👪

Inheritance

1

Autosomal recessive HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:19497603 SUPPORT Human Clinical

"ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein."

This review explicitly defines chorea-acanthocytosis as an autosomal recessive VPS13A disorder.

⚙

Pathophysiology

6

VPS13A Loss of Function and Chorein Deficiency

Chorea-acanthocytosis is caused by biallelic loss of VPS13A, which encodes chorein, a large membrane-contact-site protein. Loss of chorein is the initiating molecular defect for downstream lipid-transport, autophagy, and neurodegenerative abnormalities.

Downstream

Membrane Contact Site Dysfunction with Impaired Lipid Transport Loss of VPS13A disrupts its normal bridge-like lipid-transfer role at membrane contact sites.

Erythrocyte Lipid and Actin Cytoskeleton Remodeling VPS13A loss perturbs red-cell lipid handling and chorein-sensitive actin membrane cytoskeleton organization, creating the hematologic branch of the disease pathograph.

Striatal Medium Spiny Neuron Synaptic Dysfunction VPS13A deficiency produces actin- and Src/Lyn kinase-associated synaptic dysregulation in patient-derived striatal medium spiny neurons.

Impaired Autophagy and Muscle Homeostasis Absence of VPS13A impairs autophagy and produces downstream muscle metabolic injury.

Show evidence (2 references)

PMID:19497603 SUPPORT Human Clinical

"ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein."

This directly identifies VPS13A/chorein deficiency as the primary molecular lesion in chorea-acanthocytosis.

PMID:35130982 SUPPORT Human Clinical

"It is thought to be caused by the VPS13A (vacuolar protein sorting-associated protein 13A) mutations."

This review reinforces VPS13A mutation as the core etiologic mechanism.

Membrane Contact Site Dysfunction with Impaired Lipid Transport

VPS13A normally acts as a bridge-like lipid transfer protein at membrane contact sites. Loss of VPS13A disrupts intracellular lipid distribution and perturbs mitochondrial calcium handling, consistent with organelle homeostasis failure in patient-derived cells.

fibroblast link

lipid transport link mitochondrial calcium ion homeostasis link

Downstream

Erythrocyte Lipid and Actin Cytoskeleton Remodeling Loss of a bridge-like lipid-transfer protein at membrane contact sites leads to altered patient erythrocyte lipid species, a plausible upstream driver of red-cell shape change.

Show evidence (2 references)

PMID:41552990 SUPPORT In Vitro

"VPS13A is a membrane-residing, bridge-like protein connecting two membranes to enable bulk lipid transfer."

This patient-fibroblast study defines the expected molecular function of VPS13A as lipid transfer at membrane contact sites.

PMID:41552990 SUPPORT In Vitro

"We observed a general disturbance of membrane contact sites in VPS13A disease, accompanied by a reduction in lipid droplet formation, diminished lipid transfer into mitochondria, and unusual mitochondrial calcium uptake behavior in VPS13A disease fibroblasts."

This provides direct experimental evidence that VPS13A deficiency disrupts membrane contact sites, lipid trafficking, and mitochondrial calcium handling.

Erythrocyte Lipid and Actin Cytoskeleton Remodeling

Patient erythrocytes show altered lipid species, abnormal blood-cell mechanics, and chorein-sensitive membrane cytoskeletal changes. This red-cell branch explains how VPS13A deficiency produces acanthocyte morphology independently of the neuronal phenotype.

erythrocyte link

lipid homeostasis link ↕ DYSREGULATED actin filament organization link ↕ DYSREGULATED red blood cell morphogenesis link ⚠ ABNORMAL

Downstream

Acanthocytosis Abnormal erythrocyte lipid composition and membrane cytoskeletal mechanics produce thorn-like red-cell deformation.

Show evidence (3 references)

PMID:39665525 SUPPORT In Vitro

"alterations in certain species were detected: phosphatidylethanolamine species with both longer chain length and higher unsaturation were increased in VPS13A disease samples."

Patient-derived RBC lipidomics demonstrates specific membrane lipid abnormalities in VPS13A disease.

PMID:35444561 SUPPORT Human Clinical

"The hematological phenotype of ChAc patients hinted at a reorganization of the cytoskeleton in blood cells which partly explains the altered mechanical properties observed here."

Ex vivo blood-cell deformability data support cytoskeletal reorganization and altered mechanics in ChAc blood cells.

PMID:24129186 SUPPORT In Vitro

"Protein levels of β-adducin isoform 1 and β-actin are markedly decreased in erythrocyte membranes from a ChAc patient."

Patient erythrocyte membrane proteomics links chorein deficiency to altered beta-adducin and beta-actin abundance.

Striatal Medium Spiny Neuron Synaptic Dysfunction

ChAc patient-derived striatal medium spiny neurons show pathologically elevated synaptic activity linked to actin cytoskeleton and Src/Lyn kinase dysregulation. This neuronal dysfunction provides an intermediate between VPS13A loss and basal-ganglia-driven movement and seizure manifestations.

striatal medium spiny neuron link

regulation of synaptic activity link ↑ INCREASED actin filament organization link ↕ DYSREGULATED

striatum link

Downstream

Basal Ganglia and Caudate Degeneration Medium spiny neurons are the primary striatal neuronal population affected in the disease, placing synaptic dysfunction upstream of basal ganglia degeneration in the pathograph.

Seizure Pathologically elevated neuronal synaptic activity provides a plausible neuronal route to seizures, although the circuit-level intermediates are not fully resolved.

Show evidence (2 references)

PMID:27881786 SUPPORT In Vitro

"Electrophysiological analysis revealed a pathologically elevated synaptic activity in ChAc MSNs."

Patient-derived striatal MSN electrophysiology directly supports synaptic dysregulation.

PMID:27881786 SUPPORT In Vitro

"These data indicate that F-actin stabilization and Src kinase inhibition represent potential therapeutic targets in ChAc that may restore neuronal function."

Rescue by actin stabilization and Src kinase inhibition supports the mechanistic role of cytoskeletal signaling in ChAc neuronal dysfunction.

Impaired Autophagy and Muscle Homeostasis

VPS13A deficiency impairs autophagy and produces metabolic remodeling with oxidative damage and premature muscle aging. This mechanism plausibly contributes to the hyperCKemia and subclinical myopathy often seen early in the disease course.

muscle cell link

autophagy link ↓ DECREASED

Downstream

Elevated circulating creatine kinase concentration VPS13A-related muscle and nerve involvement produces hyperCKemia as a measurable laboratory readout of the neuromuscular branch.

Muscle weakness Progressive neuromuscular involvement can manifest clinically as weakness and wasting.

Hyporeflexia VPS13A-associated neuromuscular involvement frequently includes reduced reflexes.

Polyneuropathy Peripheral nerve involvement in VPS13A disease can produce sensorimotor axonal neuropathy.

Show evidence (3 references)

PMID:40275365 SUPPORT Model Organism

"The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response."

This Vps13a-/- mouse evidence links loss of Vps13A to impaired autophagy and downstream metabolic injury in skeletal muscle.

PMID:40275365 SUPPORT Human Clinical

"The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis."

This human-biopsy-backed conclusion supports the relevance of impaired muscle homeostasis in patients with VPS13A disease.

PMID:41030128 SUPPORT Human Clinical

"Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6)."

This human cohort directly documents neuromuscular manifestations in genetically characterized VPS13A disease.

Basal Ganglia and Caudate Degeneration

Neurodegeneration preferentially affects the basal ganglia, especially the caudate and striatum. This structural involvement aligns with the hyperkinetic movement disorder and bulbar orolingual manifestations typical of chorea-acanthocytosis.

neuron link

striatum link caudate nucleus link

Downstream

Chorea Striatal and caudate degeneration disrupts basal ganglia motor circuits, producing choreiform hyperkinesia.

Orofacial dyskinesia Basal ganglia circuit dysfunction contributes to the prominent orofacial dyskinesia and dystonia characteristic of ChAc.

Dystonia Basal ganglia motor-circuit dysfunction manifests as dystonia, including feeding and orolingual dystonia.

Vocal tics Basal ganglia circuit dysfunction can present with tic-like vocal phenomena in genetically confirmed ChAc.

Dysphagia Orolingual and feeding dystonia from basal-ganglia motor circuit dysfunction impairs swallowing.

Cognitive impairment Basal ganglia and striatal degeneration is part of the broader frontostriatal neurodegenerative phenotype that includes cognitive decline.

Psychiatric disorders Frontostriatal neurodegeneration contributes to the behavioral and psychiatric disease manifestations reported in ChAc.

Show evidence (2 references)

PMID:40554046 SUPPORT Human Clinical

"Chorea-acanthocytosis (ChAc) is a rare genetic disorder characterized by acanthocytosis and basal ganglia degeneration."

This genetically confirmed case series identifies basal ganglia degeneration as a defining pathological axis of the disorder.

PMID:40554046 SUPPORT Human Clinical

"Brain MRI showed caudate atrophy, and acanthocytes were detected in three patients."

Human neuroimaging evidence demonstrates caudate involvement in chorea-acanthocytosis.

⬡

Pathograph

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

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Phenotypes

13

Digestive 1

Dysphagia Dysphagia (HP:0002015)

Show evidence (1 reference)

PMID:40554046 SUPPORT Human Clinical

"All presented with feeding dystonia, vocal tics, and dysphagia."

This VPS13A-confirmed family series shows dysphagia as a recurrent and clinically prominent feature.

Metabolism 1

Elevated circulating creatine kinase concentration Elevated circulating creatine kinase concentration (HP:0003236)

Show evidence (2 references)

PMID:19497603 SUPPORT Human Clinical

"Routine biological screening was normal except for elevated CPK and LDH."

This case report identifies elevated creatine kinase as a reproducible laboratory abnormality in chorea-acanthocytosis.

