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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Neurology · VPS13A Disease (Choreoacanthocytosis)

Diagnostic Testing and Look-Alike Conditions

At a Glance

VPS13A disease is confirmed by finding pathogenic changes in both copies of the VPS13A gene, using sequencing plus copy-number analysis when needed. A normal acanthocyte smear does not rule it out, so protein testing and look-alike conditions may also need review.

Confirming a diagnosis of VPS13A disease is often a complex puzzle. Because the disease is so rare, the path to an answer usually requires a combination of clinical observation, specialized blood work, and advanced genetic testing [1][2]. It is important to understand that no single test—on its own—is always perfect at ruling the disease in or out.

The Problem with Blood Smears

For many years, the presence of acanthocytes (irregular, spiky red blood cells) was the primary way doctors looked for this disease [3]. However, we now know that relying on a blood smear is unreliable for several reasons:

  • Negative Results: You can have VPS13A disease even if your blood smear is completely normal [1][4]. A negative smear does not exclude the diagnosis.
  • Variable Appearance: The number of acanthocytes can change from day to day or depend on how the lab handles the blood sample [5][6].
  • Not Unique: Acanthocytes are also found in other conditions, such as McLeod syndrome or advanced liver disease, so they don’t point exclusively to VPS13A [7][8].

Definitive Testing: Genetics and Protein

The diagnosis is established by identifying biallelic pathogenic or likely pathogenic variants in the VPS13A gene (variants on both copies of the gene, ideally demonstrated to be in trans) [2]. (Note that Variants of Uncertain Significance, or VUS, do not confirm the diagnosis). This usually requires more than just a basic genetic screen.

  • Sequencing and Copy-Number Analysis: A complete report must include both sequencing (reading the gene’s “letters”) and copy-number analysis (looking for large missing or extra chunks of the gene) [9]. Standard sequencing alone can miss large deletions, leading to a “false negative” result [10].
  • Chorein Western Blot: If genetic testing is unclear or variants are ambiguous, doctors can perform a Western blot in specialized laboratories to look for chorein (the protein made by the VPS13A gene) [2]. If the chorein protein is absent or severely reduced, it provides strong supportive evidence of the disease, though this test is not universally available [10][11].

Distinguishing “Look-Alike” Conditions

Several other conditions can look very similar to VPS13A disease. Your medical team must distinguish between them because they have different risks and inheritance patterns.

Feature VPS13A Disease (ChAc) McLeod Syndrome Huntington’s Disease
Gene VPS13A [7] XK [7] HTT [12]
Inheritance Autosomal Recessive [13] X-linked (Primarily affects males, though symptomatic females rarely occur) [13] Autosomal Dominant [14]
Suggestive Clues Severe tongue/lip biting & “feeding dystonia” [15] Significant heart issues & risk of transfusion reactions [7] Predictable family history (though not always present) and specific DNA “expansion” [12]

Note: This list is not exhaustive. Wilson disease and other Huntington-like or drug-induced disorders may also be considered.

Confirmatory vs Supportive Checklist

When you review your medical records, distinguish between findings that are required and those that are supportive but not mandatory:

  1. Genetic Results (Confirmatory): Does the report specify biallelic pathogenic variants? Does it include copy-number variant (CNV) analysis? [10]
  2. Blood Chemistry (Supportive): Elevated creatine kinase (CK) levels are common but can be normal [16].
  3. Protein Analysis (Supportive): Was a chorein Western blot needed/performed? [2]
  4. Imaging (Supportive): Does a brain MRI show striatal atrophy? (This may be absent early on) [1].
  5. Differential Screens: Have you been tested for the HTT gene and the XK gene according to your specific clinical differential? [7]

Cardiac Considerations: While severe cardiac disease is strongly associated with McLeod syndrome, some patients with VPS13A develop reported mild heart issues. EKG or echocardiography should be individualized to your symptoms, exam, family history, and medication risks [17][18].

