebellum/        Pyramidal            Cortex/thalamus/
   inferior olive      tracts              limbic + tau
|                 |                      |
   Ataxia, dysarthria,  Lower-limb          Cognitive decline/
   eye movements,       spasticity           dementia
   dysgraphia

Upstream vs downstream

Upstream (initiating): GDAP2 LOF → lysosomal/stress-response deficit (the primary, generalizable lesion present in all cells).
Downstream (manifesting): selective neuronal vulnerability and regional neurodegeneration, which is what produces symptoms. The selectivity for neurons — despite GDAP2 being ubiquitously expressed — is not fully explained and is a key open question.

Ontology term suggestions

Gene/protein: HGNC:18010 (GDAP2); UniProt Q9NXN4
GO biological process: response to oxidative stress (GO:0006979); cellular response to starvation/nutrient levels (GO:0009267 / GO:0031669); neuron death (GO:0070997)
GO cellular component: lysosomal membrane (GO:0005765)
CL cell types: cerebellar Purkinje cell (CL:0000121); granule cell; neuron (CL:0000540); inferior olivary neuron
UBERON anatomy: cerebellum (UBERON:0002037); inferior olivary complex (UBERON:0002118); thalamus (UBERON:0001897); substantia nigra (UBERON:0002038); pyramidal tract (UBERON:0002435); hippocampus (UBERON:0002421); amygdala (UBERON:0001876)
CHEBI: reactive oxygen species (CHEBI:26523); ADP-ribose (CHEBI:16960)
Disease: MONDO:0032706; OMIM #618369

Section-by-Section Disease Characterization

1. Disease Information

SCAR27 is an adult-onset, autosomal recessive, slowly progressive cerebellar ataxia caused by biallelic GDAP2 loss of function. Identifiers: MONDO:0032706; OMIM phenotype #618369; gene OMIM 618128; HGNC:18010; UniProt Q9NXN4. No specific ICD-10/ICD-11 or MeSH code is assigned to SCAR27 as a distinct entity; it falls under hereditary/recessive cerebellar ataxia categories (e.g., ICD-10 G11.1/G11.2, broadly). Synonyms:* autosomal recessive spinocerebellar ataxia-27; GDAP2-related cerebellar ataxia; GDAP2-related spinocerebellar ataxia. The disease-level information is derived from aggregated case reports and curated database resources (OMIM, UniProt, ClinVar), not from large patient registries or EHR cohorts — reflecting the ultra-rare status.

2. Etiology

Causal factor: purely genetic — biallelic (homozygous or compound heterozygous) loss-of-function variants in GDAP2. Genetic risk factors: the causal variants themselves; consanguinity substantially raises risk (several reported families are consanguineous, with homozygous null alleles). No susceptibility loci, modifier genes, protective alleles, or gene-environment interactions have been established. Environmental/lifestyle/infectious factors: none identified as causal or contributory. Given the stress-vulnerability mechanism, oxidative or metabolic stressors are a theoretical modifier, but this is not demonstrated in patients.

3. Phenotypes

Phenotype	Type	HPO suggestion	Onset	Progression	Frequency
Cerebellar ataxia / gait difficulty	Clinical sign	HP:0001251 / HP:0002066	3rd–4th decade	Progressive	Core (near-universal)
Dysarthria	Clinical sign	HP:0001260	Adult	Progressive	Common; can be presenting feature
Eye-movement abnormalities	Clinical sign	HP:0000496	Adult	Progressive	Common
Lower-limb spasticity	Clinical sign	HP:0002061	Adult	Progressive	Common
Dysgraphia / difficulty writing	Clinical sign	HP:0025131	Adult	Progressive	Reported
Cognitive impairment / dementia	Behavioral/cognitive	HP:0001268 / HP:0000726	Adult	Progressive	Reported in multiple cases
Loss of independent ambulation	Functional	HP:0002540	Late	Progressive	Subset (wheelchair dependence)
Dysphagia	Clinical sign	HP:0002015	Late	Progressive	Advanced disease
Cervical dystonia	Clinical sign	HP:0002402	Adult	—	Reported (Spanish family)

Quality-of-life impact: progressive loss of mobility, speech, writing, and cognition causes substantial and increasing disability; advanced patients become wheelchair-dependent with dysphagia. No formal EQ-5D/SF-36/PROMIS data exist for this ultra-rare disease.