PMID:41030128 SUPPORT Human Clinical

"Phosphocreatine kinase was elevated in all cases"

This 2026 neuromuscular cohort confirms hyperCKemia as a consistent laboratory finding across genetically characterized VPS13A disease cases.

Musculoskeletal 1

Muscle weakness Muscle weakness (HP:0001324)

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:41030128 SUPPORT Human Clinical

"Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6)."

This cohort supports progressive neuromuscular involvement, including muscle wasting and weakness, in VPS13A disease.

Nervous System 5

Chorea Chorea (HP:0002072)

Show evidence (1 reference)

PMID:37985634 SUPPORT Human Clinical

"Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."

This abstract explicitly lists choreiform movement disorder as a defining manifestation.

Seizure Seizure (HP:0001250)

Show evidence (1 reference)

PMID:37985634 SUPPORT Human Clinical

"Here, we report a patient, who has the characteristic clinical manifestations of ChAc with limb choreiform movements, involuntary lip and tongue bites, seizures, and emotional instability."

This abstract documents seizures as part of the characteristic manifestation spectrum.

Cognitive impairment Cognitive impairment (HP:0100543)

Show evidence (1 reference)

PMID:37985634 SUPPORT Human Clinical

"Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."

This abstract directly identifies cognitive decline as a characteristic disease manifestation.

Psychiatric disorders Atypical behavior (HP:0000708)

Show evidence (1 reference)

PMID:37985634 SUPPORT Human Clinical

"Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."

This abstract directly lists psychiatric disorders among characteristic manifestations of genetically confirmed ChAc.

Dystonia Dystonia (HP:0001332)

Show evidence (1 reference)

PMID:40554046 SUPPORT Human Clinical

"All presented with feeding dystonia, vocal tics, and dysphagia."

This VPS13A-confirmed family series supports dystonia as a recurrent ChAc manifestation.

Other 5

Orofacial dyskinesia Orofacial dyskinesia (HP:0002310)

Show evidence (1 reference)

PMID:17122731 SUPPORT Human Clinical

"Clinical clues suggestive of chorea-acanthocytosis include prominent orofacial dyskinesias, often causing dysarthria and dysphagia."

This review identifies prominent orofacial dyskinesias as one of the most characteristic clinical clues.

Vocal tics Tics (HP:0100033)

Show evidence (1 reference)

PMID:40554046 SUPPORT Human Clinical

"All presented with feeding dystonia, vocal tics, and dysphagia."

This VPS13A-confirmed family series directly reports vocal tics in ChAc.

Acanthocytosis Acanthocytosis (HP:0001927)

Acanthocytes can be variably detectable and are not mandatory for diagnosis.

Show evidence (2 references)

PMID:35130982 SUPPORT Human Clinical

"Chorea-acanthocytosis (ChAc), as the most common subtype of neuroacanthocytosis syndrome, is characterized by the presence of acanthocytes and neurological symptoms."

This review supports acanthocytosis as a characteristic hematologic feature.

PMID:19497603 SUPPORT Human Clinical

"Absence or late appearance of acanthocytes in ChAc has been described in a few case reports."

This provides the key clinical caveat that acanthocytosis is characteristic but not universally detectable.

Hyporeflexia Hyporeflexia (HP:0001265)

Show evidence (1 reference)

PMID:41030128 SUPPORT Human Clinical

"Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6)."

This 2026 cohort found hyporeflexia in most assessed VPS13A disease cases.

Polyneuropathy Polyneuropathy (HP:0001271)

Show evidence (1 reference)

PMID:41030128 SUPPORT Human Clinical

"Nerve conduction studies revealed sensorimotor axonal neuropathy."

This cohort provides nerve-conduction evidence for a peripheral neuropathy phenotype in VPS13A disease.

🧬

Genetic Associations

1

VPS13A (CAUSAL)

Autosomal recessive

Show evidence (2 references)

PMID:19497603 SUPPORT Human Clinical

"ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein."

This article directly links VPS13A mutations and chorein deficiency to chorea-acanthocytosis.

PMID:37985634 SUPPORT Human Clinical

"We later identified two novel pathogenic mutations in the patient's vacuolar protein sorting homolog 13 A (VPS13A) on chromosome 9q21 by targeted gene sequencing, and she was definitively diagnosed with "ChAc.""

This genetically confirmed case supports VPS13A as the causal gene and genetic testing as the diagnostic standard.

💊

Treatments

3

Supportive care

Action: supportive care MAXO:0000950

Multidisciplinary symptomatic management, nursing support, and rehabilitation remain central because no disease-modifying therapy is established.

Show evidence (1 reference)

PMID:35130982 SUPPORT Human Clinical

"Supportive treatments and nursing are helpful to improve the quality of the patient's life."

This review explicitly supports supportive care and nursing as beneficial for quality of life.

Off-label dasatinib Src/Lyn kinase inhibition

Action: Pharmacotherapy NCIT:C15986

Agent: dasatinib ↗

Off-label dasatinib has been evaluated in a small human ChAc series as a tyrosine kinase inhibitor strategy aimed at Lyn/Src-linked cytoskeletal and autophagy abnormalities in blood cells; clinical CNS benefit is unproven.

Mechanism Target:

MODULATES Erythrocyte Lipid and Actin Cytoskeleton Remodeling — Dasatinib treatment modulates ChAc blood-cell deformability and cytoskeletal/autophagy readouts linked to the erythrocyte branch.

Show evidence (1 reference)

PMID:35444561 SUPPORT Human Clinical

"During treatment with dasatinib or lithium, we observed alterations in RBC deformability and a stiffness increase for leukocytes."

Human off-label treatment data support dasatinib as a modulator of the blood-cell mechanistic branch.

Show evidence (1 reference)

PMID:35444561 SUPPORT Human Clinical

"Here, we investigated blood cell deformability of five ChAc patients compared to healthy controls during up to 1-year individual off-label treatment with the tyrosine kinase inhibitor dasatinib or several weeks with lithium."

This directly supports an off-label human dasatinib treatment entry while clarifying that the reported effect is biomarker-level.

Globus pallidus internus deep brain stimulation

Action: deep brain stimulation MAXO:0000943

Located in: globus pallidus internus Ontology label: medial globus pallidus UBERON:0002477

GPi deep brain stimulation can substantially improve refractory motor symptoms, particularly severe oromandibular dystonia.

Show evidence (1 reference)

PMID:35880382 SUPPORT Human Clinical

"GPi-DBS is an effective and safe treatment in most patients with ChAc, but no reliable predictor of efficacy has been found."

A systematic review and meta-analysis supports GPi-DBS as the strongest disease-specific interventional option for refractory chorea-acanthocytosis.

