Autosomal Recessive Cerebellar Ataxia-Saccadic Intrusion Syndrome

Mendelian MONDO:0011811 Pathograph 14 Show in embeddings browser Hereditary ataxia

Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome (SCASI), also called spinocerebellar ataxia, autosomal recessive 4 (SCAR4), is the classic VPS13D-associated recessive ataxia represented by MONDO:0011811. It is a slowly progressive cerebellar syndrome distinguished by fixation-disrupting saccadic intrusions, especially macrosaccadic oscillations and hypermetric saccades, together with pyramidal signs and axonal sensorimotor neuropathy. Biallelic pathogenic VPS13D variants are causative. Experimental work establishes roles for VPS13D in organelle contact-site lipid handling, mitochondrial fission, mitophagic completion, mitochondrial morphology, and axonal mitochondrial distribution, but the intermediates connecting these cellular defects to the selective human cerebellar, oculomotor, corticospinal, and peripheral-nerve phenotype remain unresolved. Childhood chorea, epilepsy, dystonia, isolated spastic paraplegia, and severe tremor occur in the broader VPS13D allelic spectrum and are not treated here as defining features of classic SCASI.

Ask OpenScientist

Ask a research question about Autosomal Recessive Cerebellar Ataxia-Saccadic Intrusion Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

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

1
Mappings
1
Inheritance
7
Pathophys.
6
Phenotypes
2
Gaps
14
Pathograph
1
Genes
3
Medical Actions
4
Differentials
4
Models
17
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0011811 autosomal recessive cerebellar ataxia-saccadic intrusion syndrome
skos:exactMatch MONDO
Primary MONDO identifier for the classic SCASI/SCAR4 disease entity.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
SCASI/SCAR4 is caused by biallelic germline VPS13D variants. Most reported affected individuals carry one loss-of-function allele and one missense or other partially functional allele; this pattern is consistent with the severe consequences of complete VPS13D loss in experimental systems.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:29604224 SUPPORT Human Clinical
"Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all 7 families."
Establishes biallelic VPS13D variants in multiple recessive ataxia families.
PMID:30789691 SUPPORT Other
"VPS13D movement disorder is inherited in an autosomal recessive manner."
GeneReviews states the inheritance mode directly.
?

Discussions and Knowledge Gaps

2
Which biallelic VPS13D genotypes belong to classic SCASI/SCAR4, and which define other disorders in the broader VPS13D movement-disorder spectrum?
KNOWLEDGE GAP OPEN gap_scasi_disease_boundary_and_genotype_phenotype
Attached to
pathophysiology#Biallelic VPS13D Dysfunction pathophysiology#Cerebellar and Oculomotor Circuit Dysfunction
MONDO:0011811 is the classic cerebellar ataxia-saccadic intrusion entity, whereas published VPS13D cohorts aggregate childhood chorea/epilepsy, generalized dystonia, isolated or predominant spastic paraplegia, and tremor with classic SCASI. Residual VPS13D function, variant class, and age of onset probably influence presentation, but the current case count is too small and nosologically mixed for reliable genotype-phenotype rules. This entry therefore keeps broad-spectrum observations out of the classic phenotype and treatment rows unless explicitly contextualized.
Show evidence (2 references)
PMID:29604224 SUPPORT Human Clinical
"Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum"
Establishes a broad VPS13D ataxia-spasticity spectrum around the classic family.
PMID:41288814 SUPPORT Human Clinical
"Pediatric presentations appear to follow a more disabling course, with distinct characteristics according to age of onset."
Supports age-dependent heterogeneity and a distinct pediatric spectrum.
How do VPS13D mitochondrial and contact-site defects produce selective cerebellar, oculomotor, corticospinal, and peripheral axonal dysfunction in humans, and which model best reproduces the compound-hypomorphic disease?
HUMAN MODEL MISMATCH OPEN gap_scasi_human_model_mismatch_and_circuit_selectivity
Attached to
pathophysiology#Dysregulated VPS13D-Dependent Organelle Contact-Site Lipid Handling pathophysiology#Impaired Mitochondrial Fission and Mitophagic Completion pathophysiology#Neuronal Dysfunction and Neurodegeneration
Fly knockdown and conditional mouse knockout strongly support mitochondrial quality-control and neuronal-degeneration mechanisms, but severe depletion or null states do not reproduce the typical human combination of one loss-of-function and one missense allele. The mouse model adds a microglia-dependent inflammatory death pathway that has not been shown in human SCASI, while neither model recreates the defining macrosaccadic oscillations or establishes selective peripheral-nerve involvement. Variant-matched human iPSC-derived cerebellar and peripheral neurons with isogenic controls are needed to test the cellular-to-circuit bridge.
Show evidence (3 references)
PMID:29604224 SUPPORT Human Clinical
"All but 2 patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele."
Defines the typical human allelic architecture that complete-loss models do not reproduce.
PMID:40563011 SUPPORT Model Organism
"Depletion of microglia suppressed cell death and behavioral phenotypes but not mitochondrial changes in the neuron-specific Vps13d-knockout model"
Demonstrates a mouse-specific glial mediator whose relevance to human SCASI remains unresolved.
PMID:39957248 SUPPORT Model Organism
"vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial morphology."
A variant-based model narrows the allelic mismatch but still lacks the human circuit phenotype.
⚙

Pathophysiology

7
Biallelic VPS13D Dysfunction
Biallelic pathogenic VPS13D variants are the initiating lesion. The common configuration of one nonsense or splice-site allele with one missense allele supports partial residual function rather than uniform complete protein absence; the node therefore uses dysfunction rather than loss-of-function as its disease-wide label.
VPS13D hgnc:23595 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VPS13D (hgnc:23595). hgnc:23595 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Dysregulated VPS13D-Dependent Organelle Contact-Site Lipid Handling VPS13D depletion perturbs lipid handling at lipid-droplet-mitochondria contacts, and biochemical studies support a lipid-binding/contact-site function. Extrapolation from depletion systems to patient neurons is partial.
Impaired Mitochondrial Fission and Mitophagic Completion Vps13D loss disrupts mitochondrial size control and completion of mitophagy in experimental systems.
Show evidence (2 references)
PMID:29604224 SUPPORT Human Clinical
"This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4 (SCAR4)."
Links the original SCASI/SCAR4 family to VPS13D.
PMID:29604224 SUPPORT Human Clinical
"All but 2 patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele."
Supports the typical mixed severe-plus-missense biallelic architecture.
Dysregulated VPS13D-Dependent Organelle Contact-Site Lipid Handling
VPS13D is a large contact-site protein with a lipid-transfer domain. Its lipid-transfer domain binds glycerophospholipids and fatty acids in vitro; VPS13D depletion inhibits lipid-droplet-to-mitochondria fatty-acid trafficking, and Miro/VAP recruitment can bridge VPS13D between the ER and mitochondria. Whether VPS13D directly transports endogenous lipids in affected human neurons, and how this function contributes to SCASI, remain unproven.
VPS13D hgnc:23595 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VPS13D (hgnc:23595). hgnc:23595 is a gene from the HUGO Gene Nomenclature Committee.
intermembrane lipid transfer GO:0120009 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intermembrane lipid transfer (GO:0120009). GO:0120009 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Mitochondrial Morphology, Distribution, and Bioenergetic Abnormalities Contact-site dysregulation is proposed to contribute to the observed mitochondrial abnormalities, but the direction and intervening steps are not established as a linear disease pathway.
Show evidence (2 references)
PMID:33623047 SUPPORT In Vitro
"The lipid transfer domain of human VPS13D binds glycerophospholipids and FAs in vitro."
Establishes lipid binding by the human VPS13D lipid-transfer domain.
PMID:33891013 SUPPORT In Vitro
"VPS13D, which in turn binds the ER in a VAP-dependent way and thus could provide a lipid conduit between the ER and mitochondria."
Supports a proposed ER-mitochondria bridge while preserving the authors' conditional wording.
Impaired Mitochondrial Fission and Mitophagic Completion
Vps13D is required for mitochondrial size control, fission, and completion of mitophagy in experimental systems. Vps13D-impaired neurons accumulate enlarged mitochondria within stalled mitophagy intermediates, with separable functions in mitochondrial fission and phagophore elongation.
VPS13D hgnc:23595 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VPS13D (hgnc:23595). hgnc:23595 is a gene from the HUGO Gene Nomenclature Committee.
mitochondrial fission GO:0000266 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial fission (GO:0000266). GO:0000266 is a biological process from the Gene Ontology. ↓ DECREASED autophagy of mitochondrion GO:0000422 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagy of mitochondrion (GO:0000422). GO:0000422 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Mitochondrial Morphology, Distribution, and Bioenergetic Abnormalities Impaired fission and mitophagic completion are consistent with enlarged, poorly cleared mitochondria, but the experimental evidence does not establish every step leading to the patient-cell bioenergetic phenotype.
Show evidence (2 references)
PMID:29307555 SUPPORT Model Organism
"Vps13D is an essential gene that is necessary for autophagy, mitochondrial size, and mitochondrial clearance in Drosophila."
Establishes Vps13D-dependent mitochondrial size control and clearance in vivo.
PMID:34383748 SUPPORT Model Organism
"the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation."
Distinguishes the fission and mitophagy-completion functions in neurons.
Mitochondrial Morphology, Distribution, and Bioenergetic Abnormalities
Patient fibroblasts show abnormal mitochondrial morphology and reduced energy production or reduced abundance of respiratory-chain complex proteins. Vps13D-deficient fly neurons show altered mitochondrial morphology and impaired axonal distribution. These are convergent observations rather than proof of a single ordered sequence from contact-site function through bioenergetic failure.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
VPS13D hgnc:23595 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VPS13D (hgnc:23595). hgnc:23595 is a gene from the HUGO Gene Nomenclature Committee.
mitochondrion organization GO:0007005 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated mitochondrion organization (GO:0007005). GO:0007005 is a biological process from the Gene Ontology. ↕ DYSREGULATED oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neuronal Dysfunction and Neurodegeneration Adult neuronal depletion and conditional neuronal knockout models link mitochondrial quality-control defects to progressive neuronal dysfunction and degeneration, but the corresponding human intermediates are unknown.
Show evidence (3 references)
PMID:29604224 SUPPORT Model Organism
"Knockdown or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons."
Establishes neuronal mitochondrial morphology and axonal-distribution defects in vivo.
PMID:29604224 SUPPORT In Vitro
"Patient fibroblasts showed altered morphology and functionality including reduced energy production."
Demonstrates a human patient-cell mitochondrial morphology and bioenergetic phenotype.
PMID:35151251 SUPPORT In Vitro
"Primary fibroblasts obtained from this patient revealed an altered mitochondrial morphology, and a decrease in levels of proteins from complex I, III and IV."
Independently documents abnormal morphology and respiratory-chain protein deficits in patient fibroblasts.
Neuronal Dysfunction and Neurodegeneration
Neuronal Vps13D depletion causes progressive locomotor impairment and brain degeneration in flies, while conditional excitatory-neuron knockout in mice produces mitochondrial dysfunction, inflammatory microglial activation, neuronal death, and behavioral changes. These models support neuronal vulnerability but do not yet explain why human SCASI preferentially affects cerebellar/oculomotor, corticospinal, and peripheral axonal systems.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Cerebellar and Oculomotor Circuit Dysfunction The cellular mechanism is inferred to impair cerebellar and fixation circuits, but no patient-tissue or human-neuron study has established the intervening causal chain.
Corticospinal and Peripheral Axonal Dysfunction The mitochondrial/neuronal defect is inferred to affect corticospinal and long peripheral axons; the tissue-selective causal intermediates remain unknown.
Show evidence (2 references)
PMID:37457002 SUPPORT Model Organism
"adult-onset Vps13D RNAi expression in neurons causes the accumulation of mitophagy intermediates, progressive deficits in locomotor activity, early lethality, and brain vacuolization characteristic of neurodegeneration."
Demonstrates progressive adult neuronal degeneration after Vps13D knockdown.
PMID:40563011 SUPPORT Model Organism
"Loss of Vps13d in excitatory neurons resulted in behavioral changes and neurodegeneration."
Confirms neuronal vulnerability in an independent mammalian model.
Cerebellar and Oculomotor Circuit Dysfunction
Classic SCASI combines cerebellar ataxia with impaired visual fixation from saccadic intrusions. Quantitative recordings show overshooting horizontal saccades, macrosaccadic oscillations, and increased velocity of larger saccades. Slowed conduction in cerebellar feedback pathways has been proposed, but specific Purkinje-cell pathology and the bridge from VPS13D mitochondrial biology remain unproven.
Downstream
Progressive Cerebellar Ataxia Cerebellar circuit dysfunction produces the progressive ataxic syndrome.
Saccadic Intrusions Oculomotor circuit instability disrupts steady visual fixation.
Macrosaccadic Oscillations The fixation instability includes recurrent macrosaccadic oscillations.
Hypermetric Saccades Cerebellar saccadic dysmetria produces overshooting horizontal saccades.
Show evidence (2 references)
PMID:14681893 SUPPORT Human Clinical
"Affected patients showed overshooting horizontal saccades, macrosaccadic oscillations, and increased velocity of larger saccades; other eye movements were normal."
Defines the recorded oculomotor signature of classic SCASI.
PMID:14681893 SUPPORT Human Clinical
"Slowed conduction in axons that are selectively vulnerable to the molecular defect could explain both the sensorimotor neuropathy and the saccadic disorder"
Preserves the original paper's hypothesis-level interpretation of selective axonal slowing.
Corticospinal and Peripheral Axonal Dysfunction
Classic SCASI includes corticospinal signs and axonal sensorimotor neuropathy. Selective slowing or degeneration of vulnerable axons is a plausible systems-level explanation, but the precise affected cell populations and molecular intermediates have not been established.
Downstream
Pyramidal Signs Corticospinal system dysfunction produces pyramidal signs.
Peripheral Axonal Neuropathy Peripheral axonal dysfunction produces the sensorimotor neuropathy.
Show evidence (1 reference)
PMID:14681893 SUPPORT Human Clinical
"We describe a family of Slovenian descent with progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy, and disruption of visual fixation by saccadic intrusions."
Establishes corticospinal and peripheral axonal involvement in classic SCASI.
⬡