Common questions in this guide

What test confirms VPS13A disease?
A diagnosis is generally confirmed when testing finds pathogenic or likely pathogenic variants in both copies of the VPS13A gene, ideally showing that the variants are in trans, or inherited one from each parent. A variant of uncertain significance alone does not confirm the diagnosis.
Can a normal blood smear rule out VPS13A disease?
No. Acanthocytes can be absent from a blood smear, and their number can vary with timing and sample handling; they can also occur in McLeod syndrome and advanced liver disease. Therefore, a normal smear cannot exclude VPS13A disease.
What is a chorein Western blot used for?
A chorein Western blot measures the VPS13A protein in a specialized laboratory. Absent or severely reduced chorein supports VPS13A disease when genetic findings are unclear, but the test is not available everywhere and must be interpreted with the rest of the evaluation.
What should a VPS13A genetic test include?
A complete evaluation should include sequencing of the VPS13A gene and copy-number or deletion/duplication analysis. Sequencing alone may miss large missing or extra sections of the gene, so a negative result may need careful review.
How are McLeod syndrome and Huntington disease distinguished from VPS13A disease?
McLeod syndrome is associated with changes in the XK gene and an X-linked inheritance pattern, while Huntington disease is associated with an HTT expansion and autosomal dominant inheritance. Doctors may use XK and HTT testing, along with clinical clues such as cardiac problems, tongue or lip biting, and family history, to distinguish them.
Should people with VPS13A disease have heart testing?
Heart monitoring is individualized rather than automatic for every person. Your healthcare team may consider an EKG or echocardiogram based on symptoms, examination, family history, and medication risks; mild heart problems can occur in VPS13A disease, although severe cardiac disease is more strongly associated with McLeod syndrome.

Questions For You

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does my genetic report include 'copy-number analysis' or 'deletion/duplication' testing, or was it limited to standard sequencing?
  2. 2.Since my blood smear was negative for acanthocytes, can we perform a chorein Western blot to see if the protein is actually missing?
  3. 3.Given my symptoms, have we definitively ruled out McLeod syndrome through XK gene testing or Kell antigen screening?
  4. 4.Were my two VPS13A mutations found to be 'in trans' (one from each parent), and does the lab consider them 'pathogenic' or 'variants of uncertain significance'?
  5. 5.Based on my specific diagnosis, what is our individualized plan for baseline cardiac monitoring?

References

References (18)
  1. 1

    Progressive ataxia and orolingual chorea revealing a novel VPS13A variant: a case report of chorea-acanthocytosis without peripheral acanthocytosis with a literature review.

    Ouskri A, Bouhda N, Khaissidi K, et al.

    Neurogenetics 2026; (27(1)).

    PMID: 42631781
  2. 2

    Two case reports of chorea-acanthocytosis and review of literature.

    Huang S, Zhang J, Tao M, et al.

    European journal of medical research 2022; (27(1)):22 doi:10.1186/s40001-022-00646-7.

    PMID: 35130982
  3. 3

    Neuropathy-predominant and hyperkinetic-dystonic presentations in two siblings with a homozygous VPS13A variant: long-term follow-up and family-based clinical analysis.

    Luo Y, Chen J, Ling T, et al.

    BMC neurology 2026; doi:10.1186/s12883-026-05170-3.

    PMID: 42426634
  4. 4

    [Phenotypic variability in sisters with VPS13A disease (chorea-acanthocytosis)].

    Oner OG, Varoglu AO

    Ideggyogyaszati szemle 2025; (78(1-2)):69-72 doi:10.18071/isz.78.0069.

    PMID: 40042450
  5. 5

    Acanthocyte Sedimentation Rate as a Diagnostic Biomarker for Neuroacanthocytosis Syndromes: Experimental Evidence and Physical Justification.

    Darras A, Peikert K, Rabe A, et al.

    Cells 2021; (10(4)) doi:10.3390/cells10040788.

    PMID: 33918219
  6. 6

    Case report: Misdiagnosed orolingual dyskinesia as a consequence of seizures in a chorea-acanthocytosis patient with a novel VPS13A variation from a family with consanguineous marriage.