{ }

Source YAML

click to show

name: Chorea-acanthocytosis
creation_date: "2026-04-08T14:54:53Z"
updated_date: "2026-04-26T06:42:41Z"
category: Mendelian
description: >
  Chorea-acanthocytosis (ChAc) is an ultra-rare autosomal recessive
  neurodegenerative movement disorder caused by biallelic VPS13A loss-of-function
  variants. It belongs to the core neuroacanthocytosis syndromes and typically
  combines chorea or dystonia, prominent orofacial dyskinesia with tongue or lip
  biting, dysphagia, seizures, cognitive decline, psychiatric symptoms,
  neuromuscular involvement with hyporeflexia, sensorimotor axonal neuropathy,
  muscle weakness, elevated creatine kinase, and variably detectable
  acanthocytes. Diagnosis is established by VPS13A genetic testing or absent
  chorein on Western blot.
notes: >
  External identifiers reported in the Falcon research include OMIM:200150 and
  Orphanet:ORPHA2388; this disease file currently maps the disorder through
  MONDO and the schema does not expose dedicated OMIM or Orphanet mapping slots.
disease_term:
  preferred_term: chorea-acanthocytosis
  term:
    id: MONDO:0008695
    label: VPS13A-related neurodegenerative disease
synonyms:
- CHAC
- Levine-Critchley syndrome
- choreoacanthocytosis
parents:
- Neuroacanthocytosis
- Neurodegenerative Disorder
- Movement Disorder
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:19497603
    reference_title: "[Chorea-acanthocytosis without acanthocytes]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein."
    explanation: This review explicitly defines chorea-acanthocytosis as an autosomal recessive VPS13A disorder.
genetic:
- name: VPS13A
  association: CAUSAL
  gene_term:
    preferred_term: VPS13A
    term:
      id: hgnc:1908
      label: VPS13A
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:19497603
      reference_title: "[Chorea-acanthocytosis without acanthocytes]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein."
      explanation: This article supports autosomal recessive inheritance for VPS13A-associated chorea-acanthocytosis.
  features: >
    Biallelic VPS13A variants cause chorein deficiency; diagnosis can be
    confirmed by genetic testing or absent chorein on Western blot.
  evidence:
  - reference: PMID:19497603
    reference_title: "[Chorea-acanthocytosis without acanthocytes]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein."
    explanation: This article directly links VPS13A mutations and chorein deficiency to chorea-acanthocytosis.
  - reference: PMID:37985634
    reference_title: "A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We later identified two novel pathogenic mutations in the patient''s vacuolar protein sorting homolog 13 A (VPS13A) on chromosome 9q21 by targeted gene sequencing, and she was definitively diagnosed with "ChAc."'
    explanation: This genetically confirmed case supports VPS13A as the causal gene and genetic testing as the diagnostic standard.
pathophysiology:
- name: VPS13A Loss of Function and Chorein Deficiency
  description: >
    Chorea-acanthocytosis is caused by biallelic loss of VPS13A, which encodes
    chorein, a large membrane-contact-site protein. Loss of chorein is the
    initiating molecular defect for downstream lipid-transport, autophagy, and
    neurodegenerative abnormalities.
  gene:
    preferred_term: VPS13A
    term:
      id: hgnc:1908
      label: VPS13A
  evidence:
  - reference: PMID:19497603
    reference_title: "[Chorea-acanthocytosis without acanthocytes]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein."
    explanation: This directly identifies VPS13A/chorein deficiency as the primary molecular lesion in chorea-acanthocytosis.
  - reference: PMID:35130982
    reference_title: "Two case reports of chorea-acanthocytosis and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is thought to be caused by the VPS13A (vacuolar protein sorting-associated protein 13A) mutations."
    explanation: This review reinforces VPS13A mutation as the core etiologic mechanism.
  downstream:
  - target: Membrane Contact Site Dysfunction with Impaired Lipid Transport
    description: Loss of VPS13A disrupts its normal bridge-like lipid-transfer role at membrane contact sites.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41552990
      reference_title: "VPS13A Deficiency Leads to Impaired Lipid Distribution and Alteration of Mitochondrial Calcium Homeostasis in Fibroblasts of VPS13A Disease Patients."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of VPS13A causes alterations beyond an impairment of lipid shuttling, which includes a dysregulation of membrane contact sites as well as impaired mitochondrial calcium handling."
      explanation: This patient-fibroblast study directly supports the causal edge from VPS13A loss to membrane-contact-site dysfunction.
  - target: Erythrocyte Lipid and Actin Cytoskeleton Remodeling
    description: >
      VPS13A loss perturbs red-cell lipid handling and chorein-sensitive actin
      membrane cytoskeleton organization, creating the hematologic branch of
      the disease pathograph.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered erythrocyte lipid species and chorein-sensitive beta-adducin/actin organization
    evidence:
    - reference: PMID:39665525
      reference_title: "Phosphatidylethanolamines are the Main Lipid Class Altered in Red Blood Cells from Patients with VPS13A Disease/Chorea-Acanthocytosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "VPS13A disease is an ultra-rare disorder caused by loss of function mutations in VPS13A characterized by striatal degeneration and by red blood cell (RBC) acanthocytosis."
      explanation: This patient RBC lipidomics study anchors the erythrocyte branch to VPS13A loss-of-function disease.
    - reference: PMID:24129186
      reference_title: "Chorein, the protein responsible for chorea-acanthocytosis, interacts with β-adducin and β-actin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Adducin and actin are membrane cytoskeletal proteins, involved in synaptic function."
      explanation: This supports a chorein-sensitive membrane cytoskeletal mechanism in tissues relevant to the disorder.
  - target: Striatal Medium Spiny Neuron Synaptic Dysfunction
    description: >
      VPS13A deficiency produces actin- and Src/Lyn kinase-associated synaptic
      dysregulation in patient-derived striatal medium spiny neurons.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - elevated Lyn/Src kinase activity and increased G/F-actin ratio
    evidence:
    - reference: PMID:27881786
      reference_title: "Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This was underlined by increased G/F-actin ratios and elevated Lyn kinase activity in patient-derived MSNs."
      explanation: Patient-derived MSN data support an actin/Src-family kinase mechanism downstream of VPS13A deficiency.
  - target: Impaired Autophagy and Muscle Homeostasis
    description: Absence of VPS13A impairs autophagy and produces downstream muscle metabolic injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40275365
      reference_title: "Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response."
      explanation: This Vps13a-/- mouse study directly supports the causal edge from VPS13A loss to impaired autophagy and downstream muscle injury.
- name: Membrane Contact Site Dysfunction with Impaired Lipid Transport
  description: >
    VPS13A normally acts as a bridge-like lipid transfer protein at membrane
    contact sites. Loss of VPS13A disrupts intracellular lipid distribution
    and perturbs mitochondrial calcium handling, consistent with organelle
    homeostasis failure in patient-derived cells.
  gene:
    preferred_term: VPS13A
    term:
      id: hgnc:1908
      label: VPS13A
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: lipid transport
    term:
      id: GO:0006869
      label: lipid transport
  - preferred_term: mitochondrial calcium ion homeostasis
    term:
      id: GO:0051560
      label: mitochondrial calcium ion homeostasis
  evidence:
  - reference: PMID:41552990
    reference_title: "VPS13A Deficiency Leads to Impaired Lipid Distribution and Alteration of Mitochondrial Calcium Homeostasis in Fibroblasts of VPS13A Disease Patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "VPS13A is a membrane-residing, bridge-like protein connecting two membranes to enable bulk lipid transfer."
    explanation: This patient-fibroblast study defines the expected molecular function of VPS13A as lipid transfer at membrane contact sites.
  - reference: PMID:41552990
    reference_title: "VPS13A Deficiency Leads to Impaired Lipid Distribution and Alteration of Mitochondrial Calcium Homeostasis in Fibroblasts of VPS13A Disease Patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed a general disturbance of membrane contact sites in VPS13A disease, accompanied by a reduction in lipid droplet formation, diminished lipid transfer into mitochondria, and unusual mitochondrial calcium uptake behavior in VPS13A disease fibroblasts."
    explanation: This provides direct experimental evidence that VPS13A deficiency disrupts membrane contact sites, lipid trafficking, and mitochondrial calcium handling.
  downstream:
  - target: Erythrocyte Lipid and Actin Cytoskeleton Remodeling
    description: >
      Loss of a bridge-like lipid-transfer protein at membrane contact sites
      leads to altered patient erythrocyte lipid species, a plausible upstream
      driver of red-cell shape change.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered phosphatidylethanolamine, ceramide, phosphatidylcholine, and sphingomyelin species
    evidence:
    - reference: PMID:39665525
      reference_title: "Phosphatidylethanolamines are the Main Lipid Class Altered in Red Blood Cells from Patients with VPS13A Disease/Chorea-Acanthocytosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "VPS13A is a bridge-like protein mediating lipid transfer at membrane contact sites."
      explanation: The lipidomics study links VPS13A membrane-contact-site lipid transfer to patient RBC lipid abnormalities.
- name: Erythrocyte Lipid and Actin Cytoskeleton Remodeling
  description: >
    Patient erythrocytes show altered lipid species, abnormal blood-cell
    mechanics, and chorein-sensitive membrane cytoskeletal changes. This
    red-cell branch explains how VPS13A deficiency produces acanthocyte
    morphology independently of the neuronal phenotype.
  gene:
    preferred_term: VPS13A
    term:
      id: hgnc:1908
      label: VPS13A
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: lipid homeostasis
    term:
      id: GO:0055088
      label: lipid homeostasis
    modifier: DYSREGULATED
  - preferred_term: actin filament organization
    term:
      id: GO:0007015
      label: actin filament organization
    modifier: DYSREGULATED
  - preferred_term: red blood cell morphogenesis
    term:
      id: GO:0000902
      label: cell morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39665525
    reference_title: "Phosphatidylethanolamines are the Main Lipid Class Altered in Red Blood Cells from Patients with VPS13A Disease/Chorea-Acanthocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "alterations in certain species were detected: phosphatidylethanolamine species with both longer chain length and higher unsaturation were increased in VPS13A disease samples."
    explanation: Patient-derived RBC lipidomics demonstrates specific membrane lipid abnormalities in VPS13A disease.
  - reference: PMID:35444561
    reference_title: "Changes in Blood Cell Deformability in Chorea-Acanthocytosis and Effects of Treatment With Dasatinib or Lithium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hematological phenotype of ChAc patients hinted at a reorganization of the cytoskeleton in blood cells which partly explains the altered mechanical properties observed here."
    explanation: Ex vivo blood-cell deformability data support cytoskeletal reorganization and altered mechanics in ChAc blood cells.
  - reference: PMID:24129186
    reference_title: "Chorein, the protein responsible for chorea-acanthocytosis, interacts with β-adducin and β-actin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Protein levels of β-adducin isoform 1 and β-actin are markedly decreased in erythrocyte membranes from a ChAc patient."
    explanation: Patient erythrocyte membrane proteomics links chorein deficiency to altered beta-adducin and beta-actin abundance.
