Clinical Diagnosis

Chorea-acanthocytosis (ChAc) can be diagnosed with high certainty on clinical grounds alone; no formal criteria or obligatory findings have been established. However, since every affected individual does not exhibit the classic syndrome, molecular genetic testing or protein-based testing can be used to confirm the diagnosis.

• The movement disorder is mostly chorea, but some individuals present with a parkinsonian syndrome. Dystonia is common and affects the oral region and the tongue in particular. Characteristic unintended tongue protrusion, feeding dystonia and habitual tongue and lip biting cause dysarthria and serious dysphagia with resultant weight loss [Bader et al 2010]. The movement disorder is progressive.
• Progressive cognitive and behavioral changes resemble a frontal lobe syndrome (i.e., loss of social inhibition and executive functions) [Walterfang et al 2008].
• Seizures, observed in almost half of affected individuals, can be the initial manifestation [Rampoldi et al 2002]. Seizures mostly originate from the temporal lobes; thus, affected individuals can present with familial temporal lobe epilepsy [Scheid et al 2009].
• The myopathy is progressive and characterized by distal muscle wasting and weakness, but may remain subclinical. Depression of deep tendon reflexes and vibration sense are common, resulting from an axonal neuropathy that contributes to the observed amyotrophy. The pyramidal tracts are not involved and the plantar reflexes are flexor.
• Subtle eye movement abnormalities, e.g., impaired upgaze or slowed saccades, may be found. The retina is normal.

Neuroimaging. CT and MRI reveal atrophy of the caudate nuclei with dilatation of the anterior horns of the lateral ventricles [Gradstein et al 2005]. There may be slight generalized cerebral cortical atrophy. The extent of basal ganglia atrophy is best appreciated on sections in the frontal plane. MRI may show T₂-weighted signal increase in the caudate and putamen. Hippocampal sclerosis and atrophy are also seen frequently [Al Asmi et al 2005, Huppertz et al 2008, Scheid et al 2009].

Muscle and liver enzymes. Increased serum concentration of muscle CK is observed in the majority of individuals. Less commonly, the serum concentrations of LDH, AST, and ALT are increased.

Electrophysiologic tests demonstrate a sensory axonopathy with normal nerve conduction velocities and reduced sensory action potentials [Rampoldi et al 2002]. Electromyography commonly reveals neurogenic changes.

Testing

Acanthocytosis. Acanthocytes are found in the blood of individuals with ChAc in a highly variable proportion, usually 5%-50% of the red cell population. In some cases, acanthocytosis may be absent [Bayreuther et al 2010] or may appear only late in the course of the disease [Sorrentino et al 1999]. The proportion of acanthocytes does not correlate with disease severity.

• Scanning electron microscopy of erythrocytes fixed with glutaraldehyde is probably the most reliable method of detecting acanthocytes, but is not routinely available.
• A general standard for the determination of acanthocytosis has been proposed. Blood is diluted 1:1 with 0.9% saline and 10 U/mL heparin, and examined using phase-contrast microscopy after 30 minutes' incubation in a shaker. In normal samples, fewer than 6.3% of cells are spiculated [Storch et al 2005]. (Dry blood smears are often inadequate.)

Chorein detection. Western blot analysis revealed absence or marked reduction of chorein, the protein encoded by VPS13A, in erythrocytes from individuals with ChAc. In contrast, normal levels of chorein were observed in samples from individuals with McLeod syndrome and Huntington disease, suggesting that loss of full-length chorein is diagnostic of ChAc [Dobson-Stone et al 2004]. Testing is available on a research basis (see Author Notes) and is convenient for screening purposes. Of note, normal levels of chorein are theoretically possible for some VPS13A mutant alleles, such as some missense mutations; therefore, presence of normal levels of chorein does not exclude the diagnosis of ChAc.

Molecular Genetic Testing

Gene. VPS13A is the only gene in which mutation is currently known to cause ChAc.

Clinical testing

• Sequence analysis of genomic DNA and associated intron junctions is available clinically. Mutations are dispersed throughout the gene and comprise missense, frameshift, nonsense, splice site and deletion mutations; see Table 2 (pdf) [Rampoldi et al 2001, Ueno et al 2001, Dobson-Stone et al 2002, Dobson-Stone et al 2004, Dobson-Stone et al 2005, Walker et al 2006, Kageyama et al 2007, Velayos-Baeza et al 2008, Miki et al 2010]. The mutation detection rate is not known. Sequence analysis may not detect deletion of an exon(s) or of the whole gene.
• Deletion/duplication analysis. Homozygous intragenic deletions spanning one or more exons have been described; see Table 2 (pdf). Many such deletions will not be amplified by PCR prior to sequence analysis [Dobson-Stone et al 2005]. Homozygosity for a VPS13A allele with a deletion of exons was a founder mutation in three Japanese probands [Ueno et al 2001] and a separate founder allele was described in five probands with French Canadian ancestry [Dobson-Stone et al 2005]. Individuals with suspected ancestry from regions with these founder mutations can undergo targeted mutation analysis to detect heterozygous deletions [Kageyama et al 2007].