4. Genetic / Molecular Information

Causal gene: GDAP2 (HGNC:18010; gene OMIM 618128; Ensembl ENSG00000196505; NCBI Gene 54834). Variant classes: nonsense, frameshift, and canonical splice-site — all loss-of-function (see Finding 5 table). Functional consequence: loss of function (LOF). Allele frequency: pathogenic alleles are ultra-rare/private in gnomAD. Origin: germline. Modifier/epigenetic/chromosomal:* none established specific to SCAR27; two large multigene 1p13 CNVs are pathogenic but not SCAR27-specific. gnomAD constraint (pLI≈0, LOEUF 0.96) confirms heterozygous LOF tolerance consistent with recessive disease.

5. Environmental Information

No environmental, lifestyle, or infectious factors are implicated in SCAR27. The disease is monogenic and fully genetically determined. (Oxidative/nutrient stress is mechanistically relevant at the cellular level but is not an established patient-level environmental risk factor.)

6. Mechanism / Pathophysiology

See the Mechanistic Model section above for the full ordered causal chain. In brief: biallelic GDAP2 LOF → loss of a lysosomal-membrane, macro-domain/CRAL-TRIO stress-response protein → impaired handling of oxidative and nutrient stress → progressive, region-selective neurodegeneration (cerebellum, inferior olive, thalamus, substantia nigra, pyramidal tracts; limbic tau) → ataxia, spasticity, and cognitive decline. Key molecular features: macro domain (ADP-ribose/NAD metabolite binding), CRAL-TRIO/Sec14 lipid-binding domain, lysosomal-membrane localization. Silkworm knockout transcriptomics highlighted peroxidase activity, apoptosis, and longevity-regulation pathways (PMID: 40332832), consistent with a stress/oxidative-homeostasis role.

7. Anatomical Structures Affected

Primary organ/system: central nervous system (nervous system). Primary sites: cerebellum (UBERON:0002037) and inferior olivary complex (UBERON:0002118). Secondary involvement: thalamus (UBERON:0001897), substantia nigra (UBERON:0002038), pyramidal tracts (UBERON:0002435), hippocampus (UBERON:0002421), amygdala (UBERON:0001876). Tissue/cell: nervous tissue; cerebellar neurons (Purkinje cells CL:0000121, granule cells), olivary and brainstem neurons. Subcellular: lysosomal membrane (GO:0005765). Lateralization: bilateral/symmetric (typical of neurodegenerative ataxia).

8. Temporal Development

Onset: adult, typically 3rd–4th decade (reported onsets ~32–47 years). Onset pattern: insidious/chronic. Progression: slowly progressive over years to decades; no remission. Course: chronic, lifelong, progressive. Advanced disease → loss of ambulation and dysphagia. No episodic or relapsing-remitting pattern. Critical window: none defined; because neurodegeneration is slow, there is in principle a long window for intervention if disease-modifying therapy becomes available.

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: appears complete in biallelic LOF carriers (based on limited cases). Expressivity: variable (ranging from isolated dysarthria with normal MRI to full ataxia-spasticity-dementia). Consanguinity: an important contributor; homozygous null variants have been reported in consanguineous families. Carrier frequency: not formally established; pathogenic alleles are private/ultra-rare. Epidemiology: ultra-rare — only a handful of families reported worldwide (original/Netherlands, China, Spain, and others); true prevalence/incidence unknown and likely well under 1 per million. No founder effect, anticipation, or sex bias has been established; as an autosomal recessive disorder, males and females are affected equally.