Pathograph

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

Phenotypes

6
Nervous System 1
Progressive Cerebellar Ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cerebellar ataxia (HP:0002073). HP:0002073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14681893 SUPPORT Human Clinical
"We describe a family of Slovenian descent with progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy, and disruption of visual fixation by saccadic intrusions."
Progressive ataxia is part of the defining classic SCASI phenotype.
Other 5
Saccadic Intrusions HP:0032114 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Saccadic intrusion (HP:0032114). HP:0032114 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14681893 SUPPORT Human Clinical
"disruption of visual fixation by saccadic intrusions."
Defines the fixation-disrupting ocular motor feature.
Macrosaccadic Oscillations HP:0032105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrosaccadic oscillations (HP:0032105). HP:0032105 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14681893 SUPPORT Human Clinical
"Affected patients showed overshooting horizontal saccades, macrosaccadic oscillations, and increased velocity of larger saccades"
Macrosaccadic oscillations were captured on quantitative recordings.
Hypermetric Saccades HP:0007338 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypermetric saccades (HP:0007338). HP:0007338 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14681893 SUPPORT Human Clinical
"Affected patients showed overshooting horizontal saccades, macrosaccadic oscillations, and increased velocity of larger saccades"
Overshooting horizontal saccades correspond to saccadic hypermetria.
Pyramidal Signs Abnormal pyramidal sign HP:0007256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pyramidal sign (HP:0007256). HP:0007256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14681893 SUPPORT Human Clinical
"progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy"
Corticospinal signs are directly reported in the defining family.
Peripheral Axonal Neuropathy HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral axonal neuropathy (HP:0003477). HP:0003477 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14681893 SUPPORT Human Clinical
"progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy"
Axonal sensorimotor neuropathy is directly reported in classic SCASI.
🧬

Genetic Associations

1
Biallelic VPS13D Pathogenic Variants (Causative)
Gene: VPS13D hgnc:23595 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VPS13D (hgnc:23595). hgnc:23595 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:29604224 SUPPORT Human Clinical
"Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all 7 families."
Establishes the causative biallelic gene-disease relationship.
🗃️

External Assertions

3
Orphanet autosomal recessive cerebellar ataxia-movement disorder syndrome record
Orphanet structured disease record ORPHA:95434
Orphanet record for the recessive cerebellar ataxia-movement disorder syndrome corresponding to SCASI/SCAR4; it reports autosomal recessive inheritance, an ultra-rare prevalence class, and cross-references including OMIM:607317 and MeSH:C537310.
OMIM spinocerebellar ataxia, autosomal recessive 4 record
OMIM disease record OMIM:607317
OMIM disease record for SCAR4.
MeSH spinocerebellar ataxia, autosomal recessive 4 concept
MeSH disease concept MESH:C537310
MeSH supplementary concept for autosomal recessive spinocerebellar ataxia 4.
💊

Medical Actions

3
Multidisciplinary Rehabilitation and Supportive Care
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying treatment is established. Physical and occupational therapy, gait and fall-risk assessment, mobility aids, speech/swallow support, and symptom-directed management should be individualized.
Show evidence (2 references)
PMID:38569247 SUPPORT Human Clinical
"Although no specific treatment exists, rehabilitation and supportive therapy remain central."
Directly supports rehabilitation and supportive therapy as the management core.
PMID:30789691 SUPPORT Other
"A multidisciplinary team including occupational and physical therapists and a physiatrist is important"
Supports multidisciplinary rehabilitation for the broader VPS13D disorder spectrum.
Memantine for Disabling Saccadic Intrusions
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: memantine CHEBI:64312 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses memantine (CHEBI:64312). CHEBI:64312 is a therapeutic agent from Chemical Entities of Biological Interest.
In two brothers with SCASI, memantine 20 mg/day reduced the frequency of saccadic intrusions and produced sustained improvement in reading without reported side effects. This uncontrolled two-patient observation supports a carefully monitored symptomatic trial in selected patients, not established efficacy or disease modification.
Show evidence (1 reference)
DOI:10.1212/01.wnl.0000286952.01476.eb SUPPORT Human Clinical
"Treatment with memantine caused sustained improvement in reading in both patients without side effects."
Direct disease-specific observation, limited by the uncontrolled N=2 design.
Genetic Counseling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Provide autosomal recessive recurrence counseling, targeted carrier testing for relatives, and reproductive testing options once both familial VPS13D variants are known.
Show evidence (1 reference)
PMID:30789691 SUPPORT Other
"Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the VPS13D pathogenic variants in the family are known."
Directly supports familial carrier and prenatal testing.
🔬

Diagnosis

3
Quantitative Eye-Movement Recording
Video-oculography or an equivalent quantitative eye-movement method can document fixation-disrupting macrosaccadic oscillations, hypermetric horizontal saccades, and abnormally fast larger saccades. This is a high-value supportive phenotype test, not a substitute for molecular confirmation.
Show evidence (1 reference)
DOI:10.1212/01.wnl.0000286952.01476.eb SUPPORT Human Clinical
"Eye movements were measured (magnetic search coil technique)"
Demonstrates objective measurement of the SCASI fixation and saccade phenotype.
RNA Sequencing for Unresolved Splice-Effect Variants
When exome or genome testing identifies a VPS13D VUS with a possible splice effect, RNA sequencing can demonstrate aberrant transcription and help resolve pathogenicity. This is particularly relevant to synonymous, missense, and deep intronic variants that escape routine interpretation.
Show evidence (1 reference)
PMID:37340120 SUPPORT In Vitro
"clinicians should consider utilizing RNA-seq to clarify VUS by evaluating its effect on RNA transcription."
Directly supports RNA sequencing as a functional follow-up for unresolved VPS13D variants.
🩻

Imaging Findings

1
Mild Cerebellar Atrophy on MRI
Structural MRI can show mild cerebellar atrophy; this is supportive but not pathognomonic and may be subtle despite long disease duration.
Mri Adult-onset SCAR4 case with a 30-year course
Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:42387113 SUPPORT Human Clinical
"MRI showed mild cerebellar atrophy."
Directly documents the structured MRI finding.
📈

Progression

1
Adult-onset progressive course
Age: Adult presentation documented; the classic-SCASI-only onset distribution is not established
Classic SCASI/SCAR4 is slowly progressive. A 2026 molecularly confirmed adult case began in the twenties and progressed over 30 years. Infantile and childhood presentations reported for the wider VPS13D allelic spectrum are intentionally not assigned to this classic disease entry.
Show evidence (1 reference)
PMID:42387113 SUPPORT Human Clinical
"The patient developed gait disturbance in his twenties, followed by progressive cerebellar and sensory ataxia, pyramidal signs, and peripheral neuropathy."
Documents a slowly progressive adult-onset SCAR4 presentation.
📊

Prevalence

1
Published VPS13D/SCAR4 literature through 2026
Cases In Literature Ultra Rare
A 2026 pooled literature review identified 47 VPS13D/SCAR4 cases. This is a broad allelic-spectrum count rather than a classic-SCASI-only prevalence denominator, and no population-based incidence or point-prevalence study was identified.
Show evidence (1 reference)
PMID:42387113 SUPPORT Human Clinical
"A literature review identified 47 cases."
Provides the most recent published broad VPS13D/SCAR4 case count.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Cerebellar Ataxia-Saccadic Intrusion Syndrome:

RFC1 Spectrum Disorder / CANVAS
Overlapping Features RFC1 biallelic repeat expansions can cause adult-onset cerebellar ataxia with sensory neuropathy or neuronopathy.
Distinguishing Features
  • Bilateral vestibular areflexia and chronic cough favor CANVAS.
  • RFC1 repeat-expansion testing is required because standard exome sequencing can miss the expansion.
  • Macrosaccadic oscillations are not a defining RFC1 feature.
Friedreich Ataxia
Overlapping Features FXN-related Friedreich ataxia overlaps through progressive ataxia, pyramidal signs, and sensory neuropathy.
Distinguishing Features
  • Cardiomyopathy, diabetes, scoliosis, and characteristic sensory-potential loss favor Friedreich ataxia.
  • FXN GAA-repeat testing distinguishes it molecularly.
ARSACS and Other Recessive Spastic Ataxias
Overlapping Features SACS-, SPG7-, KIF1C-, SETX-, APTX-, and other recessive disorders can combine cerebellar ataxia, pyramidal signs, and neuropathy.
Distinguishing Features
  • Disease-specific MRI, retinal, biochemical, and neuropathy patterns guide panel or genome interpretation.
  • The classic SCASI fixation phenotype with macrosaccadic oscillations and hypermetric saccades favors VPS13D.
Autosomal Dominant Spinocerebellar Ataxias Including SCA4
Overlapping Features The historical label SCAR4 can be confused with autosomal dominant SCA4 and other dominant spinocerebellar ataxias.
Distinguishing Features
  • A dominant multigenerational pedigree argues against VPS13D-related SCAR4.
  • Biallelic VPS13D variants establish the recessive disorder.
🧫

Experimental Models

1
VPS13D Patient Fibroblast Mitochondrial Model PRIMARY_CELL_CULTURE
Primary skin fibroblasts from individuals with biallelic VPS13D variants model mitochondrial morphology, energy-production, and respiratory-chain protein abnormalities in a patient-derived human system.
Biallelic VPS13D pathogenic variants Patient-derived primary culture
fibroblast CL:0000057 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Skin fibroblasts from affected individuals
Culture
Primary adherent fibroblast culture with mitochondrial imaging and functional assays
Publication
PMID:29604224
Show evidence (2 references)
PMID:29604224 SUPPORT In Vitro
"Patient fibroblasts showed altered morphology and functionality including reduced energy production."
Establishes a patient-derived human cellular model of mitochondrial dysfunction.
PMID:35151251 SUPPORT In Vitro
"Primary fibroblasts obtained from this patient revealed an altered mitochondrial morphology, and a decrease in levels of proteins from complex I, III and IV."
Replicates the mitochondrial phenotype and adds respiratory-chain protein deficits.
🐁