  downstream:
  - target: Acanthocytosis
    description: >
      Abnormal erythrocyte lipid composition and membrane cytoskeletal mechanics
      produce thorn-like red-cell deformation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39665525
      reference_title: "Phosphatidylethanolamines are the Main Lipid Class Altered in Red Blood Cells from Patients with VPS13A Disease/Chorea-Acanthocytosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The presented alterations of particular lipid species in RBCs in VPS13A disease may contribute to (1) the understanding of acanthocyte formation, and (2) future biomarker identification."
      explanation: This directly connects RBC lipid abnormalities with acanthocyte formation.
    - reference: PMID:35444561
      reference_title: "Changes in Blood Cell Deformability in Chorea-Acanthocytosis and Effects of Treatment With Dasatinib or Lithium."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Misshaped red blood cells (RBCs), characterized by thorn-like protrusions known as acanthocytes, are a key diagnostic feature in Chorea-Acanthocytosis (ChAc), a rare neurodegenerative disorder."
      explanation: This supports the acanthocyte morphology and its relationship to altered RBC mechanical behavior.
- name: Striatal Medium Spiny Neuron Synaptic Dysfunction
  description: >
    ChAc patient-derived striatal medium spiny neurons show pathologically
    elevated synaptic activity linked to actin cytoskeleton and Src/Lyn kinase
    dysregulation. This neuronal dysfunction provides an intermediate between
    VPS13A loss and basal-ganglia-driven movement and seizure manifestations.
  gene:
    preferred_term: VPS13A
    term:
      id: hgnc:1908
      label: VPS13A
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  cell_types:
  - preferred_term: striatal medium spiny neuron
    term:
      id: CL:1001474
      label: medium spiny neuron
  biological_processes:
  - preferred_term: regulation of synaptic activity
    term:
      id: GO:0060025
      label: regulation of synaptic activity
    modifier: INCREASED
  - preferred_term: actin filament organization
    term:
      id: GO:0007015
      label: actin filament organization
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:27881786
    reference_title: "Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Electrophysiological analysis revealed a pathologically elevated synaptic activity in ChAc MSNs."
    explanation: Patient-derived striatal MSN electrophysiology directly supports synaptic dysregulation.
  - reference: PMID:27881786
    reference_title: "Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data indicate that F-actin stabilization and Src kinase inhibition represent potential therapeutic targets in ChAc that may restore neuronal function."
    explanation: Rescue by actin stabilization and Src kinase inhibition supports the mechanistic role of cytoskeletal signaling in ChAc neuronal dysfunction.
  downstream:
  - target: Basal Ganglia and Caudate Degeneration
    description: >
      Medium spiny neurons are the primary striatal neuronal population affected
      in the disease, placing synaptic dysfunction upstream of basal ganglia
      degeneration in the pathograph.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - actin-dependent synaptic dysfunction and striatal neuronal vulnerability
    evidence:
    - reference: PMID:27881786
      reference_title: "Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "human striatal medium spiny neurons (MSNs), the main target of neurodegeneration in ChAc."
      explanation: This identifies striatal MSNs as the key neuronal target of ChAc neurodegeneration.
  - target: Seizure
    description: >
      Pathologically elevated neuronal synaptic activity provides a plausible
      neuronal route to seizures, although the circuit-level intermediates are
      not fully resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27881786
      reference_title: "Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "Electrophysiological analysis revealed a pathologically elevated synaptic activity in ChAc MSNs."
      explanation: This provides mechanistic support for neuronal hyperactivity, while the exact seizure circuit remains unresolved.
- name: Impaired Autophagy and Muscle Homeostasis
  description: >
    VPS13A deficiency impairs autophagy and produces metabolic remodeling with
    oxidative damage and premature muscle aging. This mechanism plausibly
    contributes to the hyperCKemia and subclinical myopathy often seen early in
    the disease course.
  gene:
    preferred_term: VPS13A
    term:
      id: hgnc:1908
      label: VPS13A
  cell_types:
  - preferred_term: muscle cell
    term:
      id: CL:0000187
      label: muscle cell
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  evidence:
  - reference: PMID:40275365
    reference_title: "Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response."
    explanation: This Vps13a-/- mouse evidence links loss of Vps13A to impaired autophagy and downstream metabolic injury in skeletal muscle.
  - reference: PMID:40275365
    reference_title: "Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis."
    explanation: This human-biopsy-backed conclusion supports the relevance of impaired muscle homeostasis in patients with VPS13A disease.
  - reference: PMID:41030128
    reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6)."
    explanation: This human cohort directly documents neuromuscular manifestations in genetically characterized VPS13A disease.
  downstream:
  - target: Elevated circulating creatine kinase concentration
    description: >
      VPS13A-related muscle and nerve involvement produces hyperCKemia as a
      measurable laboratory readout of the neuromuscular branch.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41030128
      reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Phosphocreatine kinase was elevated in all cases"
      explanation: This cohort directly supports elevated creatine kinase as a consequence of VPS13A neuromuscular involvement.
  - target: Muscle weakness
    description: >
      Progressive neuromuscular involvement can manifest clinically as weakness
      and wasting.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41030128
      reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Initial symptoms included seizures (5/6), hyperkinesia (2/6), and muscle weakness (1/6)."
      explanation: Human cohort data support muscle weakness as part of the VPS13A disease neuromuscular spectrum.
  - target: Hyporeflexia
    description: >
      VPS13A-associated neuromuscular involvement frequently includes reduced
      reflexes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41030128
      reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6)."
      explanation: This cohort directly supports hyporeflexia as a common neuromuscular manifestation of VPS13A disease.
  - target: Polyneuropathy
    description: >
      Peripheral nerve involvement in VPS13A disease can produce sensorimotor
      axonal neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41030128
      reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nerve conduction studies revealed sensorimotor axonal neuropathy."
      explanation: This provides direct electrophysiologic evidence for peripheral neuropathy in the VPS13A neuromuscular spectrum.
- name: Basal Ganglia and Caudate Degeneration
  description: >
    Neurodegeneration preferentially affects the basal ganglia, especially the
    caudate and striatum. This structural involvement aligns with the
    hyperkinetic movement disorder and bulbar orolingual manifestations typical
    of chorea-acanthocytosis.
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  - preferred_term: caudate nucleus
    term:
      id: UBERON:0001873
      label: caudate nucleus
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:40554046
    reference_title: "Clinico-genetic profile of case series of six Tamilian chorea-acanthocytosis families with VPS13A mutations from South India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chorea-acanthocytosis (ChAc) is a rare genetic disorder characterized by acanthocytosis and basal ganglia degeneration."
    explanation: This genetically confirmed case series identifies basal ganglia degeneration as a defining pathological axis of the disorder.
  - reference: PMID:40554046
    reference_title: "Clinico-genetic profile of case series of six Tamilian chorea-acanthocytosis families with VPS13A mutations from South India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI showed caudate atrophy, and acanthocytes were detected in three patients."
    explanation: Human neuroimaging evidence demonstrates caudate involvement in chorea-acanthocytosis.
  downstream:
  - target: Chorea
    description: >
      Striatal and caudate degeneration disrupts basal ganglia motor circuits,
      producing choreiform hyperkinesia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37985634
      reference_title: "A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."
      explanation: This clinical report places choreiform movement disorder within the nervous-system phenotype of genetically confirmed ChAc.
  - target: Orofacial dyskinesia
    description: >
      Basal ganglia circuit dysfunction contributes to the prominent orofacial
      dyskinesia and dystonia characteristic of ChAc.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - disrupted basal ganglia motor output to orobulbar motor control circuits
    evidence:
    - reference: PMID:17122731
      reference_title: "Chorea-acanthocytosis: a mimicker of Huntington disease case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical clues suggestive of chorea-acanthocytosis include prominent orofacial dyskinesias, often causing dysarthria and dysphagia."
      explanation: This supports the characteristic orofacial motor phenotype downstream of the basal-ganglia movement disorder.
  - target: Dystonia
    description: >
      Basal ganglia motor-circuit dysfunction manifests as dystonia, including
      feeding and orolingual dystonia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - disrupted basal ganglia motor output to cranial and limb motor circuits
    evidence:
    - reference: PMID:40554046
      reference_title: "Clinico-genetic profile of case series of six Tamilian chorea-acanthocytosis families with VPS13A mutations from South India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All presented with feeding dystonia, vocal tics, and dysphagia."
      explanation: This VPS13A-confirmed family series documents dystonia as a recurrent motor manifestation.
  - target: Vocal tics
    description: >
      Basal ganglia circuit dysfunction can present with tic-like vocal
      phenomena in genetically confirmed ChAc.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - disrupted basal ganglia motor output and tic-generation circuits
    evidence:
    - reference: PMID:40554046
      reference_title: "Clinico-genetic profile of case series of six Tamilian chorea-acanthocytosis families with VPS13A mutations from South India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All presented with feeding dystonia, vocal tics, and dysphagia."
      explanation: This VPS13A-confirmed family series supports vocal tics as part of the ChAc motor phenotype.
  - target: Dysphagia
    description: >
      Orolingual and feeding dystonia from basal-ganglia motor circuit
      dysfunction impairs swallowing.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - feeding dystonia and orofacial dyskinesia
    evidence:
    - reference: PMID:40554046
      reference_title: "Clinico-genetic profile of case series of six Tamilian chorea-acanthocytosis families with VPS13A mutations from South India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All presented with feeding dystonia, vocal tics, and dysphagia."
      explanation: This genetically confirmed family series connects feeding dystonia with dysphagia in ChAc.
  - target: Cognitive impairment
    description: >
      Basal ganglia and striatal degeneration is part of the broader
      frontostriatal neurodegenerative phenotype that includes cognitive
      decline.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - frontostriatal network dysfunction
    evidence:
    - reference: PMID:37985634
