Clinical characteristics.

VPS13A disease, caused by VPS13A loss-of-function pathogenic variants, is characterized by a spectrum of movement disorders (chorea, dystonia, tics, sometimes parkinsonism); predominant orofacial choreic and dystonic movements and tics (with involuntary tongue protrusion on attempted swallowing, habitual tongue and lip biting resulting in self-mutilation, involuntary vocalizations); dysarthria and dysphagia; psychiatric, cognitive, and behavioral changes ("frontal lobe type"); seizures; and progressive neuromuscular involvement. Huntingtonism (triad of progressive movement disorder and cognitive and behavioral alterations) is a typical presentation. Phenotypic variability is considerable even within the same family, including for monozygotic twins. Mean age of onset is about 30 years. VPS13A disease runs a chronic progressive course and may lead to major disability within a few years. Some affected individuals are bedridden or wheelchair dependent by the third decade. Age at death ranges from 28 to 61 years; several instances of sudden unexplained death or death during epileptic seizures have been reported.

Diagnosis/testing.

The diagnosis of VPS13A disease is established in a proband with suggestive findings and biallelic pathogenic variants in VPS13A identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for VPS13A disease. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields of neurology, psychiatry, physiatry, physical therapy (PT), occupational therapy (OT), speech-language therapy, feeding, neuropsychology, and medical genetics. Pharmacotherapy for movement disorders may include dopamine antagonists/depleters such as atypical neuroleptics or tetrabenazine (or its derivatives) for limb and trunk dystonia and orofaciolingual dystonia (which may also benefit from botulinum toxin). Issues with mobility, activities of daily living, and need for assistive devices can be addressed by physiatry, PT, and OT. In persons with dysphagia, feeding assistance can include speech therapy and gastrostomy tube placement as needed to reduce weight loss and/or risk of aspiration. For dysarthria or mutism, therapy can include the use of technical means for augmentative and alternative communication, such as speech-generating devices. Seizure management can include use of phenytoin, clobazam, valproate, and levetiracetam. For psychiatric/behavioral issues, antidepressant or antipsychotic medications are used per conventional approaches.

Surveillance: Regular monitoring of existing manifestations, the individual's response to pharmacotherapy and other supportive care, and the emergence of new manifestations is recommended per the multidisciplinary treating specialists.

Agents/circumstances to avoid: Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake) and anticonvulsants that may worsen involuntary movements (e.g., carbamazepine, lamotrigine).

Genetic counseling.

VPS13A disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a VPS13A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the VPS13A pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

VPS13A disease should be suspected in probands with the following clinical, laboratory, and imaging findings and family history. "Red flag" findings are summarized in Table 1, and more detailed information follows the table.

Establishing the Diagnosis

The diagnosis of VPS13A disease is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in VPS13A identified by molecular genetic testing (see Table 2).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic VPS13A variants of uncertain significance (or of one known VPS13A pathogenic variant and one VPS13A variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches. Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of VPS13A disease is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with generalized chorea and/or epileptic seizures may be more likely to be diagnosed using genomic testing (see Option 2).

Note: Single-gene testing (sequence analysis of VPS13A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

VPS13A disease is characterized by a progressive movement disorder, orofacial choreic and dystonic movements and tics, dysarthria and dysphagia, progressive cognitive and behavioral changes, psychosis, seizures, and progressive neuropathy and myopathy. Phenotypic variability is considerable and requires consideration of the diagnosis in a wide range of clinical conditions (including epilepsy, myopathy, and Tourette syndrome), with the huntingtonism triad as one typical presentation ("Huntington disease-like"). Acanthocytes may be found in blood smears, but the relevance of their presence or absence has been overstated (see Nomenclature). Mean age of onset in VPS13A disease is about age 30 years. VPS13A disease runs a chronic progressive course and may lead to major disability within a few years. Table 3 provides an overview of the major clinical findings.