Animal Models

3
Neuronal Vps13D knockdown or loss Fruit fly (Drosophila melanogaster)
Neuronal Vps13D loss alters mitochondrial morphology and axonal distribution. Adult-onset knockdown additionally produces accumulated mitophagy intermediates, progressive locomotor deficits, early lethality, and brain vacuolization.
Abnormal mitochondrial morphology Impaired axonal mitochondrial distribution Progressive locomotor impairment Brain vacuolization
Species
Fruit fly (Drosophila melanogaster)
Genotype
Neuronal Vps13D knockdown or loss
Genes
VPS13D hgnc:23595 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns VPS13D (hgnc:23595). hgnc:23595 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:29604224 SUPPORT Model Organism
"Knockdown or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons."
Establishes the core neuronal mitochondrial fly phenotype.
PMID:37457002 SUPPORT Model Organism
"adult-onset Vps13D RNAi expression in neurons causes the accumulation of mitophagy intermediates, progressive deficits in locomotor activity, early lethality, and brain vacuolization characteristic of neurodegeneration."
Adds temporally controlled adult neurodegeneration to the fly model.
Patient-analogous vps-13D missense mutations or C-terminal deletion Roundworm (Caenorhabditis elegans)
CRISPR-engineered vps-13D alleles model patient-associated missense changes and a deletion, producing locomotor defects, abnormal mitochondrial morphology, and mitochondrial stress responses.
Locomotion defect Abnormal mitochondrial morphology Increased mitochondrial unfolded-protein response
Species
Roundworm (Caenorhabditis elegans)
Genotype
Patient-analogous vps-13D missense mutations or C-terminal deletion
Genes
VPS13D hgnc:23595 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns VPS13D (hgnc:23595). hgnc:23595 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:39957248 SUPPORT Model Organism
"vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial morphology."
Demonstrates both behavioral and mitochondrial phenotypes in variant-based worm models.
Conditional Vps13d knockout in excitatory neurons Mouse (Mus musculus)
Conditional loss in excitatory neurons causes mitochondrial ultrastructural dysfunction, cGAS-STING-associated inflammatory signaling, microglial activation, neuronal cell death, behavioral abnormalities, and neurodegeneration.
Neuronal mitochondrial ultrastructural defects Microglial activation Neurodegeneration Behavioral change
Species
Mouse (Mus musculus)
Genotype
Conditional Vps13d knockout in excitatory neurons
Genes
VPS13D hgnc:23595 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns VPS13D (hgnc:23595). hgnc:23595 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:40563011 SUPPORT Model Organism
"Loss of Vps13d in excitatory neurons resulted in behavioral changes and neurodegeneration."
Establishes the conditional mammalian neuronal-loss phenotype.
{ }