      reference_title: "A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."
      explanation: This supports cognitive decline as part of the ChAc nervous-system phenotype.
  - target: Psychiatric disorders
    description: >
      Frontostriatal neurodegeneration contributes to the behavioral and
      psychiatric disease manifestations reported in ChAc.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - frontostriatal network dysfunction
    evidence:
    - reference: PMID:37985634
      reference_title: "A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."
      explanation: This genetically confirmed clinical report explicitly includes psychiatric disorders in the ChAc phenotype.
phenotypes:
- name: Chorea
  category: Neurological
  description: >
    Choreiform hyperkinesia is one of the central motor manifestations and
    commonly drives initial comparison with Huntington disease.
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: PMID:37985634
    reference_title: "A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."
    explanation: This abstract explicitly lists choreiform movement disorder as a defining manifestation.
- name: Orofacial dyskinesia
  category: Neurological
  description: >
    Prominent involuntary mouth, tongue, and facial movements are highly
    suggestive of chorea-acanthocytosis and often lead to tongue or lip biting.
  phenotype_term:
    preferred_term: Orofacial dyskinesia
    term:
      id: HP:0002310
      label: Orofacial dyskinesia
  evidence:
  - reference: PMID:17122731
    reference_title: "Chorea-acanthocytosis: a mimicker of Huntington disease case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical clues suggestive of chorea-acanthocytosis include prominent orofacial dyskinesias, often causing dysarthria and dysphagia."
    explanation: This review identifies prominent orofacial dyskinesias as one of the most characteristic clinical clues.
- name: Dysphagia
  category: Neurological
  description: >
    Swallowing impairment is common, often occurring together with orolingual
    dystonia or dyskinesia and feeding dystonia.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:40554046
    reference_title: "Clinico-genetic profile of case series of six Tamilian chorea-acanthocytosis families with VPS13A mutations from South India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All presented with feeding dystonia, vocal tics, and dysphagia."
    explanation: This VPS13A-confirmed family series shows dysphagia as a recurrent and clinically prominent feature.
- name: Seizure
  category: Neurological
  description: >
    Epileptic seizures occur in a meaningful subset of patients and may be an
    early presenting feature before the full movement disorder is recognized.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37985634
    reference_title: "A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a patient, who has the characteristic clinical manifestations of ChAc with limb choreiform movements, involuntary lip and tongue bites, seizures, and emotional instability."
    explanation: This abstract documents seizures as part of the characteristic manifestation spectrum.
- name: Cognitive impairment
  category: Neurological
  description: >
    Progressive cognitive decline is part of the neuropsychiatric phenotype and
    can accompany the movement disorder.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:37985634
    reference_title: "A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."
    explanation: This abstract directly identifies cognitive decline as a characteristic disease manifestation.
- name: Psychiatric disorders
  category: Psychiatric
  description: >
    Behavioral and psychiatric manifestations are common in ChAc and can
    accompany cognitive decline and the movement disorder.
  phenotype_term:
    preferred_term: Psychiatric disorders
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:37985634
    reference_title: "A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders."
    explanation: This abstract directly lists psychiatric disorders among characteristic manifestations of genetically confirmed ChAc.
- name: Dystonia
  category: Neurological
  description: >
    Dystonia, particularly feeding or orolingual dystonia, is a characteristic
    motor manifestation that contributes to swallowing and feeding problems.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:40554046
    reference_title: "Clinico-genetic profile of case series of six Tamilian chorea-acanthocytosis families with VPS13A mutations from South India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All presented with feeding dystonia, vocal tics, and dysphagia."
    explanation: This VPS13A-confirmed family series supports dystonia as a recurrent ChAc manifestation.
- name: Vocal tics
  category: Neurological
  description: >
    Vocal tic-like phenomena can occur as part of the basal-ganglia motor
    phenotype in ChAc.
  phenotype_term:
    preferred_term: Vocal tics
    term:
      id: HP:0100033
      label: Tics
  evidence:
  - reference: PMID:40554046
    reference_title: "Clinico-genetic profile of case series of six Tamilian chorea-acanthocytosis families with VPS13A mutations from South India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All presented with feeding dystonia, vocal tics, and dysphagia."
    explanation: This VPS13A-confirmed family series directly reports vocal tics in ChAc.
- name: Acanthocytosis
  category: Laboratory
  description: >
    Spiculated erythrocytes are characteristic but may be absent early or on
    individual smears; their absence does not exclude the diagnosis.
  notes: Acanthocytes can be variably detectable and are not mandatory for diagnosis.
  phenotype_term:
    preferred_term: Acanthocytosis
    term:
      id: HP:0001927
      label: Acanthocytosis
  evidence:
  - reference: PMID:35130982
    reference_title: "Two case reports of chorea-acanthocytosis and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chorea-acanthocytosis (ChAc), as the most common subtype of neuroacanthocytosis syndrome, is characterized by the presence of acanthocytes and neurological symptoms."
    explanation: This review supports acanthocytosis as a characteristic hematologic feature.
  - reference: PMID:19497603
    reference_title: "[Chorea-acanthocytosis without acanthocytes]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Absence or late appearance of acanthocytes in ChAc has been described in a few case reports."
    explanation: This provides the key clinical caveat that acanthocytosis is characteristic but not universally detectable.
- name: Elevated circulating creatine kinase concentration
  category: Laboratory
  description: >
    HyperCKemia is a common early laboratory clue that reflects associated
    muscle involvement, even when overt weakness is limited.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:19497603
    reference_title: "[Chorea-acanthocytosis without acanthocytes]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Routine biological screening was normal except for elevated CPK and LDH."
    explanation: This case report identifies elevated creatine kinase as a reproducible laboratory abnormality in chorea-acanthocytosis.
  - reference: PMID:41030128
    reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phosphocreatine kinase was elevated in all cases"
    explanation: This 2026 neuromuscular cohort confirms hyperCKemia as a consistent laboratory finding across genetically characterized VPS13A disease cases.
- name: Muscle weakness
  category: Musculoskeletal
  description: >
    Weakness can occur within the underrecognized neuromuscular spectrum of
    VPS13A disease and may precede prominent hyperkinetic movement symptoms.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:41030128
    reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6)."
    explanation: This cohort supports progressive neuromuscular involvement, including muscle wasting and weakness, in VPS13A disease.
- name: Hyporeflexia
  category: Neurological
  description: >
    Reduced reflexes are a frequent neuromuscular sign in genetically confirmed
    VPS13A disease.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:41030128
    reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6)."
    explanation: This 2026 cohort found hyporeflexia in most assessed VPS13A disease cases.
- name: Polyneuropathy
  category: Neurological
  description: >
    Sensorimotor axonal neuropathy expands the ChAc phenotype beyond central
    basal-ganglia neurodegeneration.
  phenotype_term:
    preferred_term: Polyneuropathy
    term:
      id: HP:0001271
      label: Polyneuropathy
  evidence:
  - reference: PMID:41030128
    reference_title: "The Diverse Neuromuscular Spectrum of VPS13A Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies revealed sensorimotor axonal neuropathy."
    explanation: This cohort provides nerve-conduction evidence for a peripheral neuropathy phenotype in VPS13A disease.
treatments:
- name: Supportive care
  description: >
    Multidisciplinary symptomatic management, nursing support, and rehabilitation
    remain central because no disease-modifying therapy is established.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:35130982
    reference_title: "Two case reports of chorea-acanthocytosis and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supportive treatments and nursing are helpful to improve the quality of the patient's life."
    explanation: This review explicitly supports supportive care and nursing as beneficial for quality of life.
- name: Off-label dasatinib Src/Lyn kinase inhibition
  description: >
    Off-label dasatinib has been evaluated in a small human ChAc series as a
    tyrosine kinase inhibitor strategy aimed at Lyn/Src-linked cytoskeletal and
    autophagy abnormalities in blood cells; clinical CNS benefit is unproven.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dasatinib
      term:
        id: CHEBI:49375
        label: dasatinib (anhydrous)
  target_mechanisms:
  - target: Erythrocyte Lipid and Actin Cytoskeleton Remodeling
    treatment_effect: MODULATES
    description: >
      Dasatinib treatment modulates ChAc blood-cell deformability and
      cytoskeletal/autophagy readouts linked to the erythrocyte branch.
    evidence:
    - reference: PMID:35444561
      reference_title: "Changes in Blood Cell Deformability in Chorea-Acanthocytosis and Effects of Treatment With Dasatinib or Lithium."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "During treatment with dasatinib or lithium, we observed alterations in RBC deformability and a stiffness increase for leukocytes."
      explanation: Human off-label treatment data support dasatinib as a modulator of the blood-cell mechanistic branch.
  evidence:
  - reference: PMID:35444561
    reference_title: "Changes in Blood Cell Deformability in Chorea-Acanthocytosis and Effects of Treatment With Dasatinib or Lithium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we investigated blood cell deformability of five ChAc patients compared to healthy controls during up to 1-year individual off-label treatment with the tyrosine kinase inhibitor dasatinib or several weeks with lithium."
    explanation: This directly supports an off-label human dasatinib treatment entry while clarifying that the reported effect is biomarker-level.
- name: Globus pallidus internus deep brain stimulation
  description: >
    GPi deep brain stimulation can substantially improve refractory motor
    symptoms, particularly severe oromandibular dystonia.
  treatment_term:
    preferred_term: deep brain stimulation
    term:
      id: MAXO:0000943
      label: deep brain stimulation
    located_in:
      preferred_term: globus pallidus internus
      term:
        id: UBERON:0002477
        label: medial globus pallidus
  evidence:
  - reference: PMID:35880382
    reference_title: "Pallidus Stimulation for Chorea-Acanthocytosis: A Systematic Review and Meta-Analysis of Individual Data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GPi-DBS is an effective and safe treatment in most patients with ChAc, but no reliable predictor of efficacy has been found."
    explanation: A systematic review and meta-analysis supports GPi-DBS as the strongest disease-specific interventional option for refractory chorea-acanthocytosis.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 30 citations 2026-04-25T22:31:10.104172