    Wang M, Li H, Zhou Q, et al.

    Frontiers in neurology 2024; (15()):1352467 doi:10.3389/fneur.2024.1352467.

    PMID: 38933328
  7. 7

    XK-Associated McLeod Syndrome: Nonhematological Manifestations and Relation to VPS13A Disease.

    Peikert K, Hermann A, Danek A

    Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 2022; (49(1)):4-12 doi:10.1159/000521417.

    PMID: 35221863
  8. 8

    Case report: Neuroacanthocytosis associated with novel variants in the VPS13A gene with concomitant nucleotide expansion for CANVAS and assessment with osmotic gradient ektacytometry.

    Paucar M, Wincent J, Rubin C, et al.

    Frontiers in neuroscience 2024; (18()):1409366 doi:10.3389/fnins.2024.1409366.

    PMID: 39416949
  9. 9

    Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis.

    Nishida Y, Nakamura M, Urata Y, et al.

    Neurology. Genetics 2019; (5(3)):e332 doi:10.1212/NXG.0000000000000332.

    PMID: 31192303
  10. 10

    Identification of two compound heterozygous VPS13A large deletions in chorea-acanthocytosis only by protein and quantitative DNA analysis.

    Spieler D, Velayos-Baeza A, Mühlbäck A, et al.

    Molecular genetics & genomic medicine 2020; (8(9)):e1179 doi:10.1002/mgg3.1179.

    PMID: 32056394
  11. 11

    Phenotypic variability in chorea-acanthocytosis associated with novel VPS13A mutations.

    Niemelä V, Salih A, Solea D, et al.

    Neurology. Genetics 2020; (6(3)):e426 doi:10.1212/NXG.0000000000000426.

    PMID: 32494755
  12. 12

    Preserved VPS13A distribution and expression in Huntington's disease: divergent mechanisms of action for similar movement disorders?

    García-García E, Carreras-Caballé M, Coll-Manzano A, et al.

    Frontiers in neuroscience 2024; (18()):1394478 doi:10.3389/fnins.2024.1394478.

    PMID: 38903599
  13. 13

    Untangling the Thorns: Advances in the Neuroacanthocytosis Syndromes.

    Walker RH

    Journal of movement disorders 2015; (8(2)):41-54 doi:10.14802/jmd.15009.

    PMID: 26090076
  14. 14

    Huntington's Disease, Huntington's Disease Look-Alikes‎, and Benign Hereditary Chorea: What's New?

    Schneider SA, Bird T

    Movement disorders clinical practice 2016; (3(4)):342-354 doi:10.1002/mdc3.12312.

    PMID: 30713928
  15. 15

    Clinical variability of neuroacanthocytosis syndromes-a series of six patients with long follow-up.

    Dulski J, Sołtan W, Schinwelski M, et al.

    Clinical neurology and neurosurgery 2016; (147()):78-83.

    PMID: 27310290
  16. 16

    The Diverse Neuromuscular Spectrum of VPS13A Disease.

    Buchberger A, Riedel E, Hackenberg M, et al.

    Annals of clinical and translational neurology 2026; (13(1)):157-169 doi:10.1002/acn3.70198.

    PMID: 41030128
  17. 17

    Cardiac manifestation is evident in chorea-acanthocytosis but different from McLeod syndrome.

    Quick S, Heidrich FM, Winkler MV, et al.

    Parkinsonism & related disorders 2021; (88()):90-95 doi:10.1016/j.parkreldis.2021.05.015.

    PMID: 34153885
  18. 18

    Life expectancy and mortality in chorea-acanthocytosis and McLeod syndrome.

    Walker RH, Miranda M, Jung HH, Danek A

    Parkinsonism & related disorders 2019; (60()):158-161 doi:10.1016/j.parkreldis.2018.09.003.

    PMID: 30245172

This page explains VPS13A disease testing and look-alike conditions for education only and does not replace medical advice. Ask your healthcare team to interpret your genetic, blood, protein, and heart test results.