Source YAML

click to show 
name: Autosomal Recessive Cerebellar Ataxia-Saccadic Intrusion Syndrome
creation_date: "2026-06-04T12:00:00Z"
category: Mendelian
description: >-
  Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome
  (SCASI), also called spinocerebellar ataxia, autosomal recessive 4
  (SCAR4), is the classic VPS13D-associated recessive ataxia represented by
  MONDO:0011811. It is a slowly progressive cerebellar syndrome distinguished
  by fixation-disrupting saccadic intrusions, especially macrosaccadic
  oscillations and hypermetric saccades, together with pyramidal signs and
  axonal sensorimotor neuropathy. Biallelic pathogenic VPS13D variants are
  causative. Experimental work establishes roles for VPS13D in organelle
  contact-site lipid handling, mitochondrial fission, mitophagic completion,
  mitochondrial morphology, and axonal mitochondrial distribution, but the
  intermediates connecting these cellular defects to the selective human
  cerebellar, oculomotor, corticospinal, and peripheral-nerve phenotype remain
  unresolved. Childhood chorea, epilepsy, dystonia, isolated spastic
  paraplegia, and severe tremor occur in the broader VPS13D allelic spectrum
  and are not treated here as defining features of classic SCASI.
disease_term:
  preferred_term: Autosomal Recessive Cerebellar Ataxia-Saccadic Intrusion Syndrome
  term:
    id: MONDO:0011811
    label: autosomal recessive cerebellar ataxia-saccadic intrusion syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011811
      label: autosomal recessive cerebellar ataxia-saccadic intrusion syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for the classic SCASI/SCAR4 disease entity.
external_assertions:
- name: Orphanet autosomal recessive cerebellar ataxia-movement disorder syndrome record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:95434
  url: https://www.orpha.net/en/disease/detail/95434
  description: >-
    Orphanet record for the recessive cerebellar ataxia-movement disorder
    syndrome corresponding to SCASI/SCAR4; it reports autosomal recessive
    inheritance, an ultra-rare prevalence class, and cross-references including
    OMIM:607317 and MeSH:C537310.
- name: OMIM spinocerebellar ataxia, autosomal recessive 4 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:607317
  url: https://omim.org/entry/607317
  description: OMIM disease record for SCAR4.
- name: MeSH spinocerebellar ataxia, autosomal recessive 4 concept
  source: MeSH
  assertion_type: disease_concept
  external_id: MESH:C537310
  url: https://meshb.nlm.nih.gov/record/ui?ui=C537310
  description: MeSH supplementary concept for autosomal recessive spinocerebellar ataxia 4.
synonyms:
- Spinocerebellar ataxia with saccadic intrusions
- SCASI
- Spinocerebellar ataxia, autosomal recessive 4
- SCAR4
parents:
- Hereditary ataxia
references:
- reference: PMID:14681893
  title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
- reference: PMID:29307555
  title: Vps13D Encodes a Ubiquitin-Binding Protein that Is Required for the Regulation of Mitochondrial Size and Clearance.
- reference: PMID:29604224
  title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
- reference: PMID:30789691
  title: VPS13D Movement Disorder.
  tags:
  - GeneReviews
- reference: PMID:33623047
  title: An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions.
- reference: PMID:33891013
  title: VPS13D bridges the ER to mitochondria and peroxisomes via Miro.
- reference: PMID:34019822
  title: "Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease."
- reference: PMID:34383748
  title: "Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons."
- reference: PMID:35151251
  title: Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia.
- reference: PMID:37340120
  title: "RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature."
- reference: PMID:37457002
  title: An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown.
- reference: PMID:38569247
  title: Autosomal recessive spinocerebellar ataxia type 4 due to a novel homozygous mutation in the VPS13D gene in a Saudi family.
- reference: PMID:39957248
  title: VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
- reference: PMID:40563011
  title: Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration.
- reference: PMID:41288814
  title: "VPS13D-Related Disorders: Description of New Variant and Phenotypic Spectrum Based on Age of Onset."
- reference: PMID:42387113
  title: "Adult-Onset SCAR4 with a 30-Year Slowly Progressive Course: First Combined Assessment with FDG-PET and Brain Perfusion SPECT."
- reference: DOI:10.1212/01.wnl.0000286952.01476.eb
  title: SUPPRESSION OF SACCADIC INTRUSIONS IN HEREDITARY ATAXIA BY MEMANTINE
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    SCASI/SCAR4 is caused by biallelic germline VPS13D variants. Most reported
    affected individuals carry one loss-of-function allele and one missense or
    other partially functional allele; this pattern is consistent with the
    severe consequences of complete VPS13D loss in experimental systems.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified compound heterozygous mutations in VPS13D on
      chromosome 1p36 in all 7 families.
    explanation: Establishes biallelic VPS13D variants in multiple recessive ataxia families.
  - reference: PMID:30789691
    reference_title: VPS13D Movement Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: VPS13D movement disorder is inherited in an autosomal recessive manner.
    explanation: GeneReviews states the inheritance mode directly.
prevalence:
- population: Published VPS13D/SCAR4 literature through 2026
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2026 pooled literature review identified 47 VPS13D/SCAR4 cases. This is a
    broad allelic-spectrum count rather than a classic-SCASI-only prevalence
    denominator, and no population-based incidence or point-prevalence study
    was identified.
  evidence:
  - reference: PMID:42387113
    reference_title: "Adult-Onset SCAR4 with a 30-Year Slowly Progressive Course: First Combined Assessment with FDG-PET and Brain Perfusion SPECT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A literature review identified 47 cases.
    explanation: Provides the most recent published broad VPS13D/SCAR4 case count.
progression:
- phase: Adult-onset progressive course
  age_range: Adult presentation documented; the classic-SCASI-only onset distribution is not established
  notes: >-
    Classic SCASI/SCAR4 is slowly progressive. A 2026 molecularly confirmed
    adult case began in the twenties and progressed over 30 years. Infantile
    and childhood presentations reported for the wider VPS13D allelic spectrum
    are intentionally not assigned to this classic disease entry.
  evidence:
  - reference: PMID:42387113
    reference_title: "Adult-Onset SCAR4 with a 30-Year Slowly Progressive Course: First Combined Assessment with FDG-PET and Brain Perfusion SPECT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient developed gait disturbance in his twenties, followed by
      progressive cerebellar and sensory ataxia, pyramidal signs, and peripheral
      neuropathy.
    explanation: Documents a slowly progressive adult-onset SCAR4 presentation.
pathophysiology:
- name: Biallelic VPS13D Dysfunction
  description: >-
    Biallelic pathogenic VPS13D variants are the initiating lesion. The common
    configuration of one nonsense or splice-site allele with one missense
    allele supports partial residual function rather than uniform complete
    protein absence; the node therefore uses dysfunction rather than
    loss-of-function as its disease-wide label.
  gene:
    preferred_term: VPS13D
    term:
      id: hgnc:23595
      label: VPS13D
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This included a large family with 5 affected siblings with spinocerebellar
      ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia,
      recessive, type 4 (SCAR4).
    explanation: Links the original SCASI/SCAR4 family to VPS13D.
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All but 2 patients carried a loss-of-function (nonsense or splice site)
      mutation on one and a missense mutation on the other allele.
    explanation: Supports the typical mixed severe-plus-missense biallelic architecture.
  downstream:
  - target: Dysregulated VPS13D-Dependent Organelle Contact-Site Lipid Handling
    description: >-
      VPS13D depletion perturbs lipid handling at lipid-droplet-mitochondria
      contacts, and biochemical studies support a lipid-binding/contact-site
      function. Extrapolation from depletion systems to patient neurons is
      partial.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33623047
      reference_title: An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Depletion of VPS13D, TSG101, or ESCRT-III proteins inhibits FA
        trafficking from LDs to mitochondria.
      explanation: Directly links VPS13D depletion to impaired contact-site fatty-acid trafficking in cells, with partial disease-context extrapolation.
  - target: Impaired Mitochondrial Fission and Mitophagic Completion
    description: >-
      Vps13D loss disrupts mitochondrial size control and completion of
      mitophagy in experimental systems.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34383748
      reference_title: "Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        mitophagy both initiates and is completed in Drp1 impaired neurons, but
        fails to complete in Vps13D impaired neurons
      explanation: Establishes a Vps13D-specific mitophagy-completion defect in fly neurons; human disease extrapolation remains partial.
- name: Dysregulated VPS13D-Dependent Organelle Contact-Site Lipid Handling
  description: >-
    VPS13D is a large contact-site protein with a lipid-transfer domain. Its
    lipid-transfer domain binds glycerophospholipids and fatty acids in vitro;
    VPS13D depletion inhibits lipid-droplet-to-mitochondria fatty-acid
    trafficking, and Miro/VAP recruitment can bridge VPS13D between the ER and
    mitochondria. Whether VPS13D directly transports endogenous lipids in
    affected human neurons, and how this function contributes to SCASI, remain
    unproven.
  gene:
    preferred_term: VPS13D
    term:
      id: hgnc:23595
      label: VPS13D
  biological_processes:
  - preferred_term: intermembrane lipid transfer
    term:
      id: GO:0120009
      label: intermembrane lipid transfer
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:33623047
    reference_title: An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The lipid transfer domain of human VPS13D binds glycerophospholipids and
      FAs in vitro.
    explanation: Establishes lipid binding by the human VPS13D lipid-transfer domain.
  - reference: PMID:33891013
    reference_title: VPS13D bridges the ER to mitochondria and peroxisomes via Miro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      VPS13D, which in turn binds the ER in a VAP-dependent way and thus could
      provide a lipid conduit between the ER and mitochondria.
    explanation: Supports a proposed ER-mitochondria bridge while preserving the authors' conditional wording.
  downstream:
  - target: Mitochondrial Morphology, Distribution, and Bioenergetic Abnormalities
    description: >-
      Contact-site dysregulation is proposed to contribute to the observed
      mitochondrial abnormalities, but the direction and intervening steps are
      not established as a linear disease pathway.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34019822
      reference_title: "Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the function of Vps13D in mitochondria and ER contact is conserved
        between fly and human cells
      explanation: Connects VPS13D contact-site biology to mitochondrial phenotypes across models without establishing a complete causal chain.
- name: Impaired Mitochondrial Fission and Mitophagic Completion
  description: >-
    Vps13D is required for mitochondrial size control, fission, and completion
    of mitophagy in experimental systems. Vps13D-impaired neurons accumulate
    enlarged mitochondria within stalled mitophagy intermediates, with
    separable functions in mitochondrial fission and phagophore elongation.
  gene:
    preferred_term: VPS13D
    term:
      id: hgnc:23595
      label: VPS13D
  biological_processes:
  - preferred_term: mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: DECREASED
  - preferred_term: autophagy of mitochondrion
    term:
      id: GO:0000422
      label: autophagy of mitochondrion
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:29307555
    reference_title: Vps13D Encodes a Ubiquitin-Binding Protein that Is Required for the Regulation of Mitochondrial Size and Clearance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Vps13D is an essential gene that is necessary for autophagy,
      mitochondrial size, and mitochondrial clearance in Drosophila.
    explanation: Establishes Vps13D-dependent mitochondrial size control and clearance in vivo.
  - reference: PMID:34383748
    reference_title: "Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the lipid channel containing protein Vps13D has separable functions in
      mitochondrial fission and phagophore elongation.
    explanation: Distinguishes the fission and mitophagy-completion functions in neurons.
  downstream:
  - target: Mitochondrial Morphology, Distribution, and Bioenergetic Abnormalities
    description: >-
      Impaired fission and mitophagic completion are consistent with enlarged,
      poorly cleared mitochondria, but the experimental evidence does not
      establish every step leading to the patient-cell bioenergetic phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34383748
      reference_title: "Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Neurons lacking either the ataxia disease gene Vps13D or the dynamin
        related protein Drp1 contain enlarged mitochondria
      explanation: Supports the morphology component in fission-impaired neurons, while the broader cross-layer chain remains incomplete.
- name: Mitochondrial Morphology, Distribution, and Bioenergetic Abnormalities
  description: >-
    Patient fibroblasts show abnormal mitochondrial morphology and reduced
    energy production or reduced abundance of respiratory-chain complex
    proteins. Vps13D-deficient fly neurons show altered mitochondrial morphology
    and impaired axonal distribution. These are convergent observations rather
    than proof of a single ordered sequence from contact-site function through
    bioenergetic failure.
  gene:
    preferred_term: VPS13D
    term:
      id: hgnc:23595
      label: VPS13D
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: DYSREGULATED
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Knockdown or removal of Vps13D in Drosophila neurons led to changes in
      mitochondrial morphology and impairment in mitochondrial distribution
      along axons.
    explanation: Establishes neuronal mitochondrial morphology and axonal-distribution defects in vivo.
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient fibroblasts showed altered morphology and functionality including
      reduced energy production.
    explanation: Demonstrates a human patient-cell mitochondrial morphology and bioenergetic phenotype.
  - reference: PMID:35151251
    reference_title: Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Primary fibroblasts obtained from this patient revealed an altered
      mitochondrial morphology, and a decrease in levels of proteins from
      complex I, III and IV.
    explanation: Independently documents abnormal morphology and respiratory-chain protein deficits in patient fibroblasts.
  downstream:
  - target: Neuronal Dysfunction and Neurodegeneration
    description: >-
      Adult neuronal depletion and conditional neuronal knockout models link
      mitochondrial quality-control defects to progressive neuronal dysfunction
      and degeneration, but the corresponding human intermediates are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37457002
      reference_title: An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        adult-onset Vps13D RNAi expression in neurons causes the accumulation of
        mitophagy intermediates, progressive deficits in locomotor activity,
        early lethality, and brain vacuolization characteristic of
        neurodegeneration.
      explanation: Links neuronal Vps13D depletion and accumulated mitophagy intermediates to degeneration in adult flies.
    - reference: PMID:40563011
      reference_title: Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Loss of Vps13d in excitatory neurons resulted in behavioral changes and
        neurodegeneration.
      explanation: Supports a neuronal Vps13d-loss-to-neurodegeneration link in a conditional mouse model, not yet in humans.
- name: Neuronal Dysfunction and Neurodegeneration
  description: >-
    Neuronal Vps13D depletion causes progressive locomotor impairment and brain
    degeneration in flies, while conditional excitatory-neuron knockout in mice
    produces mitochondrial dysfunction, inflammatory microglial activation,
    neuronal death, and behavioral changes. These models support neuronal
    vulnerability but do not yet explain why human SCASI preferentially affects
    cerebellar/oculomotor, corticospinal, and peripheral axonal systems.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:37457002
    reference_title: An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      adult-onset Vps13D RNAi expression in neurons causes the accumulation of
      mitophagy intermediates, progressive deficits in locomotor activity,
      early lethality, and brain vacuolization characteristic of
      neurodegeneration.
    explanation: Demonstrates progressive adult neuronal degeneration after Vps13D knockdown.
  - reference: PMID:40563011
    reference_title: Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of Vps13d in excitatory neurons resulted in behavioral changes and
      neurodegeneration.
    explanation: Confirms neuronal vulnerability in an independent mammalian model.
  downstream:
  - target: Cerebellar and Oculomotor Circuit Dysfunction
    description: >-
      The cellular mechanism is inferred to impair cerebellar and fixation
      circuits, but no patient-tissue or human-neuron study has established the
      intervening causal chain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:14681893
      reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy,
        and disruption of visual fixation by saccadic intrusions.
      explanation: Establishes the co-occurring clinical systems but not the molecular-to-circuit causal intermediates.
  - target: Corticospinal and Peripheral Axonal Dysfunction
    description: >-
      The mitochondrial/neuronal defect is inferred to affect corticospinal and
      long peripheral axons; the tissue-selective causal intermediates remain
      unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42387113
      reference_title: "Adult-Onset SCAR4 with a 30-Year Slowly Progressive Course: First Combined Assessment with FDG-PET and Brain Perfusion SPECT."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        progressive cerebellar and sensory ataxia, pyramidal signs, and
        peripheral neuropathy.
      explanation: Supports the human systems-level association while leaving cellular intermediates unresolved.
- name: Cerebellar and Oculomotor Circuit Dysfunction
  description: >-
    Classic SCASI combines cerebellar ataxia with impaired visual fixation from
    saccadic intrusions. Quantitative recordings show overshooting horizontal
    saccades, macrosaccadic oscillations, and increased velocity of larger
    saccades. Slowed conduction in cerebellar feedback pathways has been
    proposed, but specific Purkinje-cell pathology and the bridge from VPS13D
    mitochondrial biology remain unproven.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients showed overshooting horizontal saccades, macrosaccadic
      oscillations, and increased velocity of larger saccades; other eye
      movements were normal.
    explanation: Defines the recorded oculomotor signature of classic SCASI.
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Slowed conduction in axons that are selectively vulnerable to the
      molecular defect could explain both the sensorimotor neuropathy and the
      saccadic disorder
    explanation: Preserves the original paper's hypothesis-level interpretation of selective axonal slowing.
  downstream:
  - target: Progressive Cerebellar Ataxia
    description: Cerebellar circuit dysfunction produces the progressive ataxic syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14681893
      reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy,
        and disruption of visual fixation by saccadic intrusions.
      explanation: Directly documents progressive ataxia in the defining SCASI family.
  - target: Saccadic Intrusions
    description: Oculomotor circuit instability disrupts steady visual fixation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14681893
      reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: disruption of visual fixation by saccadic intrusions.
      explanation: Directly documents the defining fixation abnormality.
  - target: Macrosaccadic Oscillations
    description: The fixation instability includes recurrent macrosaccadic oscillations.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14681893
      reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected patients showed overshooting horizontal saccades, macrosaccadic
        oscillations, and increased velocity of larger saccades
      explanation: Directly documents macrosaccadic oscillations on eye-movement recording.