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: Chorea-acanthocytosis
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Chorea-acanthocytosis 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

Chorea-acanthocytosis (VPS13A disease) — Comprehensive Disease Characteristics Report

Target disease: Chorea-acanthocytosis (ChAc), increasingly referred to as “VPS13A disease”. (lin2024exploringthepathophysiological pages 1-2)

Evidence-note: The report synthesizes human clinical cohorts/case reports, human biomarker/diagnostic studies, and model-organism/cell-model mechanistic work. For several ontology identifiers (e.g., MeSH, ICD-10/11), no explicit codes appeared in the retrieved full text; these are flagged as not available from the present evidence set.

Disease	Identifiers	Gene / inheritance	Typical onset	Key phenotypes (approx. frequency)	Key diagnostics / biomarkers	Emerging disease-modifying approaches
Chorea-acanthocytosis (VPS13A disease; ChAc)	MONDO: MONDO_0008695; OMIM: 200150; Orphanet: ORPHA2388	VPS13A; autosomal recessive; loss-of-function / biallelic variants	Usually 20–40 y; mean ~30–35 y; broader reported range 20–50 y	Seizures ~33–45%; psychiatric symptoms in >50%; acanthocytes often ~5–50% in blood, but may be absent/variable; movement disorder, orolingual dystonia/self-biting, neuropathy common (lin2024exploringthepathophysiological pages 3-4, perrone2025anovelvps13a pages 1-2, lin2024exploringthepathophysiological pages 1-2)	Peripheral smear for acanthocytes (repeat/wet prep may help); CK usually mildly elevated / hyperCKemia; chorein (VPS13A) Western blot in RBCs often absent/low; MRI may show caudate/striatal atrophy; FDG-PET striatal hypometabolism; DaTscan presynaptic dopaminergic deficit; sNfL increased in small studies (lin2024exploringthepathophysiological pages 3-4, lin2024exploringthepathophysiological pages 4-6, niemela2020phenotypicvariabilityin pages 1-2, lin2024exploringthepathophysiological pages 6-7, dobson‐stone2004choreindetectionfor pages 1-2)	Lyn kinase pathway is a leading target; nilotinib improved hematologic/neurologic phenotypes in Vps13a−/− mice and crosses BBB; dasatinib off-label in 3 patients showed RBC target engagement (↓ active Lyn, improved autophagy/actin markers) but no clear short-term CNS benefit; symptomatic care/DBS still standard (lin2024exploringthepathophysiological pages 3-4, peikert2021targetinglynkinase pages 1-2, lin2024exploringthepathophysiological pages 4-6, peikert2021targetinglynkinase pages 8-10)

Table: This table condenses the most actionable disease-characteristic facts for chorea-acanthocytosis/VPS13A disease, including identifiers, genetics, onset, phenotype frequencies, diagnostics, and emerging disease-modifying strategies. It is designed for direct embedding in a knowledge-base style report.

1. Disease Information

1.1 Concise overview (what is the disease?)

Chorea-acanthocytosis is an ultra-rare, progressive neurodegenerative disorder in the neuroacanthocytosis spectrum, characterized by basal ganglia/striatal degeneration and acanthocytosis (spiculated red blood cells) in peripheral blood, with prominent hyperkinetic movement disorder, psychiatric/cognitive features, seizures, and neuromuscular involvement. (jung2011neuroacanthocytosissyndromes pages 1-2, lin2024exploringthepathophysiological pages 1-2)

A key framing in recent literature is that the disorder reflects loss-of-function of VPS13A (chorein), a lipid-transfer protein at membrane contact sites, and that the clinical phenotype may occur even when acanthocytosis is subtle or intermittently undetectable—supporting the “VPS13A disease” term. (lin2024exploringthepathophysiological pages 3-4, lin2024exploringthepathophysiological pages 1-2)

1.2 Key identifiers (as available)

OMIM: 200150 (explicitly stated). (dobson‐stone2004choreindetectionfor pages 1-2, weber2019choreaacanthocytosispresentingas pages 1-3)
Orphanet: ORPHA2388 (explicitly stated). (jung2011neuroacanthocytosissyndromes pages 1-2)
MONDO: Not present in the retrieved papers’ text excerpts; however, OpenTargets disease object returned MONDO_0008695 for “chorea-acanthocytosis.” (sharma2024identificationofpivotal pages 1-2)
MeSH / ICD-10 / ICD-11: Not found in retrieved full-text excerpts (not inferable from current evidence set). (perrone2025anovelvps13a pages 1-2, jung2011neuroacanthocytosissyndromes pages 1-2)

1.3 Synonyms / alternative names

Chorea-acanthocytosis (ChAc) (jung2011neuroacanthocytosissyndromes pages 1-2)
VPS13A disease (increasingly used in recent reviews) (lin2024exploringthepathophysiological pages 1-2)
Neuroacanthocytosis syndrome (as a group context) (jung2011neuroacanthocytosissyndromes pages 1-2)

1.4 Source type of disease information

Most structured disease information here derives from aggregated disease-level resources and cohorts (Orphanet Journal of Rare Diseases review; Spanish and Swedish cohorts), supplemented with individual case reports and mechanistic reviews. (jung2011neuroacanthocytosissyndromes pages 1-2, estevezfraga2018phenomenologyanddisease pages 1-2, niemela2020phenotypicvariabilityin pages 1-2, chen2023novelheterozygousvps13a pages 1-2)

URLs & dates (examples): - Jung et al., Orphanet J Rare Dis (Published 2011-10-25): https://doi.org/10.1186/1750-1172-6-68 (jung2011neuroacanthocytosissyndromes pages 1-2) - Lin et al., Frontiers in Neurology (2024-11): https://doi.org/10.3389/fneur.2024.1482936 (lin2024exploringthepathophysiological pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: biallelic (autosomal recessive) VPS13A pathogenic variants leading to loss of VPS13A protein (“chorein”) or functional deficiency. (dobson‐stone2004choreindetectionfor pages 1-2, lin2024exploringthepathophysiological pages 1-2)

Definition-level quote (abstract-based) supporting causality: The 2024 Frontiers review states: “VPS13A disease (also known as Chorea-Acanthocytosis, ChAc) … is a rare autosomal recessive genetic disorder caused by loss-of-function variants in the VPS13A gene.” (lin2024exploringthepathophysiological pages 1-2)

2.2 Risk factors

Genetic: autosomal recessive inheritance; familial clustering and founder effects in certain populations are reported. (jung2011neuroacanthocytosissyndromes pages 1-2)
Environmental: no validated environmental risk factors were identified in the retrieved evidence set; the disorder is presented as monogenic. (lin2024exploringthepathophysiological pages 1-2)

2.3 Protective factors

No genetic or environmental protective factors were identified in the retrieved evidence set. (jung2011neuroacanthocytosissyndromes pages 1-2, lin2024exploringthepathophysiological pages 1-2)

2.4 Gene–environment interactions

No gene–environment interactions were identified in the retrieved evidence set. (lin2024exploringthepathophysiological pages 1-2)

3. Phenotypes

3.1 Core phenotype domains (with HPO suggestions)

Below are high-yield phenotypes, typical characteristics, and suggested HPO terms (term labels given; exact IDs should be validated against HPO database when populating a KB).

1) Hyperkinetic movement disorder (symptom/sign) - Features: chorea, dystonia, tics; some cases show parkinsonism later/less frequent. (estevezfraga2018phenomenologyanddisease pages 1-2) - HPO suggestions: Chorea, Dystonia, Tic, Parkinsonism, Hyperkinesia.

2) Orofacial/orolingual dyskinesia and feeding dystonia - Hallmark clinical signs include tongue/lip biting and feeding dystonia. (peikert2021targetinglynkinase pages 1-2, estevezfraga2018phenomenologyanddisease pages 1-2) - HPO suggestions: Orofacial dyskinesia, Self-injurious behavior (for self-biting), Dysphagia.

3) Epilepsy / seizures - Frequency: seizures reported around ~45% in the 2024 review; other sources emphasize seizures as common and sometimes presenting symptom. (lin2024exploringthepathophysiological pages 1-2, estevezfraga2018phenomenologyanddisease pages 1-2) - Cohort statistic (Spain): 9/12 had seizures; one presented with status epilepticus; all but one became seizure-free on a single antiepileptic. (estevezfraga2018phenomenologyanddisease pages 1-2) - HPO suggestions: Seizure, Epilepsy, Status epilepticus.

4) Psychiatric symptoms and cognitive/behavioral change - Psychiatric symptoms reported in >50% in the 2024 review; Spanish cohort 10/12. (lin2024exploringthepathophysiological pages 1-2, estevezfraga2018phenomenologyanddisease pages 1-2) - HPO suggestions: Obsessive-compulsive behavior, Depression, Anxiety, Cognitive impairment, Dementia.

5) Neuromuscular involvement (peripheral neuropathy / areflexia / myopathy) - Areflexia and axonal neuropathy are repeatedly noted in NA syndromes; Spanish cohort had neuropathy in all but one. (jung2011neuroacanthocytosissyndromes pages 1-2, estevezfraga2018phenomenologyanddisease pages 1-2) - HPO suggestions: Areflexia, Peripheral neuropathy, Muscle weakness, Elevated serum creatine kinase.

6) Hematologic abnormality: acanthocytosis (laboratory) - Acanthocytes are variable; reported as commonly ~5–50%, and detection is method-dependent; false negatives occur. (lin2024exploringthepathophysiological pages 3-4, spieler2020identificationoftwo pages 2-4) - HPO suggestions: Acanthocytosis.

3.2 Phenotype characteristics (onset, progression)

Onset: typically adult onset; the 2024 review describes onset usually 20–40 years with mean onset around ~35 years. (lin2024exploringthepathophysiological pages 1-2)
Spanish cohort (n=12): mean onset 24 years (range 6–34) with mean diagnosis age 34 (26–42) and mean follow-up 18 years. (estevezfraga2018phenomenologyanddisease pages 1-2)
Swedish cohort (n=4): mean onset 34 (range 30–38) years; disease duration 9.5 years (range 2–17). (niemela2020phenotypicvariabilityin pages 1-2)

3.3 Quality-of-life impact (evidence-based description)

Cohort data indicate major functional decline over time. In the Spanish progression study, after 10 years every patient needed 24-h supervision. (estevezfraga2018phenomenologyanddisease pages 2-2)

4. Genetic / Molecular Information

4.1 Causal gene(s)

VPS13A (protein: VPS13A / chorein) is presented as the only known pathogenic gene for ChAc in recent reviews. (lin2024exploringthepathophysiological pages 1-2)

4.2 Pathogenic variant spectrum (types + examples)

The disorder is typically associated with loss-of-function mechanisms (truncating, frameshift, splice, and structural variants), though some missense variants may impair function without eliminating protein. (lin2024exploringthepathophysiological pages 1-2, lin2024exploringthepathophysiological pages 4-6)