Limb and trunk chorea is common and can include flinging arm and leg movements, shoulder shrugs, and pelvic thrusts. Stance and gait are typically affected by involuntary movements such as foot or leg chorea and dystonia. Violent trunk spasms may occur with sudden flexion or extension movements; head drops and head banging with a risk of head and neck injury can also occur [Schneider et al 2010].

A peculiar "rubber person gait" may appear due to a sudden lapse of muscle tone in the trunk or legs [Thomas & Jankovic 2003, Termsarasab & Frucht 2018] and may be interpreted as being functional (psychogenic). Impaired postural reflexes may result in falls, as may sudden buckling of knees [Yamamoto et al 1982] and equinovarus foot deformity, the latter related to dystonia as well as atrophy of the peroneal muscles.

The choreic syndrome gradually evolves into predominant parkinsonism with dystonia in about one third of affected individuals. Increased rigid muscle tone, rest tremor, impaired postural reflexes, bradykinesia, facial masking, and micrographia may appear. Occasionally, parkinsonism may be the presenting manifestation.

Orofacial chorea, dystonia, and tics. Predominance of orofacial chorea is very common. The involuntary movements that affect the face, mouth, tongue, pharynx, and larynx are the most characteristic.

Action-induced dystonic protrusion of the tongue while feeding is typical and causes the tongue to push the food out of the mouth. "Feeding dystonia" is the term commonly applied for this pattern of movement [Bader et al 2010].

Continuous tongue and lip biting caused by behavioral compulsion or tic/chorea can lead to self-mutilation, which can result in serious and challenging infections of the oral region. Affected individuals typically try to avoid this by keeping an object such as a handkerchief between the teeth, which may function either as a sensory trick to reduce dystonia or as a mechanical obstacle.

Involuntary vocalizations (vocal tics) are present in about two thirds of affected individuals [Saiki et al 2004]. The variety of described vocalizations (tics) include clicking, gasping, sighing, whistling, blowing, sucking, grunting noises, perseveration of word elements or phrases, and continuous humming.

There may be habitual teeth grinding (bruxism), spitting, or involuntary belching [Wihl et al 2001, Sibon et al 2004].

Dysphagia. The oral phase of swallowing is often impaired (while pharyngeal and esophageal phases seem intact), resulting in dysphagia with drooling and reduced caloric intake and potentially severe weight loss.

Dysarthria is common; slurred speech may be a presenting manifestation. In the course of VPS13A disease, communication may become limited to grunting or whispering. The hyperkinetic orofacial state may eventually progress to mutism [Aasly et al 1999].

Cognitive decline is common. Memory and executive functions, such as the ability to sustain concentration over time, planning, and modifying behavior, seem particularly affected. These findings resemble those of frontotemporal dementia [Danek et al 2004].

Behavioral/psychiatric changes. Changes in personality and behavior along with psychopathologic abnormalities occur in about two thirds of affected individuals [Danek et al 2004]. Apathy, depression, and bradyphrenia (slowness of thought) can be seen, but hyperactivity, irritability, distractibility, and emotional instability can also be observed. Individuals may behave in a disinhibited manner that can include sexual disinhibition. They may show obsessive-compulsive behavior including trichotillomania [Lossos et al 2005, Walterfang et al 2008] and self-inflicted chronic excoriations on the head [Walker et al 2006]. Loss of insight, self-neglect, anxiety, paranoia, aggression against others, and autoaggression are observed. Suicide and suicidal ideation are part of the disease spectrum [Sorrentino et al 1999].

Epilepsy is observed in almost half of affected individuals and can be the initial manifestation [Al-Asmi et al 2005]. It usually manifests as generalized tonic-clonic seizures and is probably secondarily generalized, for example, from temporal lobe foci [Scheid et al 2009, Bader et al 2011]. There may be prolonged states of memory impairment and confusion most likely corresponding to nonconvulsive seizures [Bader et al 2011, Mente et al 2017].