  - target: Hypermetric Saccades
    description: Cerebellar saccadic dysmetria produces overshooting horizontal saccades.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14681893
      reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected patients showed overshooting horizontal saccades, macrosaccadic
        oscillations, and increased velocity of larger saccades
      explanation: Directly documents the hypermetric saccade phenotype.
- name: Corticospinal and Peripheral Axonal Dysfunction
  description: >-
    Classic SCASI includes corticospinal signs and axonal sensorimotor
    neuropathy. Selective slowing or degeneration of vulnerable axons is a
    plausible systems-level explanation, but the precise affected cell
    populations and molecular intermediates have not been established.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a family of Slovenian descent with progressive ataxia,
      corticospinal signs, axonal sensorimotor neuropathy, and disruption of
      visual fixation by saccadic intrusions.
    explanation: Establishes corticospinal and peripheral axonal involvement in classic SCASI.
  downstream:
  - target: Pyramidal Signs
    description: Corticospinal system dysfunction produces pyramidal signs.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14681893
      reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy
      explanation: Directly documents corticospinal signs in the defining family.
  - target: Peripheral Axonal Neuropathy
    description: Peripheral axonal dysfunction produces the sensorimotor neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14681893
      reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy
      explanation: Directly documents axonal sensorimotor neuropathy.
phenotypes:
- name: Progressive Cerebellar Ataxia
  category: Neurologic
  description: Slowly progressive gait, truncal, and limb ataxia is the core motor syndrome.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a family of Slovenian descent with progressive ataxia,
      corticospinal signs, axonal sensorimotor neuropathy, and disruption of
      visual fixation by saccadic intrusions.
    explanation: Progressive ataxia is part of the defining classic SCASI phenotype.
- name: Saccadic Intrusions
  category: Neurologic
  description: >-
    Frequent unwanted saccades disrupt steady visual fixation and can severely
    impair reading.
  diagnostic: true
  phenotype_term:
    preferred_term: Saccadic intrusion
    term:
      id: HP:0032114
      label: Saccadic intrusion
  evidence:
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: disruption of visual fixation by saccadic intrusions.
    explanation: Defines the fixation-disrupting ocular motor feature.
- name: Macrosaccadic Oscillations
  category: Neurologic
  description: Large back-to-back saccades oscillate around the fixation target.
  phenotype_term:
    preferred_term: Macrosaccadic oscillations
    term:
      id: HP:0032105
      label: Macrosaccadic oscillations
  evidence:
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients showed overshooting horizontal saccades, macrosaccadic
      oscillations, and increased velocity of larger saccades
    explanation: Macrosaccadic oscillations were captured on quantitative recordings.
- name: Hypermetric Saccades
  category: Neurologic
  description: Horizontal saccades overshoot their target.
  phenotype_term:
    preferred_term: Hypermetric saccades
    term:
      id: HP:0007338
      label: Hypermetric saccades
  evidence:
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients showed overshooting horizontal saccades, macrosaccadic
      oscillations, and increased velocity of larger saccades
    explanation: Overshooting horizontal saccades correspond to saccadic hypermetria.
- name: Pyramidal Signs
  category: Neurologic
  description: Corticospinal involvement produces abnormal pyramidal signs.
  phenotype_term:
    preferred_term: Abnormal pyramidal sign
    term:
      id: HP:0007256
      label: Abnormal pyramidal sign
  evidence:
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy
    explanation: Corticospinal signs are directly reported in the defining family.
- name: Peripheral Axonal Neuropathy
  category: Neurologic
  description: Axonal sensorimotor peripheral neuropathy contributes to sensory and motor disability.
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:14681893
    reference_title: Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy
    explanation: Axonal sensorimotor neuropathy is directly reported in classic SCASI.
imaging_findings:
- name: Mild Cerebellar Atrophy on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  located_in:
    preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  diagnostic: false
  description: >-
    Structural MRI can show mild cerebellar atrophy; this is supportive but not
    pathognomonic and may be subtle despite long disease duration.
  context: Adult-onset SCAR4 case with a 30-year course
  evidence:
  - reference: PMID:42387113
    reference_title: "Adult-Onset SCAR4 with a 30-Year Slowly Progressive Course: First Combined Assessment with FDG-PET and Brain Perfusion SPECT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MRI showed mild cerebellar atrophy.
    explanation: Directly documents the structured MRI finding.
genetic:
- name: Biallelic VPS13D Pathogenic Variants
  gene_term:
    preferred_term: VPS13D
    term:
      id: hgnc:23595
      label: VPS13D
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: Positive
  notes: >-
    SCASI/SCAR4 is caused by biallelic germline VPS13D variants, frequently a
    loss-of-function allele in trans with a missense or other residual-function
    allele. No individual variant is represented here because the previously
    listed p.Gln1106Ter claim lacked variant-specific evidence in the available
    reference cache.
  evidence:
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified compound heterozygous mutations in VPS13D on
      chromosome 1p36 in all 7 families.
    explanation: Establishes the causative biallelic gene-disease relationship.
diagnosis:
- name: Molecular Confirmation of VPS13D-Related SCASI/SCAR4
  description: >-
    Confirm the diagnosis by identifying biallelic pathogenic or likely
    pathogenic VPS13D variants. Multigene ataxia testing or exome/genome
    sequencing is appropriate when the phenotype is not recognized a priori;
    segregation analysis should establish that the two variants are in trans.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:30789691
    reference_title: VPS13D Movement Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of VPS13D movement disorder is established in a proband by
      identification of biallelic pathogenic variants in VPS13D on molecular
      genetic testing.
    explanation: GeneReviews defines molecular confirmation by biallelic pathogenic VPS13D variants.
- name: Quantitative Eye-Movement Recording
  description: >-
    Video-oculography or an equivalent quantitative eye-movement method can
    document fixation-disrupting macrosaccadic oscillations, hypermetric
    horizontal saccades, and abnormally fast larger saccades. This is a
    high-value supportive phenotype test, not a substitute for molecular
    confirmation.
  evidence:
  - reference: DOI:10.1212/01.wnl.0000286952.01476.eb
    reference_title: SUPPRESSION OF SACCADIC INTRUSIONS IN HEREDITARY ATAXIA BY MEMANTINE
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eye movements were measured (magnetic search coil technique)
    explanation: Demonstrates objective measurement of the SCASI fixation and saccade phenotype.
- name: RNA Sequencing for Unresolved Splice-Effect Variants
  description: >-
    When exome or genome testing identifies a VPS13D VUS with a possible splice
    effect, RNA sequencing can demonstrate aberrant transcription and help
    resolve pathogenicity. This is particularly relevant to synonymous,
    missense, and deep intronic variants that escape routine interpretation.
  evidence:
  - reference: PMID:37340120
    reference_title: "RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      clinicians should consider utilizing RNA-seq to clarify VUS by evaluating
      its effect on RNA transcription.
    explanation: Directly supports RNA sequencing as a functional follow-up for unresolved VPS13D variants.
differential_diagnoses:
- name: RFC1 Spectrum Disorder / CANVAS
  description: >-
    RFC1 biallelic repeat expansions can cause adult-onset cerebellar ataxia
    with sensory neuropathy or neuronopathy.
  distinguishing_features:
  - Bilateral vestibular areflexia and chronic cough favor CANVAS.
  - RFC1 repeat-expansion testing is required because standard exome sequencing can miss the expansion.
  - Macrosaccadic oscillations are not a defining RFC1 feature.
- name: Friedreich Ataxia
  description: >-
    FXN-related Friedreich ataxia overlaps through progressive ataxia,
    pyramidal signs, and sensory neuropathy.
  distinguishing_features:
  - Cardiomyopathy, diabetes, scoliosis, and characteristic sensory-potential loss favor Friedreich ataxia.
  - FXN GAA-repeat testing distinguishes it molecularly.
- name: ARSACS and Other Recessive Spastic Ataxias
  description: >-
    SACS-, SPG7-, KIF1C-, SETX-, APTX-, and other recessive disorders can
    combine cerebellar ataxia, pyramidal signs, and neuropathy.
  distinguishing_features:
  - Disease-specific MRI, retinal, biochemical, and neuropathy patterns guide panel or genome interpretation.
  - The classic SCASI fixation phenotype with macrosaccadic oscillations and hypermetric saccades favors VPS13D.
- name: Autosomal Dominant Spinocerebellar Ataxias Including SCA4
  description: >-
    The historical label SCAR4 can be confused with autosomal dominant SCA4 and
    other dominant spinocerebellar ataxias.
  distinguishing_features:
  - A dominant multigenerational pedigree argues against VPS13D-related SCAR4.
  - Biallelic VPS13D variants establish the recessive disorder.
treatments:
- name: Multidisciplinary Rehabilitation and Supportive Care
  action_category: THERAPEUTIC
  description: >-
    No disease-modifying treatment is established. Physical and occupational
    therapy, gait and fall-risk assessment, mobility aids, speech/swallow
    support, and symptom-directed management should be individualized.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38569247
    reference_title: Autosomal recessive spinocerebellar ataxia type 4 due to a novel homozygous mutation in the VPS13D gene in a Saudi family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although no specific treatment exists, rehabilitation and supportive
      therapy remain central.
    explanation: Directly supports rehabilitation and supportive therapy as the management core.
  - reference: PMID:30789691
    reference_title: VPS13D Movement Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A multidisciplinary team including occupational and physical therapists
      and a physiatrist is important
    explanation: Supports multidisciplinary rehabilitation for the broader VPS13D disorder spectrum.
- name: Memantine for Disabling Saccadic Intrusions
  action_category: THERAPEUTIC
  description: >-
    In two brothers with SCASI, memantine 20 mg/day reduced the frequency of
    saccadic intrusions and produced sustained improvement in reading without
    reported side effects. This uncontrolled two-patient observation supports a
    carefully monitored symptomatic trial in selected patients, not established
    efficacy or disease modification.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: memantine
      term:
        id: CHEBI:64312
        label: memantine
  evidence:
  - reference: DOI:10.1212/01.wnl.0000286952.01476.eb
    reference_title: SUPPRESSION OF SACCADIC INTRUSIONS IN HEREDITARY ATAXIA BY MEMANTINE
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with memantine caused sustained improvement in reading in both
      patients without side effects.
    explanation: Direct disease-specific observation, limited by the uncontrolled N=2 design.
- name: Genetic Counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Provide autosomal recessive recurrence counseling, targeted carrier testing
    for relatives, and reproductive testing options once both familial VPS13D
    variants are known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30789691
    reference_title: VPS13D Movement Disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Carrier testing for at-risk relatives and prenatal testing for a pregnancy
      at increased risk are possible if the VPS13D pathogenic variants in the
      family are known.
    explanation: Directly supports familial carrier and prenatal testing.
animal_models:
- species: Fruit fly (Drosophila melanogaster)
  genotype: Neuronal Vps13D knockdown or loss
  genes:
  - preferred_term: VPS13D
    term:
      id: hgnc:23595
      label: VPS13D
  description: >-
    Neuronal Vps13D loss alters mitochondrial morphology and axonal
    distribution. Adult-onset knockdown additionally produces accumulated
    mitophagy intermediates, progressive locomotor deficits, early lethality,
    and brain vacuolization.
  associated_phenotypes:
  - Abnormal mitochondrial morphology
  - Impaired axonal mitochondrial distribution
  - Progressive locomotor impairment
  - Brain vacuolization
  evidence:
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Knockdown or removal of Vps13D in Drosophila neurons led to changes in
      mitochondrial morphology and impairment in mitochondrial distribution
      along axons.
    explanation: Establishes the core neuronal mitochondrial fly phenotype.
  - reference: PMID:37457002
    reference_title: An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      adult-onset Vps13D RNAi expression in neurons causes the accumulation of
      mitophagy intermediates, progressive deficits in locomotor activity,
      early lethality, and brain vacuolization characteristic of
      neurodegeneration.
    explanation: Adds temporally controlled adult neurodegeneration to the fly model.
- species: Roundworm (Caenorhabditis elegans)
  genotype: Patient-analogous vps-13D missense mutations or C-terminal deletion
  genes:
  - preferred_term: VPS13D
    term:
      id: hgnc:23595
      label: VPS13D
  description: >-
    CRISPR-engineered vps-13D alleles model patient-associated missense changes
    and a deletion, producing locomotor defects, abnormal mitochondrial
    morphology, and mitochondrial stress responses.
  associated_phenotypes:
  - Locomotion defect
  - Abnormal mitochondrial morphology
  - Increased mitochondrial unfolded-protein response
  evidence:
  - reference: PMID:39957248
    reference_title: VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial
      morphology.
    explanation: Demonstrates both behavioral and mitochondrial phenotypes in variant-based worm models.
- species: Mouse (Mus musculus)
  genotype: Conditional Vps13d knockout in excitatory neurons
  genes:
  - preferred_term: VPS13D
    term:
      id: hgnc:23595
      label: VPS13D
  description: >-
    Conditional loss in excitatory neurons causes mitochondrial
    ultrastructural dysfunction, cGAS-STING-associated inflammatory signaling,
    microglial activation, neuronal cell death, behavioral abnormalities, and
    neurodegeneration.
  associated_phenotypes:
  - Neuronal mitochondrial ultrastructural defects
  - Microglial activation
  - Neurodegeneration
  - Behavioral change
  evidence:
  - reference: PMID:40563011
    reference_title: Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of Vps13d in excitatory neurons resulted in behavioral changes and
      neurodegeneration.
    explanation: Establishes the conditional mammalian neuronal-loss phenotype.
experimental_models:
- name: VPS13D Patient Fibroblast Mitochondrial Model
  description: >-
    Primary skin fibroblasts from individuals with biallelic VPS13D variants
    model mitochondrial morphology, energy-production, and respiratory-chain
    protein abnormalities in a patient-derived human system.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  conditions:
  - Biallelic VPS13D pathogenic variants
  - Patient-derived primary culture
  cell_source: Skin fibroblasts from affected individuals
  culture_system: Primary adherent fibroblast culture with mitochondrial imaging and functional assays
  publication: PMID:29604224
  evidence:
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient fibroblasts showed altered morphology and functionality including
      reduced energy production.
    explanation: Establishes a patient-derived human cellular model of mitochondrial dysfunction.
  - reference: PMID:35151251
    reference_title: Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Primary fibroblasts obtained from this patient revealed an altered
      mitochondrial morphology, and a decrease in levels of proteins from
      complex I, III and IV.
    explanation: Replicates the mitochondrial phenotype and adds respiratory-chain protein deficits.
discussions:
- discussion_id: gap_scasi_disease_boundary_and_genotype_phenotype
  prompt: >-
    Which biallelic VPS13D genotypes belong to classic SCASI/SCAR4, and which
    define other disorders in the broader VPS13D movement-disorder spectrum?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic VPS13D Dysfunction
  - pathophysiology#Cerebellar and Oculomotor Circuit Dysfunction
  rationale: >-
    MONDO:0011811 is the classic cerebellar ataxia-saccadic intrusion entity,
    whereas published VPS13D cohorts aggregate childhood chorea/epilepsy,
    generalized dystonia, isolated or predominant spastic paraplegia, and
    tremor with classic SCASI. Residual VPS13D function, variant class, and age
    of onset probably influence presentation, but the current case count is too
    small and nosologically mixed for reliable genotype-phenotype rules. This
    entry therefore keeps broad-spectrum observations out of the classic
    phenotype and treatment rows unless explicitly contextualized.
  evidence:
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study demonstrates that compound heterozygous mutations in VPS13D
      cause movement disorders along the ataxia-spasticity spectrum
    explanation: Establishes a broad VPS13D ataxia-spasticity spectrum around the classic family.
  - reference: PMID:41288814
    reference_title: "VPS13D-Related Disorders: Description of New Variant and Phenotypic Spectrum Based on Age of Onset."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pediatric presentations appear to follow a more disabling course, with
      distinct characteristics according to age of onset.
    explanation: Supports age-dependent heterogeneity and a distinct pediatric spectrum.
- discussion_id: gap_scasi_human_model_mismatch_and_circuit_selectivity
  prompt: >-
    How do VPS13D mitochondrial and contact-site defects produce selective
    cerebellar, oculomotor, corticospinal, and peripheral axonal dysfunction in
    humans, and which model best reproduces the compound-hypomorphic disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated VPS13D-Dependent Organelle Contact-Site Lipid Handling
  - pathophysiology#Impaired Mitochondrial Fission and Mitophagic Completion
  - pathophysiology#Neuronal Dysfunction and Neurodegeneration
  rationale: >-
    Fly knockdown and conditional mouse knockout strongly support mitochondrial
    quality-control and neuronal-degeneration mechanisms, but severe depletion
    or null states do not reproduce the typical human combination of one
    loss-of-function and one missense allele. The mouse model adds a
    microglia-dependent inflammatory death pathway that has not been shown in
    human SCASI, while neither model recreates the defining macrosaccadic
    oscillations or establishes selective peripheral-nerve involvement.
    Variant-matched human iPSC-derived cerebellar and peripheral neurons with
    isogenic controls are needed to test the cellular-to-circuit bridge.
  evidence:
  - reference: PMID:29604224
    reference_title: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All but 2 patients carried a loss-of-function (nonsense or splice site)
      mutation on one and a missense mutation on the other allele.
    explanation: Defines the typical human allelic architecture that complete-loss models do not reproduce.
  - reference: PMID:40563011
    reference_title: Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Depletion of microglia suppressed cell death and behavioral phenotypes but
      not mitochondrial changes in the neuron-specific Vps13d-knockout model
    explanation: Demonstrates a mouse-specific glial mediator whose relevance to human SCASI remains unresolved.
  - reference: PMID:39957248
    reference_title: VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial
      morphology.
    explanation: A variant-based model narrows the allelic mismatch but still lacks the human circuit phenotype.
notes: >-
  Scope and nomenclature: this entry represents classic
  SCASI/SCAR4 (MONDO:0011811; ORPHA:95434; OMIM:607317;
  MeSH:C537310), historically also called SCA24. The unqualified synonym
  "VPS13D-related disorder" was removed because it spans clinically distinct
  childhood and adult presentations. Tremor and deep-brain stimulation were
  also removed from the treatment/phenotype rows because the reported DBS case
  represents a broader severe spastic-ataxia presentation, not the defining
  classic SCASI family. The previous p.Gln1106Ter variant row was removed
  because available evidence supported only a general variant class, not that
  exact variant-level assertion. Phenotype frequency bands are intentionally
  omitted because classic-SCASI denominators are too small and are often pooled
  with the broader VPS13D spectrum.
📚