Examples explicitly reported in retrieved clinical genetics papers: - Nonsense: NM_033305.2 c.8215G>T (p.Glu2739Ter) (reported as pathogenic). (chen2023novelheterozygousvps13a pages 1-2) - Large multi-exon deletion: deletion of exons 25–31 (reported pathogenic/expected LoF). (chen2023novelheterozygousvps13a pages 1-2) - Frameshift (case report): novel homozygous c.2061dup (frameshift) plus c.6796A>T dual mutations in one patient. (chen2023novelheterozygousvps13a pages 1-2)

Diagnostic caveat: genomic DNA sequencing alone may miss large deletions/duplications, motivating the integration of protein testing (chorein Western blot) and quantitative DNA assays (e.g., MLPA/qPCR approaches). (spieler2020identificationoftwo pages 2-4)

4.3 Molecular function and key mechanistic concepts (current understanding)

Key concept (2023–2024 framing): VPS13A is a “bridge-like” lipid-transfer protein localized to membrane contact sites and capable of bulk lipid transport between organelles, including ER–mitochondria interfaces. (kaestner2023proceedingsofthe pages 6-7, lin2024exploringthepathophysiological pages 3-4)

The 2024 mechanistic review highlights organellar and cellular consequences of VPS13A deficiency including ER–mitochondria contact disruption, mitochondrial fragmentation, and reduced mitochondrial autophagy, consistent with mitochondrial dysfunction. (lin2024exploringthepathophysiological pages 3-4)

4.4 Interactors / modifier evidence (emerging)

XK scramblase: interaction between VPS13A and XK is described as important for VPS13A function in humans. (lin2024exploringthepathophysiological pages 4-6)
Ubiquitin-ligase pathway in yeast model: RSP5 binding partner evidence in yeast (meeting proceedings), suggesting regulation of lipid biosynthesis pathways as a modifier-like mechanism in model systems. (kaestner2023proceedingsofthe pages 8-10)

Evidence for true human clinical “modifier genes” remains limited in the retrieved set; case-level co-variant discussions exist but are not yet definitive. (perrone2025anovelvps13a pages 9-10)

4.5 Ontology suggestions (for KB mapping)

GO Biological Process (suggested): - lipid transport / intermembrane lipid transfer (kaestner2023proceedingsofthe pages 6-7) - autophagy / mitophagy (kaestner2023proceedingsofthe pages 8-10) - actin cytoskeleton organization (lin2024exploringthepathophysiological pages 3-4) - regulation of kinase activity / Src-family kinase signaling (Lyn) (lin2024exploringthepathophysiological pages 3-4) - PI3K signaling / Rac1–PAK signaling (lin2024exploringthepathophysiological pages 4-6)

Cell Ontology (CL) suggestions: - medium spiny neuron (striatal vulnerability; discussed as loss of striatal neurons and MSN-related models) (peikert2021targetinglynkinase pages 1-2) - erythrocyte (RBC acanthocytosis; RBC biomarkers) (peikert2021targetinglynkinase pages 8-10)

5. Environmental Information

No consistent non-genetic environmental or infectious contributors were identified in the retrieved evidence set. The disease is consistently framed as Mendelian/monogenic. (lin2024exploringthepathophysiological pages 1-2)

6. Mechanism / Pathophysiology

6.1 Causal chain (high-level)

1) VPS13A loss-of-function → impaired bulk lipid transport at membrane contact sites (ER–mitochondria and other organelle contacts). (kaestner2023proceedingsofthe pages 6-7, lin2024exploringthepathophysiological pages 3-4) 2) Disrupted membrane/organelle lipid homeostasis and trafficking → mitochondrial abnormalities and autophagy/mitophagy defects (mitochondrial fragmentation; reduced mitochondrial autophagy; altered autophagy markers). (lin2024exploringthepathophysiological pages 3-4, kaestner2023proceedingsofthe pages 8-10) 3) Downstream cellular dysfunction in neurons and RBCs → striatal neurodegeneration and RBC membrane/cytoskeletal defects causing acanthocytosis. (peikert2021targetinglynkinase pages 1-2, lin2024exploringthepathophysiological pages 3-4)

6.2 Lyn kinase / cytoskeletal axis (translationally actionable mechanism)

A central translational hypothesis is that aberrant accumulation of activated Lyn kinase contributes to RBC membrane/cytoskeletal abnormalities and potentially neuronal phenotypes, and that Src-family kinase inhibition can reverse some cellular readouts in models. (lin2024exploringthepathophysiological pages 3-4, peikert2021targetinglynkinase pages 1-2)

Visual evidence (human off-label treatment biomarker readouts): Peikert et al. show that dasatinib suppressed overactive Lyn and modulated downstream RBC autophagy markers (ULK1, p62) and actin features; Lyn activity rebounded after withdrawal. (peikert2021targetinglynkinase media 79551084, peikert2021targetinglynkinase media 70826a04)

6.3 Candidate “wet biomarkers” under investigation (2024 review)

Because acanthocyte detection is inconsistent, recent work highlights exploratory biomarkers including serum neurofilament light chain (sNfL) and plasma PRX5 (noted in mouse work and modulated by nilotinib in preclinical context). (lin2024exploringthepathophysiological pages 4-6)

7. Anatomical Structures Affected

7.1 Organ and system level

Central nervous system: basal ganglia/striatal degeneration with MRI evidence of caudate/putamen atrophy and functional imaging evidence of striatal hypometabolism. (estevezfraga2018phenomenologyanddisease pages 1-2, niemela2020phenotypicvariabilityin pages 1-2)
Peripheral blood (RBC morphology): acanthocytosis and RBC cytoskeletal alterations. (lin2024exploringthepathophysiological pages 3-4, peikert2021targetinglynkinase pages 8-10)
Peripheral nervous system / muscle: axonal neuropathy, areflexia, hyperCKemia and muscle involvement reported in NA syndromes and cohorts. (jung2011neuroacanthocytosissyndromes pages 1-2, estevezfraga2018phenomenologyanddisease pages 1-2)

7.2 UBERON suggestions

striatum, caudate nucleus, putamen (estevezfraga2018phenomenologyanddisease pages 1-2)
blood, erythrocyte (as cell type; CL) (lin2024exploringthepathophysiological pages 3-4)

8. Temporal Development

8.1 Onset

Typical onset is early adult; reviews describe most commonly 20–40 years with mean around ~35 years. (lin2024exploringthepathophysiological pages 1-2)

8.2 Progression and stages

The disease is relentlessly progressive. Orphanet review characterizes NA syndromes as progressing over two to three decades. (jung2011neuroacanthocytosissyndromes pages 1-2)

Functional decline metrics from Spain: after 10 years every patient required 24-hour supervision. (estevezfraga2018phenomenologyanddisease pages 2-2)

9. Inheritance and Population

9.1 Inheritance

Autosomal recessive inheritance is repeatedly emphasized. (lin2024exploringthepathophysiological pages 1-2, dobson‐stone2004choreindetectionfor pages 1-2)

9.2 Epidemiology / prevalence

ChAc is exceptionally rare. Estimates from the Orphanet review: - Prevalence for each NA disorder: <1 to 5 per 1,000,000 inhabitants. (jung2011neuroacanthocytosissyndromes pages 1-2) - Total known/estimated ChAc cases worldwide: ~1,000. (jung2011neuroacanthocytosissyndromes pages 1-2)

The Spanish cohort paper similarly notes ~1,000 cases worldwide and discusses higher local prevalence in Japan and French-Canadian communities (consistent with founder effects). (estevezfraga2018phenomenologyanddisease pages 1-2)

9.3 Population genetics notes

Founder-effect language appears in Japan and French-Canadian clusters. (jung2011neuroacanthocytosissyndromes pages 1-2)

Carrier frequency and penetrance were not quantified in the retrieved evidence set. (jung2011neuroacanthocytosissyndromes pages 1-2)

10. Diagnostics

10.1 Clinical tests and biomarkers (real-world implementation)

Core tests repeatedly used in practice include: - Peripheral blood smear for acanthocytes (variable; method dependent; repeat testing helpful). (lin2024exploringthepathophysiological pages 3-4, spieler2020identificationoftwo pages 2-4) - Serum creatine kinase (CK): often elevated/hyperCKemia and may be a useful indicator, though it can fluctuate (exercise, seizures). (peikert2021targetinglynkinase pages 8-10, spieler2020identificationoftwo pages 2-4) - Chorein (VPS13A) Western blot on RBCs: often absent/low and highly informative. (dobson‐stone2004choreindetectionfor pages 1-2, jung2011neuroacanthocytosissyndromes pages 1-2) - Neuroimaging: MRI caudate/striatal atrophy; FDG-PET striatal hypometabolism; DaTscan dopaminergic deficiency; MRS metabolic ratios in striatum. (niemela2020phenotypicvariabilityin pages 1-2, weber2019choreaacanthocytosispresentingas pages 1-3)

10.2 Genetic testing strategy

Given VPS13A size and variant heterogeneity, multiple modalities may be required: - sequencing for SNVs/indels (WES/WGS/panels) - copy-number detection (MLPA/qPCR) for large deletions/duplications - protein-level confirmation (chorein Western blot) This multi-assay strategy is highlighted by evidence that some variants may be missed by routine sequencing and that acanthocytosis may not be consistently detectable. (spieler2020identificationoftwo pages 2-4, lin2024exploringthepathophysiological pages 4-6)

10.3 Differential diagnosis

NA syndromes should be considered in the differential for Huntington disease phenocopies, including Huntington disease-like syndromes and McLeod syndrome; Orphanet review highlights that NA disorders must be included particularly if Huntington testing is negative. (jung2011neuroacanthocytosissyndromes pages 7-8)

11. Outcome / Prognosis

11.1 Course and mortality

NA syndromes are described as eventually fatal, with possible sudden death due to seizure or autonomic dysfunction, and late complications such as aspiration pneumonia/infections. (jung2011neuroacanthocytosissyndromes pages 7-8)
In the Swedish cohort, one patient died during sleep at 42 years (noted as sudden death in a case series context). (niemela2020phenotypicvariabilityin pages 1-2)