10. Diagnostics

Genetic testing is the diagnostic cornerstone: whole-exome sequencing (WES) or hereditary-ataxia gene panels (e.g., adult-onset hereditary ataxia panels such as PanelApp) detect biallelic GDAP2 LOF variants; whole-genome sequencing and Sanger confirmation/segregation are adjuncts. Imaging: brain MRI may show cerebellar atrophy, but — importantly — can be normal early or in atypical presentations (PMID: 42633453); thus normal MRI does not exclude SCAR27. Routine labs and neurophysiology are typically unremarkable. No specific biomarker exists. Differential diagnosis: other autosomal recessive cerebellar ataxias (e.g., ATM/ataxia-telangiectasia, SACS/ARSACS, COQ8A, APTX/AOA1, SYNE1, Friedreich ataxia) — distinguished by genetic testing; GDAP2 is now included on adult-onset ataxia panels. Screening: cascade carrier testing within affected families; no newborn or population screening.

11. Outcome / Prognosis

SCAR27 is a chronic, progressive, disabling neurodegenerative disease. Patients experience accumulating disability — loss of gait, speech, writing, and cognition — with a subset becoming wheelchair-dependent and developing dysphagia. No formal survival, mortality, or life-expectancy data exist given the rarity, but as an adult-onset neurodegenerative ataxia, life expectancy may be reduced in advanced disease (e.g., via aspiration/dysphagia complications). Prognostic factors are not formally defined; earlier/more severe cognitive and pyramidal involvement likely portends worse functional outcome. No prognostic biomarkers are established.

12. Treatment

There is no disease-modifying or curative therapy for SCAR27. Management is supportive and rehabilitative: physical therapy for gait/spasticity, occupational therapy (including writing aids for dysgraphia), speech therapy for dysarthria/dysphagia, antispasticity agents (e.g., baclofen — skeletal muscle relaxant class), mobility aids, swallow management, and cognitive/social support. No pharmacotherapy, gene therapy, RNA-based therapy, or targeted therapy is approved or in trials specific to GDAP2. NCIT intervention concepts: Physical Therapy, Occupational Therapy, Speech Therapy, Supportive Care. Because the mechanism involves oxidative/metabolic stress vulnerability, antioxidant strategies are a theoretical direction but are not evidence-based for this disease.

13. Prevention

No primary prevention exists for a monogenic recessive disorder. Genetic counseling is the principal preventive tool: at-risk couples (especially consanguineous) can be offered carrier testing, and families with a known GDAP2 variant can pursue cascade testing, prenatal diagnosis, or preimplantation genetic testing (PGT-M). Tertiary prevention = rehabilitative management to limit complications (falls, aspiration). No immunization or public-health intervention applies.

14. Other Species / Natural Disease

No naturally occurring GDAP2-related disease has been reported in companion animals or wildlife (no OMIA entry for a GDAP2 natural disease). GDAP2 is evolutionarily conserved with clear orthologs: mouse Gdap2 (NCBI 14547), rat Gdap2 (362004), zebrafish gdap2 (447824), Drosophila Gdap2 (59173), and Bombyx mori BmGDAP2 (101738783). The macro + CRAL-TRIO domain architecture and stress-response role appear conserved from insects to humans. No zoonotic or cross-species transmission component (non-infectious disease).

15. Model Organisms

See Finding 6. Available LOF models are all invertebrate:

Model	Type	Key phenotype	PMID
Drosophila Gdap2 knockdown	RNAi knockdown	Shortened lifespan, motor defects, stress hypersensitivity	30084953
Silkworm BmGDAP2	CRISPR/Cas9 KO	Extended lifespan, reduced size, 149 DEGs (peroxidase/apoptosis/longevity)	40332832
Silkworm GDAP2	Systemic KO	Delayed development, 4th-instar arrest; Dimm target	40205793
Rodent (GDAP2 overexpression)	Gain of dosage (not KO)	Dendritic/synaptic changes, increased seizures	35158016

No mammalian knockout recapitulating adult-onset neurodegeneration exists. The Drosophila knockdown best models the neuromotor/stress phenotype; silkworm models inform development/longevity biology but not neurodegeneration. iPSC-derived neurons and conditional mouse knockouts are obvious unfilled needs.