References & Deep Research

References

17
PMID:14681893
Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions.
No top-level findings curated for this source.
PMID:29307555
Vps13D Encodes a Ubiquitin-Binding Protein that Is Required for the Regulation of Mitochondrial Size and Clearance.
No top-level findings curated for this source.
PMID:29604224
Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
No top-level findings curated for this source.
PMID:30789691
VPS13D Movement Disorder.
No top-level findings curated for this source.
PMID:33623047
An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions.
No top-level findings curated for this source.
PMID:33891013
VPS13D bridges the ER to mitochondria and peroxisomes via Miro.
No top-level findings curated for this source.
PMID:34019822
Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease.
No top-level findings curated for this source.
PMID:34383748
Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons.
No top-level findings curated for this source.
PMID:35151251
Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia.
No top-level findings curated for this source.
PMID:37340120
RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature.
No top-level findings curated for this source.
PMID:37457002
An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown.
No top-level findings curated for this source.
PMID:38569247
Autosomal recessive spinocerebellar ataxia type 4 due to a novel homozygous mutation in the VPS13D gene in a Saudi family.
No top-level findings curated for this source.
PMID:39957248
VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
No top-level findings curated for this source.
PMID:40563011
Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration.
No top-level findings curated for this source.
PMID:41288814
VPS13D-Related Disorders: Description of New Variant and Phenotypic Spectrum Based on Age of Onset.
No top-level findings curated for this source.
PMID:42387113
Adult-Onset SCAR4 with a 30-Year Slowly Progressive Course: First Combined Assessment with FDG-PET and Brain Perfusion SPECT.
No top-level findings curated for this source.
DOI:10.1212/01.wnl.0000286952.01476.eb
SUPPRESSION OF SACCADIC INTRUSIONS IN HEREDITARY ATAXIA BY MEMANTINE
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 26 citations 2026-06-04T18:39:55.577543

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Autosomal Recessive Cerebellar Ataxia-Saccadic Intrusion Syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Autosomal Recessive Cerebellar Ataxia-Saccadic Intrusion Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Autosomal Recessive Cerebellar Ataxia–Saccadic Intrusion Syndrome (SCASI) / SCAR4 (VPS13D-related disorder)

Executive summary

Autosomal Recessive Cerebellar Ataxia–Saccadic Intrusion Syndrome is best aligned with spinocerebellar ataxia, autosomal recessive 4 (SCAR4), historically described clinically as spinocerebellar ataxia with saccadic intrusions (SCASI; formerly “SCA24”) and caused by biallelic pathogenic variants in VPS13D at chromosome 1p36. Key features include progressive cerebellar ataxia with prominent saccadic intrusions/abnormal pursuit, often combined with spasticity/pyramidal signs and peripheral neuropathy; onset ranges from infancy through adulthood and progression is usually slow, with a substantial subset losing independent ambulation. Mechanistic evidence supports mitochondrial network/quality-control defects consistent with VPS13D’s role as a bulk lipid transporter at membrane contact sites and its involvement in autophagy/mitochondrial homeostasis. (seong2018mutationsinvps13d pages 1-5, seong2018mutationsinvps13d pages 30-32)

Disease / synonyms Inheritance Causal gene / IDs Locus Key papers (date; URL) Key clinical hallmarks Typical onset range Citations
Autosomal Recessive Cerebellar Ataxia–Saccadic Intrusion Syndrome; Spinocerebellar ataxia with saccadic intrusions (SCASI); Spinocerebellar ataxia, autosomal recessive 4 (SCAR4); formerly SCA24 Autosomal recessive VPS13D; disease SCAR4 OMIM #607317; gene VPS13D OMIM *608877 1p36 Seong et al., 2018-06, Ann Neurol; https://doi.org/10.1002/ana.25220 • Kistol et al., 2024-05, Int J Mol Sci; https://doi.org/10.3390/ijms25105127 Progressive cerebellar ataxia, spasticity/pyramidal signs, saccadic intrusions/ocular-motor abnormalities, neuropathy; some cases with developmental delay or loss of ambulation Infancy to adulthood; reported from <1 year to 39 years (seong2018mutationsinvps13d pages 1-5, kistol2024newcaseof pages 1-3)
Historical family-based SCASI description before gene identification Autosomal recessive Gene not yet identified in 2003 family report; later resolved as VPS13D Linked to chromosome 1p36 in later studies Swartz et al., 2003-12, Ann Neurol; https://doi.org/10.1002/ana.10758 • Akbar & Ashizawa, 2015-02, Neurol Clin; https://doi.org/10.1016/j.ncl.2014.09.004 Progressive ataxia with difficulty reading, macrosaccadic oscillations/saccadic oscillations intruding on fixation, pyramidal signs, myoclonus, axonal sensorimotor neuropathy, pes cavus; mild cerebellar vermis atrophy reported Review/table source lists 3rd decade onset for SCASI; family studies support slow progression (swartz2003pathogenesisofclinical pages 1-2, akbar2015ataxia pages 18-20)
VPS13D-related disorder spectrum encompassing SCAR4/SCASI Autosomal recessive (usually biallelic, often compound heterozygous) VPS13D; representative pathogenic variants include c.3569G>A (p.Gly1190Asp), c.3316C>T (p.Gln1106Ter), p.Tyr1803Ter, p.Ala4210Val, c.2237-1G>C, c.941+3A>G, c.9998+4A>C, c.9388C>T (p.Arg3130Ter), c.9679G>T (p.Gly3227Trp) 1p36 Seong et al., 2018-06, https://doi.org/10.1002/ana.25220 • Pauly et al., 2023-01, https://doi.org/10.3390/ijms24031874 • Kistol et al., 2024-05, https://doi.org/10.3390/ijms25105127 Ataxia-spasticity spectrum with dysarthria, tremor, dystonia/chorea in some patients, saccadic pursuit or square-wave/macro-saccadic intrusions, peripheral axonal neuropathy, variable cognitive/developmental involvement; mitochondrial abnormalities in fibroblasts support mechanism Broad range from early childhood/infancy to adult-onset; slowly progressive (seong2018mutationsinvps13d pages 30-32, seong2018mutationsinvps13d pages 8-12, kistol2024newcaseof pages 3-5, pauly2023nottomiss pages 1-2)

Table: This table compacts the key identifiers, genetics, landmark papers, and hallmark clinical features for autosomal recessive cerebellar ataxia–saccadic intrusion syndrome. It is useful as a quick-reference scaffold for a disease knowledge base entry focused on VPS13D-related SCAR4/SCASI.

1. Disease information

1.1 What is the disease?

SCASI/SCAR4 is a rare, genetically defined autosomal recessive neurodegenerative/movement-disorder syndrome on the ataxia–spasticity spectrum in which ocular fixation is disrupted by saccadic intrusions (e.g., macrosaccadic oscillations, square-wave-like intrusions) accompanying progressive cerebellar dysfunction. The disorder was initially characterized clinically in families with prominent saccadic intrusions and later molecularly resolved as biallelic VPS13D mutations. (seong2018mutationsinvps13d pages 1-5, swartz2003pathogenesisofclinical pages 1-2)

1.2 Key identifiers and ontologies

  • OMIM disease: Spinocerebellar ataxia, autosomal recessive 4 (SCAR4) #607317 (reported in a 2024 case report) (kistol2024newcaseof pages 1-3)
  • OMIM gene: VPS13D *608877 (kistol2024newcaseof pages 1-3)
  • Genomic locus: 1p36 (akbar2015ataxia pages 18-20, seong2018mutationsinvps13d pages 1-5)
  • MONDO (from OpenTargets associations):
  • Spinocerebellar ataxia type 4: MONDO_0010847 (OpenTargets Search: spinocerebellar ataxia,hereditary ataxia,spastic ataxia-VPS13D)
  • Cerebellar ataxia: MONDO_0000437 (OpenTargets Search: spinocerebellar ataxia,hereditary ataxia,spastic ataxia-VPS13D)
  • Orphanet / ICD-10/ICD-11 / MeSH: Not identified in the retrieved sources for this specific entity; additional direct lookup in Orphanet/ICD/MeSH would be required for authoritative identifiers.

1.3 Synonyms / alternative names

  • “Spinocerebellar ataxia with saccadic intrusions (SCASI)” (seong2018mutationsinvps13d pages 1-5, swartz2003pathogenesisofclinical pages 1-2)
  • “Spinocerebellar ataxia, recessive, type 4 (SCAR4)” (seong2018mutationsinvps13d pages 1-5)
  • “Formerly SCA24” (as stated in a clinical review table) (akbar2015ataxia pages 18-20)

1.4 Evidence sources and aggregation level

Evidence is derived from: - Family studies with quantitative eye-movement recordings (human clinical physiology) (swartz2003pathogenesisofclinical pages 1-2) - Case series with exome sequencing and functional validation in patient fibroblasts and Drosophila (human + model organism + in vitro) (seong2018mutationsinvps13d pages 1-5, seong2018mutationsinvps13d pages 30-32) - Recent case reports/reviews summarizing variant spectra (human clinical genetics) (kistol2024newcaseof pages 1-3, pauly2023nottomiss pages 1-2) - Consensus methodology papers for oculomotor biomarkers in hereditary ataxia trials (expert consensus/systematic review) (garces2024quantitativeoculomotorassessment pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: biallelic pathogenic variants in VPS13D (autosomal recessive), typically compound heterozygosity with one loss-of-function (nonsense/splice) allele and one missense (or non-canonical splice region) allele. (seong2018mutationsinvps13d pages 1-5)

Abstract quote (primary genetics + functional validation): - Seong et al. (Ann Neurol; 2018-06; https://doi.org/10.1002/ana.25220) reported: “Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all seven families.” (seong2018mutationsinvps13d pages 1-5)

2.2 Risk factors

  • Genetic: carrying two pathogenic VPS13D alleles (biallelic). (seong2018mutationsinvps13d pages 1-5)
  • Environmental/lifestyle risk factors: not established in retrieved sources.

2.3 Protective factors

Not established in retrieved sources.

2.4 Gene–environment interactions

Not established in retrieved sources.

3. Phenotypes

3.1 Core neurological and oculomotor phenotypes

Ataxia + spasticity spectrum - In the key multi-center series, the phenotype was broad, with ataxia predominant in most and additional/predominant spasticity in others, with onset from infancy to 39 years and slow progression. (seong2018mutationsinvps13d pages 1-5)

Abstract quote (natural history): - Seong et al. reported: “Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5.” (seong2018mutationsinvps13d pages 1-5)

Oculomotor abnormalities (saccadic intrusions) - In a foundational family physiology study, fixation was disrupted by saccadic oscillations and macrosaccadic oscillations, with hypermetric saccades; smooth pursuit/vestibular/vergence could be normal. (swartz2003pathogenesisofclinical pages 1-2)

3.2 Additional phenotypes reported in the VPS13D spectrum (relevant to SCAR4 presentations)

Recent summaries and case reports note variable additional findings beyond classic ataxia/spasticity: - tremor, dystonia/chorea, seizures, cognitive/developmental involvement, neuropathy (counts in review), and leukoencephalopathy in some individuals. (kistol2024newcaseof pages 3-5, pauly2023nottomiss pages 1-2)

Review statistics (counts of features; 2023): Pauly et al. (Int J Mol Sci; 2023-01-18; https://doi.org/10.3390/ijms24031874) reported for VPS13D-related disorder: “neuropathy (n = 10…), dystonia (n = 7 …), myoclonus (n = 5 …) and chorea (n = 4 …)” with “variable age at onset from infantile to adulthood onset.” (pauly2023nottomiss pages 1-2)

3.3 Phenotype characteristics (onset, progression, frequency)

  • Age at onset: infancy to adulthood; in SCASI/SCAR4 families, onset can be early adult (historical SCASI) or very early in severe forms. (seong2018mutationsinvps13d pages 1-5)
  • Progression: generally slow; however, severe childhood-onset cases can progress to walker/wheelchair dependence. In Seong et al., 5/12 lost independent ambulation. (seong2018mutationsinvps13d pages 1-5)

3.4 Quality-of-life impact

QoL was not directly measured in retrieved sources, but functional dependence is implied by loss of independent ambulation and impaired reading due to fixation instability in SCASI-like phenotypes. (akbar2015ataxia pages 18-20, seong2018mutationsinvps13d pages 1-5)