Table 1. Summary of Molecular Genetic Testing Used in Chorea-Acanthocytosis

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
VPS13A	Sequence analysis	Sequence variants 2	Unknown	Clinical
	Deletion /duplication analysis 3	Deletion of exon(s) or of the whole gene	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. When clinical findings suggest the diagnosis of ChAc, the next step is to check for elevated levels of serum creatine kinase (CK) and liver enzymes.

• If these tests support the diagnosis of ChAc, McLeod syndrome (see Differential Diagnosis) should be excluded by detailed characterization of Kell antigen expression on red blood cells (request exclusion of “McLeod phenotype”).
• If a diagnosis of ChAc is further supported, Western blot screening test should be carried out.
• In case of doubt or negative diagnosis by Western blot, but strongly suggestive clinical picture, genetic sequencing of VPS13A should be considered.

Carrier testing for at-risk relatives usually requires prior identification of the disease-causing mutations in the family. In those instances in which the diagnosis of ChAc has been confirmed by Western blot analysis, but the specific mutations are unknown, haplotyping (i.e., linkage analysis) could be used.

Note: (1) No laboratories offering this testing are listed in the GeneTests™ Laboratory Directory. (2) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in VPS13A.

Natural History

Mean age of onset in chorea-acanthocytosis (ChAc) is about age 30 years, although ChAc can develop as early as the first decade or as late as the seventh decade. It 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 [Aasly et al 1999]. Life expectancy is reduced and several instances of sudden unexplained death or death during epileptic seizures have been reported. Age at death ranges from 28 to 61 years.

Movement disorder. Limb chorea is the most common movement disorder in individuals with ChAc. Flinging arm and leg movements, shoulder shrugs, and pelvic thrusts are common. An unsteadiness of stance and gait, often with falls, seems to have choreiform as well as dystonic components. Ambulation may be severely impaired. Violent trunk spasms may occur with sudden flexion or extension movements, the latter causing head drop and head banging with a risk of head and neck injury [Schneider et al 2010]. Impaired postural reflexes may result in falls, as may sudden buckling of knees and equinovarus foot deformity, the latter related to dystonia as well as atrophy of the peroneal muscles.

Most characteristic of ChAc are the involuntary movements that affect face, mouth, tongue, pharynx, and larynx. Involuntary vocalizations (vocal tics) are present in about two thirds of affected individuals [Saiki et al 2004]. A variety of vocalizations have been described. These may consist of 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]. Continuous tongue and lip biting can lead to mutilation, which affected individuals typically try to avoid 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.

Swallowing is often impaired in the oral phase (while pharyngeal and esophageal phases of swallowing seem to be intact), resulting in dysphagia with reduced caloric intake and potentially severe weight loss. Action-induced protrusion dystonia of the tongue while feeding is typical and causes the tongue to push the food out of the mouth [Bader et al 2010]. Abnormal swallowing causes drooling.

Dysarthria is common; slurred speech may be a presenting symptom. In the course of ChAc, communication may become limited to grunting or whispering, and individuals may become mute and dependent on computer-based speech aids [Aasly et al 1999].

As the hyperkinetic orofacial state progresses to mutism, the choreiform and dystonic syndrome gradually evolves into parkinsonism in about one third of affected individuals. Increased muscle tone, rest tremor, impaired postural reflexes, bradykinesia, facial masking, and micrographia may appear. Parkinsonism has occasionally been reported as the presenting symptom of ChAc [Bostantjopoulou et al 2000].

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

Behavior 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 an immature or disinhibited manner that includes 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].

Cognitive changes. Cognitive deterioration 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 in the frontal lobe syndrome observed in frontotemporal dementia [Danek et al 2004], but may also be associated with temporal lobe epilepsy [Bader et al, submitted].

Seizures. Epilepsy is observed in almost half of affected individuals and can be the initial manifestation [Al-Asmi et al 2005]. It is usually manifested as grand mal seizures and is probably secondarily generalized, for example, from temporal lobe foci [Scheid et al 2009; Bader et al, submitted]. There may be prolonged states of memory impairment and confusion most likely corresponding to non-convulsive seizures [Bader et al, submitted].

Neuropathy and myopathy. Nerve and muscle involvement causes ankle areflexia in almost all affected individuals and muscle atrophy and weakness in at least half. Sensory loss is usually slight or may only be detected as reduced vibration sense.

Cardiomyopathy. Cardiomyopathy, for example, of the dilated type [Kageyama et al 2000, 2007], may occur but is uncommon, in clear contrast to McLeod syndrome (see Differential Diagnosis) [Mohiddin & Fananapazir 2004].