EEG may show temporal spikes, both interictally and with seizure onset [Scheid et al 2009].

Neuropathy and myopathy. Nerve and muscle involvement resulting in ankle areflexia is seen in almost all affected individuals and muscle atrophy and weakness in at least half of affected individuals. Symptoms suggestive of motor neuron disease have been reported [Neutel et al 2012]. Primary myopathic alterations can also be detected [Vaisfeld et al 2021]. Sensory loss is usually slight or may only be detected as reduced vibration sense. Pyramidal tract signs are usually absent, but bilateral extensor plantar responses were noted in one individual [Neutel et al 2012], and upper motor neuron involvement was found post mortem in another [Miki et al 2010].

Ocular motor abnormalities have been noted on occasion, with apraxia of lid opening, intermittent blepharospasm, frequent square wave jerks, slowing of saccades (mainly vertical), and reduced saccadic range [Gradstein et al 2005].

Other clinical findings

• Dilated cardiomyopathy is rare [Kageyama et al 2007]; however, mild cardiac involvement may be more common than previously thought [Quick et al 2021].
• Splenomegaly is occasionally noted and may be caused by erythrocyte dysfunction and hemolysis, as shown by reduced levels of hemoglobin and haptoglobin.
• Hepatomegaly may be present, along with elevated liver enzymes; to date the clinical significance of this is unclear.
• Autonomic nervous system dysfunction was described in one affected individual [Kihara et al 2002].
• In a few individuals, sleep disturbance was demonstrated by polysomnography [Dolenc-Groselj et al 2004].
• Chance co-occurrences with other conditions may complicate the clinical diagnostic process [Anheim et al 2010].

Other studies

• MR spectroscopy may reveal abnormal proton spectra from the basal ganglia [Niemelä et al 2020].
• Tracer imaging studies of the type presently available in most major medical centers may support a suspicion of VPS13A disease. Regional cerebral glucose metabolism, measured using ¹⁸F-fluorodeoxy-glucose positron emission tomography, shows striatal hypometabolism [Ehrlich & Walker 2017, Niemelä et al 2020].
• Imaging of dopaminergic and serotoninergic transmission. Although ratios of binding to striatal dopamine transporters and serotonin transporters in the hypothalamus midbrain area as determined using (123)I-beta-CIT-SPECT fell within the normal ranges in two affected individuals, a significant difference in binding to presynaptic striatal dopamine transporters was observed [Müller-Vahl et al 2007]. Presynaptic dopaminergic deficiency was identified in some individuals [Niemelä et al 2020].
• CT scanning of leg muscles reveals a selective pattern of symmetric fatty change [Ishikawa et al 2000].
• Cerebrospinal fluid studies, when reported, have been normal.
• Serum neurofilament light chain is significantly increased in affected individuals compared to healthy controls [Peikert et al 2020], as it is in many other neurodegenerative disorders.
• Peripheral nerve biopsy has demonstrated loss of myelinated fibers, particularly those of larger diameter. Unmyelinated fibers may also be affected. Signs of regeneration have been observed [Sorrentino et al 1999].
• Muscle biopsy revealed findings indicative of both neurogenic and myopathic atrophy [Vaisfeld et al 2021]. "Nemaline" rods in muscle have been reported, although their exact composition is unknown [Tamura et al 2005].

Neuropathology. Systematic neuropathologic studies are still lacking. Click here (pdf) for more information.

Prognosis. Life expectancy is reduced. Age at death ranges from 28 to 61 years.

Several instances of sudden unexplained death or death during epileptic seizures have been reported [Walker et al 2019].

Genotype-Phenotype Correlations

To date, available data are inconclusive with regard to genotype-phenotype correlations involving clinical manifestations and laboratory findings for VPS13A disease.

Nomenclature

To incorporate the genetic etiology of the disorder, Walker & Danek [2021] proposed that chorea-acanthocytosis be renamed VPS13A disease. The term "VPS13A disease" is preferred because the presence of chorea and/or acanthocytosis is neither necessary nor sufficient to diagnose the disorder [Walker & Danek 2021.]