3.5 Suggested HPO terms (examples; non-exhaustive)

Based on the cited clinical descriptions: - Cerebellar ataxia (HP:0001251) - Spasticity (HP:0001257) - Hyperreflexia (HP:0001347) - Peripheral neuropathy / axonal neuropathy (HP:0009830 / HP:0003477) - Nystagmus (HP:0000639) - Saccadic intrusions / square wave jerks / macrosaccadic oscillations (phenotype class; map to closest HPO terms such as abnormal saccadic pursuit or abnormal ocular fixation; precise HPO term selection should be validated against HPO browser) - Dysarthria (HP:0001260) - Tremor (HP:0001337)

4. Genetic / molecular information

4.1 Causal gene

  • VPS13D (vacuolar protein sorting 13 homolog D) at 1p36, OMIM *608877. (kistol2024newcaseof pages 1-3)

4.2 Representative pathogenic variants (examples from primary sources)

From the multi-family Annals of Neurology series (2018): multiple truncating/splice/missense variants were reported across families (examples listed in the text/table evidence), including (not exhaustive): - c.3569G>A (p.Gly1190Asp) and c.3316C>T (p.Gln1106Ter) in the historically described SCASI/SCAR4 family (seong2018mutationsinvps13d pages 8-12) - splice/near-splice variants c.2237-1G>C, c.941+3A>G, c.9998+4A>C and multiple truncating/missense changes (seong2018mutationsinvps13d pages 30-32)

From a 2024 adult case report: - c.9388C>T, p.(Arg3130Ter) (pathogenic) - c.9679G>T, p.(Gly3227Trp) (likely pathogenic; novel in the report) (kistol2024newcaseof pages 3-5)

4.3 Variant type/class and functional consequences

  • Many affected individuals carry one loss-of-function allele (nonsense/splice) plus a missense/non-canonical splice allele, consistent with partial functional preservation and with intolerance to complete loss-of-function. (seong2018mutationsinvps13d pages 1-5)

4.4 Molecular function and pathogenic mechanism (current understanding)

Bulk lipid transport at membrane contact sites; mitochondrial network integrity - Kistol et al. (2024-05-08; https://doi.org/10.3390/ijms25105127) describe VPS13D as a “bulk lipid transporter” at membrane contact sites and state that loss-of-function results in “enlarged spherical mitochondria that accumulate in the perinuclear region and often break.” (kistol2024newcaseof pages 1-3)

Mitochondrial morphology and energy production defects (human + model) - Seong et al. demonstrated neuronal mitochondrial distribution/morphology defects in Drosophila and altered mitochondrial morphology and reduced energy production in patient fibroblasts. (seong2018mutationsinvps13d pages 1-5)

Visual evidence (table/figures): - Cropped Table 1 and mitochondrial defect figures from Seong et al. show patient variant/phenotype aggregation and fibroblast mitochondrial defects/ATP reduction. (seong2018mutationsinvps13d media 1bc218ff, seong2018mutationsinvps13d media 8a1f9878, seong2018mutationsinvps13d media d463dc10)

4.5 Modifier genes / epigenetics / chromosomal abnormalities

Not established in retrieved sources.

5. Environmental information

No established environmental/lifestyle/infectious contributors identified in retrieved sources.

6. Mechanism / pathophysiology

6.1 Proposed causal chain (integrated)

  1. Biallelic VPS13D variants impair VPS13D protein function (often one truncating allele plus a milder allele). (seong2018mutationsinvps13d pages 1-5)
  2. VPS13D dysfunction disrupts bulk lipid transfer at organelle contact sites and processes required for autophagy/mitochondrial size control and clearance. (kistol2024newcaseof pages 1-3)
  3. Cells exhibit mitochondrial network abnormalities (rounded/spherical/donut-shaped mitochondria, perinuclear accumulation) and reduced energy production in patient fibroblasts; neurons show impaired mitochondrial distribution along axons in Drosophila. (seong2018mutationsinvps13d pages 1-5)
  4. Circuit-level dysfunction in cerebellar and brainstem oculomotor networks yields ataxia and ocular fixation instability (saccadic intrusions/macrosaccadic oscillations), with additional corticospinal/peripheral nerve involvement causing spasticity and neuropathy. (swartz2003pathogenesisofclinical pages 1-2, seong2018mutationsinvps13d pages 1-5)

6.2 Suggested GO biological process terms (examples)

  • Mitochondrial organization; mitochondrial fission/fusion balance
  • Autophagy / mitophagy
  • Lipid transport at membrane contact sites

6.3 Suggested CL (cell types) and GO cellular component terms

  • Purkinje cell (CL term; cerebellar cortex) and cerebellar interneurons as plausible key vulnerable cell types (inferred from clinical phenotype and cerebellar involvement; direct cell-type-specific evidence not present in retrieved sources)
  • Mitochondrion (GO:0005739), axon (neuronal mitochondrial distribution) (seong2018mutationsinvps13d pages 1-5)

7. Anatomical structures affected

7.1 Organ/system level

  • Central nervous system, prominently cerebellum (ataxia; mild cerebellar vermis atrophy reported in early SCASI family study) (swartz2003pathogenesisofclinical pages 1-2)
  • Corticospinal system (pyramidal signs/spasticity) (seong2018mutationsinvps13d pages 1-5)
  • Peripheral nervous system (axonal sensorimotor neuropathy in SCASI physiology study; neuropathy frequency noted in VPS13D review) (swartz2003pathogenesisofclinical pages 1-2, pauly2023nottomiss pages 1-2)

7.2 UBERON suggestions

  • Cerebellum (UBERON:0002037)
  • Cerebellar vermis (UBERON:0002128)
  • Peripheral nerve (UBERON:0001021)

8. Temporal development

  • Onset: broad, from infancy to 39 years in the multi-family cohort (seong2018mutationsinvps13d pages 1-5)
  • Course: typically slowly progressive (seong2018mutationsinvps13d pages 1-5)
  • Functional staging (evidence-based anchor): loss of independent ambulation occurred in 5/12 in the 2018 cohort. (seong2018mutationsinvps13d pages 1-5)

9. Inheritance and population

  • Inheritance: autosomal recessive; often compound heterozygous. (seong2018mutationsinvps13d pages 1-5)
  • Epidemiology (prevalence/incidence): not identified in retrieved sources; appears rare with published case counts on the order of a few dozen (e.g., “about 33 patients” in 2024 case report; “31 published cases” in 2023 review). (kistol2024newcaseof pages 1-3, pauly2023nottomiss pages 1-2)
  • Penetrance/expressivity: variable expressivity is strongly supported by heterogeneous phenotypes and intrafamilial variability noted in the 2018 and 2023 reports. (seong2018mutationsinvps13d pages 1-5, pauly2023nottomiss pages 1-2)

10. Diagnostics

10.1 Clinical and laboratory evaluation

A structured approach for adult-onset ataxia with neuropathy emphasizes objective phenotyping using: - electrophysiology (neuropathy characterization) - vestibular testing - oculomotor measurement (video-oculography) to identify gaze-evoked nystagmus, dysmetric/slow saccades, and saccadic intrusions (roberts2022overviewofthe pages 1-2)

Abstract quote (diagnostic workflow): - Roberts et al. (Neurol Genet; 2022-10; https://doi.org/10.1212/nxg.0000000000200021): “Objective diagnostic modalities including electrophysiology, oculomotor, and vestibular function testing are invaluable in accurately defining an individual’s phenotype.” (roberts2022overviewofthe pages 1-2)

10.2 Neuroimaging

  • Brain MRI may show cerebellar atrophy and, in some VPS13D presentations, leukoencephalopathy; an adult SCAR4 case reported “leukoencephalopathy with cortical and cerebellar atrophy.” (kistol2024newcaseof pages 1-3)

10.3 Genetic testing strategy

  • Stepwise genetic testing ranging from gene panels to WES/WGS guided by inheritance and age at onset is recommended in the broader ataxia diagnostic literature (roberts2022overviewofthe pages 1-2)
  • In the 2018 SCAR4/SCASI series, prior gene panel testing was negative and exome sequencing resolved the diagnosis in seven families. (seong2018mutationsinvps13d pages 1-5)

10.4 Quantitative oculomotor biomarkers (latest consensus; 2023–2024)

Garces et al. consensus/systematic review (Accepted online 2023-04-28; The Cerebellum 2024; https://doi.org/10.1007/s12311-023-01559-9) provides a harmonized framework for eye-movement endpoints in hereditary ataxia trials: - Abstract quote (core eye-movement set): “we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex” (garces2024quantitativeoculomotorassessment pages 1-2) - Evidence base size: 117 articles; genetically confirmed ataxia subjects n=1134, suspected hereditary ataxia n=198, sporadic degenerative ataxia n=480. (garces2024quantitativeoculomotorassessment pages 1-2) - Implementation statistics: among included studies, modalities included EOG (40 studies; 915 subjects) and VOG (43 studies; 639 subjects). (garces2024quantitativeoculomotorassessment pages 9-10)

10.5 Differential diagnosis (high level)

Oculomotor signatures (slow saccades, saccadic intrusions, gaze-evoked nystagmus) can aid differentiation among hereditary ataxias, and the consensus paper explicitly notes that patterns of abnormalities can facilitate differential diagnosis and targeted workup. (garces2024quantitativeoculomotorassessment pages 1-2)

11. Outcomes / prognosis

  • Course: slowly progressive but heterogeneous; substantial disability can occur.
  • Ambulation: 5/12 lost independent ambulation in the 2018 multi-family cohort. (seong2018mutationsinvps13d pages 1-5)
  • Mortality/life expectancy: not reported in retrieved sources.

12. Treatment

12.1 Disease-modifying therapy

No disease-modifying therapies were identified in retrieved sources.

12.2 Symptomatic / supportive care (current real-world implementations)

Rehabilitation therapy - Pauly et al. note that before their report, “there are no reports of successful treatment apart from rehabilitation therapy” for VPS13D-related disorder. (pauly2023nottomiss pages 1-2)

Deep brain stimulation (DBS) for refractory tremor - Pauly et al. report tremor “improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus.” (pauly2023nottomiss pages 1-2) - Quantified outcome: Fahn tremor scale improved from 87/144 to 70/144 immediately after surgery, enabling independent eating/drinking. (pauly2023nottomiss pages 2-4)

Levodopa and baclofen - Levodopa produced mild improvement in one VPS13D patient with tremor; baclofen response reported as poor in the reviewed literature. (pauly2023nottomiss pages 2-4, pauly2023nottomiss pages 4-7)

Memantine for saccadic intrusions (evidence from related recessive ataxia phenotypes) - In a small familial adult cerebellar ataxia study (memantine 20 mg/day for 6 months), memantine reduced saccadic intrusions (SWI magnitude/frequency) and authors concluded: “memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO” and recommended controlled trials. (rosini2013ocularmotorprofileand pages 5-7) - Quantitative saccade data showed significantly abnormal saccade latency/velocity/accuracy versus controls (e.g., 18° peak velocity ~300.8±69.4°/s vs 385.4±41.8°/s; p<0.001). (rosini2013ocularmotorprofileand pages 5-7)

12.3 Clinical trials

A clinical-trials search using “VPS13D AND (ataxia OR spastic ataxia OR spastic paraplegia OR SCAR4 OR SCASI)” did not return relevant VPS13D-directed interventional trials in the retrieved trial set. (garces2024quantitativeoculomotorassessment pages 1-2)

12.4 Suggested MAXO terms (examples)

  • Physical therapy / rehabilitation therapy
  • Deep brain stimulation (thalamic VIM DBS)
  • Dopaminergic therapy (levodopa)
  • Antispasticity therapy (baclofen)
  • NMDA receptor antagonist therapy (memantine) for fixation instability (symptomatic)

13. Prevention

No primary prevention is established for this Mendelian disorder. Preventive strategies are primarily genetic: - Carrier testing and reproductive counseling for at-risk families (standard practice for autosomal recessive disorders; not directly detailed in retrieved sources). - Secondary/tertiary prevention: fall prevention and aspiration risk reduction via multidisciplinary care is recommended in ataxia management broadly. (roberts2022overviewofthe pages 1-2)

14. Other species / natural disease

No naturally occurring animal disease analogs were identified in retrieved sources.