Evidence Base

PMID	Title (abbreviated)	Role in this report
30084953	GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia	Landmark — defines SCAR27; biallelic LOF; adult onset, spasticity, dementia; Drosophila stress model; human neuropathology
32437512	Novel GDAP2 pathogenic variants … SCAR27 in a Chinese family	Independent replication of gene-disease relationship
32428220	Homozygous GDAP2 LOF variant in adult-onset cerebellar ataxia	Additional adult-onset LOF case
40469082	ARCA-27 … novel LOF of GDAP2 in a Spanish family	Novel premature-stop homozygous variant; onset age 32; dysarthria→ataxia, spasticity, dystonia, cognitive impairment
42633453	Progressive slurred speech as atypical presentation of GDAP2 ataxia	Expands spectrum — isolated dysarthria, normal MRI, homozygous nonsense variant
35158016	GDAP2 overexpression affects neurons / synaptic transmission	Over-expression (gain-of-dosage) rodent study — informs GDAP2 neuronal function but not the recessive LOF mechanism
40332832	CRISPR/Cas9 knockout of BmGDAP2 (silkworm)	Invertebrate KO; stress/longevity transcriptomics
40205793	Dimm targets GDAP2 to regulate larval development (silkworm)	GDAP2 regulation and developmental KO phenotype
32428197 / 32658981	Reply/erratum correspondence	Document ongoing variant/family reporting

Evidence source types: human clinical/genetic (30084953, 32437512, 32428220, 40469082, 42633453; ClinVar; UniProt; OMIM); model organism (30084953 Drosophila; 40332832, 40205793 silkworm; 35158016 rodent overexpression); computational/database (gnomAD constraint; UniProt domain and GO annotation).

Limitations and Knowledge Gaps

Very small patient numbers. The disease rests on a handful of families worldwide. Phenotype frequencies, penetrance, expressivity, natural history, survival, and QoL are estimates from case reports, not cohort data.
No mammalian LOF model. All knockout models are invertebrate; the only rodent study used overexpression (opposite dosage direction). This limits mechanistic dissection and preclinical therapeutic testing.
Mechanism is largely inferred. The stress-vulnerability model is best supported in flies; the lysosomal-membrane localization is from a single high-throughput assay (GO evidence code HDA) and warrants targeted validation. Exactly how GDAP2's macro and CRAL-TRIO domains execute stress protection, and why neurons are selectively vulnerable despite ubiquitous expression, remain unknown.
No biomarkers or disease-modifying therapy. Diagnosis is genetic; there are no fluid/imaging biomarkers and no targeted treatment.
Imaging can be normal, complicating recognition; clinicians may under-diagnose SCAR27 in progressive dysarthria/ataxia without cerebellar atrophy.
Epidemiology unknown — prevalence, incidence, carrier frequency, and any founder effects are not established.

Proposed Follow-up Experiments / Actions

Generate a conditional mouse knockout (neuronal/cerebellar Cre) and characterize for adult-onset ataxia, Purkinje/olivary degeneration, tau pathology, and stress vulnerability — the single highest-priority gap.
iPSC-derived cerebellar/Purkinje neurons and organoids from patients (and isogenic LOF lines) to test oxidative/nutrient-stress sensitivity, lysosomal/autophagic function, and candidate protective compounds (e.g., antioxidants).
Validate subcellular localization and interactome of GDAP2 at the lysosomal membrane (confocal + proximity labeling/BioID), contrasting with GDAP1's mitochondrial role; define macro-domain ADP-ribose/NAD and CRAL-TRIO lipid ligands biochemically.
International patient registry / GeneMatcher-driven case collection to establish phenotype frequencies, natural history, penetrance, imaging spectrum, and genotype-phenotype correlations.
Biomarker discovery — oxidative-stress markers, neurofilament light chain (axonal injury), and lysosomal-function readouts in patient CSF/blood.
Clinical awareness — include GDAP2 on all adult-onset hereditary-ataxia panels and consider SCAR27 in progressive dysarthria/ataxia even with normal MRI; offer genetic counseling and cascade/PGT options to affected families.