"Neuroacanthocytosis" – a nonspecific umbrella term that may refer to any disorder with neurologic abnormalities and acanthocytosis (including McLeod neuroacanthocytosis syndrome) – should be used with great caution and is not a substitute for a definitive genetic diagnosis [Walker & Danek 2021].

The term "Levine-Critchley syndrome" is obsolete [Velayos-Baeza et al 2011; Danek et al, unpublished data].

Other outdated terms include "chorea-amyotrophy-acanthocytosis syndrome" and "familial amyotrophic chorea with acanthocytosis."

Prevalence

The number of individuals with VPS13A disease worldwide is estimated to be approximately 1:1,000,000 [Jung et al 2011].

The following observations might speak to founder effects; however, to date the overall prevalence of the following variants and VPS13A disease in these populations is unknown (see Table 8).

• An intragenic deletion of exons 60-61 was observed in several Japanese families [Ueno et al 2001, Tomiyasu et al 2011].
• An intragenic deletion of exons 70-73 was observed in French Canadian families [Dobson-Stone et al 2005].
• The variant c.2343delA was reported in three Jewish families from Djerba Island, Tunisia.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VPS13A disease, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for VPS13A disease.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended, as for other disorders with similar findings. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended (see Table 7).

Agents/Circumstances to Avoid

Avoid the following:

• Seizure-provoking circumstances (e.g., sleep deprivation, alcohol intake)
• Anticonvulsants that may worsen involuntary movements/tics (e.g., carbamazepine, lamotrigine)

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early recognition and treatment of potential manifestations of the disease such as seizures, as possible complications (e.g., status epilepticus, sudden unexpected death in epilepsy) may be severe.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Several studies showed pathologically elevated tyrosine kinase Lyn activity in individuals with VSP13A disease and in disease models [De Franceschi et al 2011, De Franceschi et al 2012, Peikert et al 2021a, Peikert et al 2021b]. Lyn kinase inhibition was able to rescue the blood phenotype [Lupo et al 2016] and the neuronal phenotype [Stanslowsky et al 2016]. This evidence encouraged off-label treatment with the tyrosine kinase inhibitor dasatinib in three affected individuals. Although the reduction of both elevated Lyn kinase activity and accumulated autophagy markers suggested target engagement in red blood cells during treatment, clinical parameters remained essentially unchanged; of note, no clinically relevant side effects occurred. Putative biomarkers such as creatine kinase, serum neurofilament levels, and acanthocyte count failed to show consistent effects [Peikert et al 2021a]. Experimental follow up suggested failure of central nervous system targeting by orally administered dasatinib [Peikert et al 2021b]. Tyrosine kinase inhibitors with improved blood-brain barrier penetration would thus be needed. Thus, based on currently available information, tyrosine kinase inhibitors cannot be recommended to treat VPS13A disease.

VPS13A loss of function was reported to impair PI3K signaling leading to reduced store-operated Ca²⁺ entry (SOCE) and increased cell death [Pelzl et al 2017a, Pelzl et al 2017b]. VPS13A upregulates the serum- and glucocorticoid-inducible kinase SGK1, which targets Na⁺/K⁺-ATPase, whose capacity was shown to be reduced in the absence of VSP13A [Hosseinzadeh et al 2020]. Both phenotypes were restored in cell models by lithium treatment. Although this observation suggests that lithium treatment might be preferable to other mood stabilizers should they be indicated in an individual with VPS13A disease, no systematic studies of lithium treatment have been reported to date.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

VPS13A disease is inherited in an autosomal recessive manner.

Note: Previous speculation as to possible autosomal dominant inheritance of VPS13A disease has been disproven in the respective families [Danek et al 2012].