15. Model organisms

Drosophila (in vivo functional genetics) - Knock-down/removal of Vps13D in Drosophila neurons produced mitochondrial morphology changes and impaired axonal mitochondrial distribution, supporting causal mechanism. (seong2018mutationsinvps13d pages 1-5)

Patient fibroblasts (in vitro functional assays) - Patient-derived fibroblasts demonstrated altered mitochondrial morphology/function and reduced energy production. (seong2018mutationsinvps13d pages 1-5)

2023–2024 “latest research” highlights and expert interpretation

  1. Standardization of oculomotor digital biomarkers for trials: The Ataxia Global Initiative consensus emphasizes that oculomotor deficits are common but underused endpoints, and proposes harmonized paradigms/parameters for multicenter studies; this is directly relevant to SCASI/SCAR4 where fixation/saccadic intrusions are prominent. (garces2024quantitativeoculomotorassessment pages 1-2, garces2024quantitativeoculomotorassessment pages 9-10)
  2. Variant-detection expansion beyond canonical splice sites: The 2023 VPS13D review stresses “looking for mutations outside the canonical splice sites” in heterogeneous presentations, reflecting the increasing importance of WGS/WES + RNA studies. (pauly2023nottomiss pages 1-2)
  3. Growing variant catalogs and phenotypic expansion: The 2024 SCAR4 case report notes expanding ClinVar/HGMD variant counts and reiterates that VPS13D phenotypes can include Leigh-like presentations, implying diagnostic overlap with mitochondrial/leukoencephalopathy syndromes. (kistol2024newcaseof pages 3-5)

Notes on evidence gaps (for KB curation)

  • Orphanet/ICD/MeSH identifiers, prevalence/incidence, and validated QoL instruments specific to SCAR4/SCASI were not located in the retrieved sources.
  • Gene–environment effects, protective factors, and epigenetic modifiers have not been established in the cited materials.
  • Many phenotype ontology mappings (HPO) for saccadic intrusion subtypes may require manual curation against the HPO catalog to choose the most specific term(s).

References

  1. (seong2018mutationsinvps13d pages 1-5): Eunju Seong, Ryan Insolera, Marija Dulovic, Erik‐Jan Kamsteeg, Joanne Trinh, Norbert Brüggemann, Erin Sandford, Sheng Li, Ayse Bilge Ozel, Jun Z. Li, Tamison Jewett, Anneke J. A. Kievit, Alexander Münchau, Vikram Shakkottai, Christine Klein, Catherine A. Collins, Katja Lohmann, Bart P. van de Warrenburg, and Margit Burmeister. Mutations in vps13d lead to a new recessive ataxia with spasticity and mitochondrial defects. Annals of Neurology, 83:1075-1088, Jun 2018. URL: https://doi.org/10.1002/ana.25220, doi:10.1002/ana.25220. This article has 197 citations and is from a highest quality peer-reviewed journal.

  2. (seong2018mutationsinvps13d pages 30-32): Eunju Seong, Ryan Insolera, Marija Dulovic, Erik‐Jan Kamsteeg, Joanne Trinh, Norbert Brüggemann, Erin Sandford, Sheng Li, Ayse Bilge Ozel, Jun Z. Li, Tamison Jewett, Anneke J. A. Kievit, Alexander Münchau, Vikram Shakkottai, Christine Klein, Catherine A. Collins, Katja Lohmann, Bart P. van de Warrenburg, and Margit Burmeister. Mutations in vps13d lead to a new recessive ataxia with spasticity and mitochondrial defects. Annals of Neurology, 83:1075-1088, Jun 2018. URL: https://doi.org/10.1002/ana.25220, doi:10.1002/ana.25220. This article has 197 citations and is from a highest quality peer-reviewed journal.

  3. (kistol2024newcaseof pages 1-3): Denis Kistol, Polina Tsygankova, Fatima Bostanova, Maria Orlova, and Ekaterina Zakharova. New case of spinocerebellar ataxia, autosomal recessive 4, due to vps13d variants. International Journal of Molecular Sciences, 25:5127, May 2024. URL: https://doi.org/10.3390/ijms25105127, doi:10.3390/ijms25105127. This article has 3 citations.

  4. (swartz2003pathogenesisofclinical pages 1-2): Barbara E. Swartz, Sheng Li, Irina Bespalova, Margit Burmeister, Eugene Dulaney, Farrel R. Robinson, and R. John Leigh. Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions. Annals of Neurology, 54:824-828, Dec 2003. URL: https://doi.org/10.1002/ana.10758, doi:10.1002/ana.10758. This article has 48 citations and is from a highest quality peer-reviewed journal.

  5. (akbar2015ataxia pages 18-20): Umar Akbar and Tetsuo Ashizawa. Ataxia. Feb 2015. URL: https://doi.org/10.1016/j.ncl.2014.09.004, doi:10.1016/j.ncl.2014.09.004. This article has 130 citations and is from a peer-reviewed journal.

  6. (seong2018mutationsinvps13d pages 8-12): Eunju Seong, Ryan Insolera, Marija Dulovic, Erik‐Jan Kamsteeg, Joanne Trinh, Norbert Brüggemann, Erin Sandford, Sheng Li, Ayse Bilge Ozel, Jun Z. Li, Tamison Jewett, Anneke J. A. Kievit, Alexander Münchau, Vikram Shakkottai, Christine Klein, Catherine A. Collins, Katja Lohmann, Bart P. van de Warrenburg, and Margit Burmeister. Mutations in vps13d lead to a new recessive ataxia with spasticity and mitochondrial defects. Annals of Neurology, 83:1075-1088, Jun 2018. URL: https://doi.org/10.1002/ana.25220, doi:10.1002/ana.25220. This article has 197 citations and is from a highest quality peer-reviewed journal.

  7. (kistol2024newcaseof pages 3-5): Denis Kistol, Polina Tsygankova, Fatima Bostanova, Maria Orlova, and Ekaterina Zakharova. New case of spinocerebellar ataxia, autosomal recessive 4, due to vps13d variants. International Journal of Molecular Sciences, 25:5127, May 2024. URL: https://doi.org/10.3390/ijms25105127, doi:10.3390/ijms25105127. This article has 3 citations.

  8. (pauly2023nottomiss pages 1-2): Martje G. Pauly, Norbert Brüggemann, Stephanie Efthymiou, Anne Grözinger, Sokhna Haissatou Diaw, Viorica Chelban, Valentina Turchetti, Barbara Vona, Vera Tadic, Henry Houlden, Alexander Münchau, and Katja Lohmann. Not to miss: intronic variants, treatment, and review of the phenotypic spectrum in vps13d-related disorder. International Journal of Molecular Sciences, 24:1874, Jan 2023. URL: https://doi.org/10.3390/ijms24031874, doi:10.3390/ijms24031874. This article has 16 citations.

  9. (OpenTargets Search: spinocerebellar ataxia,hereditary ataxia,spastic ataxia-VPS13D): Open Targets Query (spinocerebellar ataxia,hereditary ataxia,spastic ataxia-VPS13D, 3 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  10. (garces2024quantitativeoculomotorassessment pages 1-2): Pilar Garces, Chrystalina A. Antoniades, Anna Sobanska, Norbert Kovacs, Sarah H. Ying, Anoopum S. Gupta, Susan Perlman, David J. Szmulewicz, Chiara Pane, Andrea H. Németh, Laura B. Jardim, Giulia Coarelli, Michaela Dankova, Andreas Traschütz, and Alexander A. Tarnutzer. Quantitative oculomotor assessment in hereditary ataxia: systematic review and consensus by the ataxia global initiative working group on digital-motor biomarkers. Cerebellum (London, England), 23:896-911, Apr 2024. URL: https://doi.org/10.1007/s12311-023-01559-9, doi:10.1007/s12311-023-01559-9. This article has 21 citations.

  11. (seong2018mutationsinvps13d media 1bc218ff): Eunju Seong, Ryan Insolera, Marija Dulovic, Erik‐Jan Kamsteeg, Joanne Trinh, Norbert Brüggemann, Erin Sandford, Sheng Li, Ayse Bilge Ozel, Jun Z. Li, Tamison Jewett, Anneke J. A. Kievit, Alexander Münchau, Vikram Shakkottai, Christine Klein, Catherine A. Collins, Katja Lohmann, Bart P. van de Warrenburg, and Margit Burmeister. Mutations in vps13d lead to a new recessive ataxia with spasticity and mitochondrial defects. Annals of Neurology, 83:1075-1088, Jun 2018. URL: https://doi.org/10.1002/ana.25220, doi:10.1002/ana.25220. This article has 197 citations and is from a highest quality peer-reviewed journal.

  12. (seong2018mutationsinvps13d media 8a1f9878): Eunju Seong, Ryan Insolera, Marija Dulovic, Erik‐Jan Kamsteeg, Joanne Trinh, Norbert Brüggemann, Erin Sandford, Sheng Li, Ayse Bilge Ozel, Jun Z. Li, Tamison Jewett, Anneke J. A. Kievit, Alexander Münchau, Vikram Shakkottai, Christine Klein, Catherine A. Collins, Katja Lohmann, Bart P. van de Warrenburg, and Margit Burmeister. Mutations in vps13d lead to a new recessive ataxia with spasticity and mitochondrial defects. Annals of Neurology, 83:1075-1088, Jun 2018. URL: https://doi.org/10.1002/ana.25220, doi:10.1002/ana.25220. This article has 197 citations and is from a highest quality peer-reviewed journal.

  13. (seong2018mutationsinvps13d media d463dc10): Eunju Seong, Ryan Insolera, Marija Dulovic, Erik‐Jan Kamsteeg, Joanne Trinh, Norbert Brüggemann, Erin Sandford, Sheng Li, Ayse Bilge Ozel, Jun Z. Li, Tamison Jewett, Anneke J. A. Kievit, Alexander Münchau, Vikram Shakkottai, Christine Klein, Catherine A. Collins, Katja Lohmann, Bart P. van de Warrenburg, and Margit Burmeister. Mutations in vps13d lead to a new recessive ataxia with spasticity and mitochondrial defects. Annals of Neurology, 83:1075-1088, Jun 2018. URL: https://doi.org/10.1002/ana.25220, doi:10.1002/ana.25220. This article has 197 citations and is from a highest quality peer-reviewed journal.

  14. (roberts2022overviewofthe pages 1-2): Leslie J. Roberts, Michael McVeigh, Linda Seiderer, Ian H. Harding, Louise A. Corben, Martin Delatycki, and David J. Szmulewicz. Overview of the clinical approach to individuals with cerebellar ataxia and neuropathy. Neurology Genetics, Oct 2022. URL: https://doi.org/10.1212/nxg.0000000000200021, doi:10.1212/nxg.0000000000200021. This article has 17 citations.

  15. (garces2024quantitativeoculomotorassessment pages 9-10): Pilar Garces, Chrystalina A. Antoniades, Anna Sobanska, Norbert Kovacs, Sarah H. Ying, Anoopum S. Gupta, Susan Perlman, David J. Szmulewicz, Chiara Pane, Andrea H. Németh, Laura B. Jardim, Giulia Coarelli, Michaela Dankova, Andreas Traschütz, and Alexander A. Tarnutzer. Quantitative oculomotor assessment in hereditary ataxia: systematic review and consensus by the ataxia global initiative working group on digital-motor biomarkers. Cerebellum (London, England), 23:896-911, Apr 2024. URL: https://doi.org/10.1007/s12311-023-01559-9, doi:10.1007/s12311-023-01559-9. This article has 21 citations.

  16. (pauly2023nottomiss pages 2-4): Martje G. Pauly, Norbert Brüggemann, Stephanie Efthymiou, Anne Grözinger, Sokhna Haissatou Diaw, Viorica Chelban, Valentina Turchetti, Barbara Vona, Vera Tadic, Henry Houlden, Alexander Münchau, and Katja Lohmann. Not to miss: intronic variants, treatment, and review of the phenotypic spectrum in vps13d-related disorder. International Journal of Molecular Sciences, 24:1874, Jan 2023. URL: https://doi.org/10.3390/ijms24031874, doi:10.3390/ijms24031874. This article has 16 citations.

  17. (pauly2023nottomiss pages 4-7): Martje G. Pauly, Norbert Brüggemann, Stephanie Efthymiou, Anne Grözinger, Sokhna Haissatou Diaw, Viorica Chelban, Valentina Turchetti, Barbara Vona, Vera Tadic, Henry Houlden, Alexander Münchau, and Katja Lohmann. Not to miss: intronic variants, treatment, and review of the phenotypic spectrum in vps13d-related disorder. International Journal of Molecular Sciences, 24:1874, Jan 2023. URL: https://doi.org/10.3390/ijms24031874, doi:10.3390/ijms24031874. This article has 16 citations.

  18. (rosini2013ocularmotorprofileand pages 5-7): Francesca Rosini, Pamela Federighi, Elena Pretegiani, Pietro Piu, R. John Leigh, Alessandro Serra, Antonio Federico, and Alessandra Rufa. Ocular-motor profile and effects of memantine in a familial form of adult cerebellar ataxia with slow saccades and square wave saccadic intrusions. PLoS ONE, 8:e69522, Jul 2013. URL: https://doi.org/10.1371/journal.pone.0069522, doi:10.1371/journal.pone.0069522. This article has 32 citations and is from a peer-reviewed journal.

Artifacts