Report compiled from database-verified findings (OMIM, UniProt, HGNC, Ensembl, ClinVar, gnomAD, NCBI Gene) and primary literature across 5 investigation iterations. GDAP2 is the causal gene of SCAR27 (MONDO:0032706; OMIM #618369).

Artifacts

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Outcome	Count
References checked	10
Resolved	10
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	10
On topic	6
Off topic	0

All extracted references resolved successfully.

Term Validation

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Outcome	Count
Terms checked	29
Resolved	26
Unresolved (possible confabulation)	1
Obsolete	1
Unverifiable	1
Terms whose name was checked	11
Terms named correctly	0
Terms named as a different term	6
Terms whose name is worth a second look	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0001260 (1 mention) - the report calls it "Clinical sign"; HP calls it Dysarthria
HP:0000496 (1 mention) - the report calls it "Clinical sign"; HP calls it Abnormality of eye movement
HP:0002061 (1 mention) - the report calls it "Clinical sign"; HP calls it Lower limb spasticity
HP:0025131 (1 mention) - the report calls it "Clinical sign"; HP calls it Finger swelling
HP:0002540 (1 mention) - the report calls it "Functional"; HP calls it Inability to walk
HP:0002015 (1 mention) - the report calls it "Clinical sign"; HP calls it Dysphagia

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0002402 (1 mention), reported as "Clinical sign" - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0070997 (obsolete neuron death) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0005765 (4 mentions) - the report calls it "GO cellular component: lysosomal membrane"; GO calls it lysosomal membrane**
GO:0006979 (1 mention) - the report calls it "GO biological process: response to oxidative stress"; GO calls it response to oxidative stress**
CL:0000121 (2 mentions) - the report calls it "CL cell types: cerebellar Purkinje cell"; CL calls it Purkinje cell**, and lists "cerebellar Purkinje cell" among its other names
UBERON:0002037 (2 mentions) - the report calls it "UBERON anatomy: cerebellum"; UBERON calls it cerebellum**
CHEBI:26523 (1 mention) - the report calls it "CHEBI: reactive oxygen species"; CHEBI calls it reactive oxygen species**

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Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Diagnosis

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Spinocerebellar Ataxia, Autosomal Recessive 27 (SCAR27) — Comprehensive Disease Report

Summary

Key Findings

Finding 1 — SCAR27 is an adult-onset autosomal recessive cerebellar ataxia caused by biallelic GDAP2 loss-of-function

Finding 2 — GDAP2 links cerebellar ataxia to defective cellular stress responses

Finding 3 — GDAP2 is a 497-aa macro-domain + CRAL-TRIO protein on 1p13.2, with constraint consistent with recessive LOF

Finding 4 — The SCAR27 clinical spectrum includes eye-movement abnormalities and dysgraphia beyond ataxia/spasticity/cognitive impairment

Finding 5 — Pathogenic GDAP2 variants are uniformly loss-of-function (truncating/splice), confirming the LOF mechanism

Finding 6 — All GDAP2 loss-of-function animal models are invertebrate; no faithful mammalian neurodegeneration model exists

Finding 7 — GDAP2 localizes to the lysosomal membrane, distinguishing it from its mitochondrial paralog GDAP1

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Branch point

Upstream vs downstream

Ontology term suggestions

Section-by-Section Disease Characterization

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Unresolved terms

Obsolete terms

Terms whose name is worth a second look