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a VPS13A pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a VPS13A pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Based on current knowledge, heterozygotes (carriers) do not have features of VPS13A disease and not at risk of developing the disorder [Walker et al 2012b].

Sibs of a proband

• If both parents are known to be heterozygous for a VPS13A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Significant phenotypic variability may be observed between affected sibs who inherit the same biallelic pathogenic variants [Merwick et al 2014]; different phenotypes have even been observed in monozygotic twins [Müller-Vahl et al 2007].
• Based on current knowledge, heterozygotes (carriers) do not have features of VPS13A disease and are not at risk of developing the disorder [Walker et al 2012b].

Offspring of a proband. Unless an individual with VPS13A disease has children with an affected individual or a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in VPS13A (see Related Genetic Counseling Issues, Family planning).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a VPS13A pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the VPS13A pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be affected with or carriers of VPS13A disease, particularly if consanguinity is likely and/or if both partners are of the same ethnic background.
  • Consanguinity has been reported in a number of families with VPS13A disease [Sorrentino et al 1999, Dobson-Stone et al 2002, Bohlega et al 2003, Al-Asmi et al 2005, Sokolov et al 2012].
  • Recurrent VPSA13A pathogenic variants have been identified in individuals of Japanese, French Canadian, and Sephardic Jewish ancestry (see Table 8).

Prenatal Testing and Preimplantation Genetic Testing

Once the VPS13A pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

VPS13A encodes the protein VPS13A (also called chorein), a member of a recently recognized superfamily of bridge-like lipid transfer proteins [Leonzino et al 2021, Neuman et al 2022]. These proteins are localized at membrane contact sites, where pairs of intracellular membranes are held in close apposition [Lang et al 2015, Park et al 2016, Kumar et al 2018, Yeshaw et al 2019].

VPS13A is one of four very similar mammalian VPS13 paralogues that have different subcellular localizations and functions in cell and organismal physiology [Kolehmainen et al 2003, Velayos-Baeza et al 2004, Lesage et al 2016, Gauthier et al 2018, Seong et al 2018]. VPS13 family proteins are characterized by a conserved structural organization: they are large, rod-shaped proteins with a hydrophobic channel that extends along the entire length of the protein [Li et al 2020, Dziurdzik & Conibear 2021, Leonzino et al 2021, Adlakha et al 2022, Cai et al 2022]. The ends of the protein interact with the two closely apposed membranes, so that the hydrophobic channel provides a conduit for the flow of lipids between them. VPS13A has been localized to contact sites between the endoplasmic reticulum (ER) and three different structures, the mitochondrion, the lipid droplet, and the plasma membrane [Kumar et al 2018, Yeshaw et al 2019, Guillén-Samander et al 2022]. It has also been found at contacts between mitochondria and endosomes [Muñoz-Braceras et al 2019]. Disruption of lipid exchange at one or more of these contacts is thought to be the basis for functional impairment of neurons and red blood cells (neurodegeneration and acanthocytosis, respectively).

It is not yet known how lipid flow through VPS13A is regulated or at which of these contact sites the loss of lipid flow is relevant to disease causation. However, the extreme C-terminal end of VPS13A (a PH domain) has been shown to bind directly to the XK protein, loss of which is responsible for McLeod neuroacanthocytosis syndrome (also referred to as McLeod syndrome or XK disease), a disorder characterized by clinical manifestations very similar to those of VPS13A disease [Ho et al 1994, Urata et al 2019, Park & Neiman 2020, Guillén-Samander et al 2022, Park et al 2022, Peikert et al 2022a]. XK is a plasma membrane-localized lipid scramblase that mediates movement of phospholipids between the two leaflets of a lipid bilayer [Suzuki et al 2014, Ryoden et al 2022]. One effect of this scramblase activity is exposure to the cell surface of phosphatidylserine, a phospholipid normally confined to the cytosolic leaflet of the plasma membrane [Suzuki et al 2014, Ryoden et al 2022]. A VPS13A-XK complex is found at ER-to-plasma membrane contact sites, where it may pair transport of lipids between the ER and plasma membrane with movement of lipids between the two plasma membrane leaflets [Guillén-Samander et al 2022]. Given the similarity of VPS13A disease to McLeod syndrome, disruption of the functional partnership between the proteins VPS13A and XK is likely to have a key role in disease causation [Peikert & Danek 2023].