11.2 Disability trajectory

Spanish progression metrics indicate profound disability accumulation: every patient required 24-hour supervision by 10 years. (estevezfraga2018phenomenologyanddisease pages 2-2)

12. Treatment

12.1 Current standard of care (symptomatic/supportive)

No curative therapies are established; management is largely symptomatic. (jung2011neuroacanthocytosissyndromes pages 1-2, lin2024exploringthepathophysiological pages 4-6)

Common symptomatic approaches include: - Movement disorder management similar to Huntington disease (dopamine antagonists or depleters are described in NA review). (jung2011neuroacanthocytosissyndromes pages 7-8) - Seizure control: generally responsive to standard anticonvulsants; the NA review warns that some anticonvulsants may worsen involuntary movements. (jung2011neuroacanthocytosissyndromes pages 7-8) - Multidisciplinary supportive care: swallowing/nutrition support (including feeding tube when necessary) and PT/OT are recommended in NA review. (jung2011neuroacanthocytosissyndromes pages 7-8)

Spanish cohort real-world prescribing patterns included antiepileptics, atypical antipsychotics, benzodiazepines; tetrabenazine and other agents were also used. (estevezfraga2018phenomenologyanddisease pages 2-2)

MAXO suggestions: - Symptomatic pharmacotherapy (pharmacotherapy) - Antiseizure therapy (anticonvulsant therapy) - Botulinum toxin injection (botulinum toxin therapy) - Deep brain stimulation (deep brain stimulation) - Enteral feeding (gastrostomy tube placement / enteral nutrition) - Physical/occupational therapy (rehabilitation therapy)

12.2 Deep brain stimulation (DBS)

Swedish case series: bilateral GPi DBS transiently attenuated feeding dystonia but did not improve gait/chorea. (niemela2020phenotypicvariabilityin pages 1-2)
Spanish cohort: 3 patients underwent GPi DBS with follow-up ~6 years; progressive lack of efficacy was noted in all cases and stimulation could worsen akinesia/gait in some settings. (estevezfraga2018phenomenologyanddisease pages 2-2)

12.3 Experimental / disease-modifying approaches (Lyn kinase targeting)

Dasatinib (off-label, human case series; translational biomarker approach): In 3 patients, dasatinib treatment appeared reasonably safe and showed RBC target engagement (reduced Lyn activity, reduced accumulated autophagy-related proteins, partial restoration of actin cytoskeleton), but clinical CNS effects were not proven over the short treatment period. (peikert2021targetinglynkinase pages 8-10)

Nilotinib (preclinical; repurposing rationale): The 2024 review summarizes that nilotinib crosses the BBB in mice and ameliorated hematological and neurological phenotypes in Vps13a−/− models, supporting repurposing rationale. (lin2024exploringthepathophysiological pages 3-4)

Figure-based evidence of target engagement (dasatinib): the extracted Figure 4 panels demonstrate suppression of active Lyn under dasatinib and changes in RBC autophagy markers and actin staining. (peikert2021targetinglynkinase media 79551084, peikert2021targetinglynkinase media 70826a04)

13. Prevention

No primary prevention is currently available beyond genetic counseling, carrier testing in affected families, and reproductive options, consistent with monogenic autosomal recessive inheritance; explicit screening guideline statements were not present in the retrieved evidence set. (lin2024exploringthepathophysiological pages 1-2)

14. Other Species / Natural Disease

Natural disease in non-human species was not identified in the retrieved evidence set.

15. Model Organisms

Multiple experimental systems are described: - Vps13a−/− mouse models that phenocopy aspects of human disease and are used for mechanistic and therapeutic (nilotinib) testing. (lin2024exploringthepathophysiological pages 3-4) - Human iPSC-derived neuronal models (including medium spiny neuron–relevant models) used to study hyperexcitability and response to Src inhibition in mechanistic review. (lin2024exploringthepathophysiological pages 3-4) - Yeast and Dictyostelium models for VPS13 biology and autophagy-related functions (discussed in meeting proceedings). (kaestner2023proceedingsofthe pages 8-10)

Recent developments and “latest research” highlights (2023–2024 prioritized)

1) Mechanistic consolidation around VPS13A as a bridge-like lipid transfer protein at membrane contact sites, connecting lipid transport defects to downstream mitochondrial/autophagy/cytoskeletal phenotypes. (Frontiers review, 2024) (lin2024exploringthepathophysiological pages 3-4) 2) Biomarker emphasis (“wet biomarkers”): recognition that acanthocytosis is variably detected and increasing interest in sNfL and red-cell functional readouts. (lin2024exploringthepathophysiological pages 4-6, peikert2021targetinglynkinase pages 8-10) 3) Clinical trial readiness gaps: off-label Lyn kinase inhibition demonstrates target engagement in RBCs but highlights the need for robust biomarkers and longitudinal natural history to power trials. (peikert2021targetinglynkinase pages 8-10) 4) Registry/consortium momentum: 2023 international meeting proceedings emphasize registries and future perspectives for NA syndromes research. (kaestner2023proceedingsofthe pages 6-7)

Limitations of this report (evidence availability)

ICD/MeSH codes and some ontology identifiers were not present in retrieved full-text excerpts; they should be filled from curated coding resources directly (OMIM/Orphanet/MeSH/ICD registries) during KB ingestion. (perrone2025anovelvps13a pages 1-2, jung2011neuroacanthocytosissyndromes pages 1-2)
Some mechanistic and therapeutic claims (e.g., nilotinib efficacy) are summarized in review-level evidence; direct primary mouse-study full text was not retrieved here. (lin2024exploringthepathophysiological pages 3-4)

References

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(kaestner2023proceedingsofthe pages 8-10): Lars Kaestner. Proceedings of the eleventh international meeting on neuroacanthocytosis syndromes. Collection, Dec 2023. URL: https://doi.org/10.22028/d291-41331, doi:10.22028/d291-41331. This article has 4 citations.
(perrone2025anovelvps13a pages 9-10): Benedetta Perrone, Viviana Mosca, Martina Pecoraro, Paola Ruffo, Elda Del Giudice, Alberta Leon, Martina Maino, Vincenzo La Bella, Rossella Spataro, and Francesca Luisa Conforti. A novel vps13a deletion in vps13a disease (chorea-acanthocytosis): a case report with brief literature summary. International Journal of Molecular Sciences, 26:11521, Nov 2025. URL: https://doi.org/10.3390/ijms262311521, doi:10.3390/ijms262311521. This article has 0 citations.
(peikert2021targetinglynkinase media 79551084): K. Peikert, Hannes Glaß, E. Federti, A. Matte, L. Pelzl, K. Akgün, T. Ziemssen, R. Ordemann, Florian Lang, The Lung Study Foch Hospital Group for Immunosuppresse Patients, L. De Franceschi, and A. Hermann. Targeting lyn kinase in chorea-acanthocytosis: a translational treatment approach in a rare disease. Journal of Personalized Medicine, 11:392, May 2021. URL: https://doi.org/10.3390/jpm11050392, doi:10.3390/jpm11050392. This article has 15 citations.
(peikert2021targetinglynkinase media 70826a04): K. Peikert, Hannes Glaß, E. Federti, A. Matte, L. Pelzl, K. Akgün, T. Ziemssen, R. Ordemann, Florian Lang, The Lung Study Foch Hospital Group for Immunosuppresse Patients, L. De Franceschi, and A. Hermann. Targeting lyn kinase in chorea-acanthocytosis: a translational treatment approach in a rare disease. Journal of Personalized Medicine, 11:392, May 2021. URL: https://doi.org/10.3390/jpm11050392, doi:10.3390/jpm11050392. This article has 15 citations.
(jung2011neuroacanthocytosissyndromes pages 7-8): Hans H Jung, Adrian Danek, and Ruth H Walker. Neuroacanthocytosis syndromes. Orphanet Journal of Rare Diseases, 6:68-68, Oct 2011. URL: https://doi.org/10.1186/1750-1172-6-68, doi:10.1186/1750-1172-6-68. This article has 255 citations and is from a peer-reviewed journal.

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OpenScientist Report

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Chorea-acanthocytosis (VPS13A disease) — Comprehensive Disease Characteristics Report

1. Disease Information

1.1 Concise overview (what is the disease?)

1.2 Key identifiers (as available)

1.3 Synonyms / alternative names

1.4 Source type of disease information

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotype domains (with HPO suggestions)

3.2 Phenotype characteristics (onset, progression)

3.3 Quality-of-life impact (evidence-based description)

4. Genetic / Molecular Information

4.1 Causal gene(s)

4.2 Pathogenic variant spectrum (types + examples)

4.3 Molecular function and key mechanistic concepts (current understanding)

4.4 Interactors / modifier evidence (emerging)

4.5 Ontology suggestions (for KB mapping)

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Causal chain (high-level)

6.2 Lyn kinase / cytoskeletal axis (translationally actionable mechanism)

6.3 Candidate “wet biomarkers” under investigation (2024 review)

7. Anatomical Structures Affected

7.1 Organ and system level

7.2 UBERON suggestions

8. Temporal Development

8.1 Onset

8.2 Progression and stages

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology / prevalence

9.3 Population genetics notes

10. Diagnostics

10.1 Clinical tests and biomarkers (real-world implementation)

10.2 Genetic testing strategy

10.3 Differential diagnosis

11. Outcome / Prognosis

11.1 Course and mortality

11.2 Disability trajectory

12. Treatment

12.1 Current standard of care (symptomatic/supportive)

12.2 Deep brain stimulation (DBS)

12.3 Experimental / disease-modifying approaches (Lyn kinase targeting)

13. Prevention

14. Other Species / Natural Disease