Loss of VPS13A has been associated with increased Lyn kinase activity, disturbed autophagy, and alteration of the actin cytoskeleton [De Franceschi et al 2011, Föller et al 2012, Lupo et al 2016]. Indeed, inhibitors of Lyn kinase have been shown to be effective in restoring the peripheral blood cell phenotypes of individuals with VPS13A disease [Peikert et al 2021a]. However, cellular phenotypes in neuronal cells derived from individuals with VPS13A disease were only partially reverted by Lyn kinase inhibition [Stanslowsky et al 2016, Glaß et al 2018]. Given the biochemical function of VPS13A in lipid transfer, the question of how impairment of this function may cause alterations of Lyn kinase activity and of actin organization has yet to be resolved.

Vps13a^-/- mice recapitulate key features of individuals with VSP13A disease, showing loss of VPS13A and presence of blood cell acanthocytosis, disturbed autophagy, neuronal loss, and neuroinflammation in the basal ganglia and motor disturbances, but the neurologic changes occurred late and appeared mild in comparison to findings in humans [Peikert et al 2021b]. Similar findings were reported in another mouse model, with exons 60-61 deletion in Vps13a [Tomemori et al 2005]. Further characterization of these mouse models is needed.

Mechanism of disease causation. Loss of function. In addition to the majority of VPS13A disease-associated variants being predicted to be loss-of-function variants, western blotting has shown that many result in loss of VPS13A expression. Occasionally individuals with VPS13A disease may express VPS13A that lacks the PH domain that binds to the XK protein [Park et al 2022].

VPS13A-specific laboratory technical considerations. Absence or marked reduction of VPS13A (also known as chorein) on western blot analysis has been shown in erythrocytes from individuals with VPS13A disease. In contrast, normal levels of VPS13A are observed in samples from individuals with Huntington disease and healthy controls [Dobson-Stone et al 2004]. Therefore, western blot analysis of VPS13A may be helpful in the following circumstances:

• Variants of uncertain significance (VUS) in VPS13A
• Negative molecular analysis of VPS13A in a proband whose phenotype is consistent with VPS13A disease
• Used as a first diagnostic indicator when DNA analysis is not affordable or generally unavailable

Individuals with reduced levels of VPS13A need further diagnostic workup by molecular genetic testing [Spieler et al 2020].

Notes: (1) Some pathogenic variants in VPS13A are known to be associated with normal levels of VPS13A (e.g., some missense substitutions that do not result in misfolding and protein degradation or small deletions leading to expression of a truncated protein whose electrophoretic motility is very similar to wild type protein [Park et al 2022]); therefore, the presence of normal levels of VPS13A does not exclude the diagnosis of VPS13A disease. (2) Because reduced VPS13A immunoreactivity has been observed in individuals with McLeod neuroacanthocytosis syndrome (most likely because of destabilization of VPS13A in the absence of the protein XK, with which it forms a complex [Urata et al 2019]), immunohistochemistry of VPS13A needs to be carefully interpreted in the context of the clinical findings.

Author Notes

The following web pages provide descriptions of our clinical work, research interests, and contact information:

• Adrian Danek, MD
• Ruth H Walker, MD, PhD
• Kevin Peikert, MD, and Andreas Hermann, MD, PhD, Translational Neurodegeneration Section "Albrecht Kossel," Neuroacanthocytosis Syndromes

As an international community of clinicians, scientists, and families dealing with VPS13A disease (chorea-acanthocytosis), XK disease (McLeod neuroacanthocytosis syndrome), and related disorders, we initiated the bimonthly virtual "VPS13 forum." In this forum, we regularly discuss all aspects (from bench to bedside) of this emerging field [Peikert & Danek 2023]. For invitations to future VPS13 forum sessions, contact ed.kcotsor-inu.dem@trekiep.nivek.

Drs Adrian Danek (ed.uml@kenad), Ruth Walker (ude.mssm@reklaw.htur), Andreas Hermann (ed.kcotsor-inu.dem@nnamreh.saerdna), Kevin Peikert (ed.kcotsor-inu.dem@trekiep.nivek), and Hans Jung (hc.zsu@gnuj.snah) are actively involved in clinical research regarding individuals with VPS13A disease. They would be happy to communicate with persons who have any questions regarding the diagnosis of VPS13A disease or other considerations.

Drs Adrian Danek (ed.uml@kenad), Ruth Walker (ude.mssm@reklaw.htur), Andreas Hermann (ed.kcotsor-inu.dem@nnamreh.saerdna), Kevin Peikert (ed.kcotsor-inu.dem@trekiep.nivek), and Hans Jung (hc.zsu@gnuj.snah) are also interested in hearing from clinicians treating families affected by "neuroacanthocytosis" syndromes and Huntington disease-like syndromes in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Drs Gabriel Miltenberger-Miltenyi (tp.aobsilu.anicidem@iynetlimg) and/or Dr Antonio Velayos Baeza (moc.liamtoh@soyaleva; ku.ca.xo.gapd@soyalev.oinotna) to inquire about review of VPS13A variants of uncertain significance.

Western blot analysis for VPS13A is currently available on a research basis (contact ed.kcotsor-inu.dem@trekiep.nivek).

Acknowledgments

We are grateful to Glenn Irvine, who sadly passed away, and Ginger Irvine, the founders of the Advocacy for Neuroacanthocytosis Patients, and to Susan Wagner and Joy Willard-Williford as representatives of Neuroacanthocytosis Advocacy USA. In Glenn Irvine's memory a prize for research in VPS13A and XK diseases (chorea-acanthocytosis and McLeod neuroacanthocytosis syndrome) is awarded to junior investigators whose work has substantially contributed to the field.

We thank Antonio Velayos Baeza and Benedikt Bader, former coauthors of this GeneReview on chorea-acanthocytosis / VPS13A disease, for their work in the field and the highly appreciated contribution to this valuable resource. Some years ago, Profs Thomas Witt and Alexander Storch provided decisive input.

Author History

Benedikt Bader, MD; Ludwig-Maximilians-Universität (2010-2023)

Adrian Danek, MD (2002-present)

Pietro De Camilli, PhD (2023-present)

Carol Dobson-Stone, DPhil (2002-present)

Andreas Hermann, MD, PhD (2023-present)

Gabriel Miltenberger-Miltenyi, MD (2023-present)

Anthony P Monaco, MD, PhD (2002-present)

Aaron Neiman, PhD (2023-present)

Kevin Peikert, MD (2023-present)

Luca Rampoldi, PhD (2002-present)

Antonio Velayos Baeza, PhD; Wellcome Trust Centre for Human Genetics (2004-2023)

Ruth H Walker, MB, ChB, PhD (2006-present)

Revision History

• 30 March 2023 (bp) Comprehensive update posted live
• 18 April 2019 (avb) Revision: New information on VPS13C and VPS13D
• 30 January 2014 (me) Comprehensive update posted live
• 18 August 2011 (cd) Revision: prenatal testing available clinically as listed in the GeneTests Laboratory Directory
• 6 July 2010 (me) Comprehensive update posted live
• 13 October 2006 (me) Comprehensive update posted live
• 10 January 2005 (ad) Revision: Differential Diagnosis; Testing
• 16 July 2004 (me) Comprehensive update posted live
• 14 June 2002 (me) Review posted live
• 7 March 2002 (lr) Original submission

Literature Cited

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