Phenotypic variability. Phenotypic variability is considerable. For example, a woman in her thirties who had initially shown orofacial dyskinesia and instability of stance and gait became mute and wheelchair dependent, while her brother, also in his thirties, had seizures and showed only a minor movement disorder [Aasly et al 1999]. Similarly, different phenotypes have been described in twins [Müller-Vahl et al 2007].

Molecular genetic testing has identified VPS13A mutations [Dobson-Stone et al 2002] in individuals with the characteristic clinical picture but no apparent acanthocytosis [Johnson et al 1998].

Other clinical findings. Splenomegaly is occasionally noted and may be caused by erythrocyte dysfunction and hemolysis as shown by the reduced levels of hemoglobin and haptoglobin. Hepatomegaly may be present, along with elevated liver enzymes; the clinical significance of this is as yet unclear.

Autonomic nervous system dysfunction was described in one individual [Kihara et al 2002].

In a few individuals, sleep disturbance was demonstrated by polysomnography [Dolenc-Groselj et al 2004].

Other studies

• MR spectroscopy has revealed abnormal proton spectra from the basal ganglia in two individuals with probable ChAc [Antonio Molina et al 1998].
• Tracer imaging studies of the type presently available in most major medical centers may support a suspicion of ChAc. Regional cerebral glucose metabolism can be measured using ¹⁸F-fluorodeoxy-glucose positron emission tomography (FDG-PET) and regional cerebral perfusion can be depicted with single photon emission computed tomography (SPECT with e.g. HMPAO or ECD). They show reduced tracer accumulation in the caudate nucleus and putamen [Milanez et al 2001, Müller-Vahl et al 2007] and occasionally in the thalamus and frontal cortex. The metabolic changes may precede gross atrophy or MRI signal change [Bader et al, submitted].
• Imaging of dopaminergic and serotoninergic transmission measured by presynaptic D₂-receptor binding (DAT) in the striatum and serotonin transporters in the hypothalamus midbrain is described to be within normal levels. However, hemispheric asymmetry was found in one individual [Müller-Vahl et al 2007].
• CT scanning of leg muscles reveals a selective pattern of fatty change that (in contrast to McLeod syndrome) tends to be symmetric [Ishikawa et al 2000].
• CSF studies, when reported, have been normal.
• EEG may show temporal spikes, both interictally and with seizure onset [Tiftikcioglu et al 2006, Scheid et al 2009].
• Peripheral nerve biopsy shows loss of myelinated fibers, particularly those of larger diameter. Unmyelinated fibers may also be affected. Signs of regeneration are observed [Sorrentino et al 1999].
• Muscle biopsy reveals central nuclei and atrophic fibers. Most changes on biopsy, however, support the predominance of neurogenic atrophy, with variation in muscle fiber diameter and occurrence of small angulated fibers. "Nemaline" rods in muscle have been reported, although their exact composition is unknown [Tamura et al 2005].

Neuropathology. On autopsy, the cerebral cortex appears unaffected. There is macroscopic bilateral atrophy of the caudate nucleus, the putamen, and the globus pallidus, corresponding to histologic loss of neurons and gliosis, which is particularly severe in the caudate and less so in the putamen and the external and internal pallidum [Vital et al 2002, Arzberger et al 2005, Bader et al 2008, Ishida et al 2009]. Pronounced neuronal loss in the substantia nigra is the likely neuropathological correlate of parkinsonism. Gliosis and extraneuronal pigment, but no Lewy bodies, are observed in the substantia nigra. The locus coeruleus, inferior olives, and cerebellum appear unaffected. Loss of spinal cord anterior horn cells, a correlate of neurogenic muscle atrophy, is seen in some of the autopsies of individuals with ChAc. Gliosis may also occur in the thalamus.

Glutamic acid decarboxylase (GAD) and choline acetyltransferase levels were reported to be normal in caudate nucleus and putamen; GAD was increased in substantia nigra in the absence of neuronal loss. Substance P and dopamine metabolites were reduced in the brains of individuals with ChAc [De Yebenes et al 1988, Galatioto et al 1993].

Genotype-Phenotype Correlations

Presently available data are inconclusive with regard to genotype-phenotype correlation in ChAc.

Nomenclature

In the recent literature, the term “chorea-acanthocytosis” is more frequently used than the term “choreoacanthocytosis”.

The term "neuroacanthocytosis" is nonspecific and may refer to any disorder with neurologic abnormalities and acanthocytosis, including McLeod syndrome, abetalipoproteinemia (Bassen-Kornzweig syndrome), or hypobetalipoproteinemia.

The term "Levine-Critchley syndrome" is inconclusive. Recent evaluations have been performed only in the kindred initially reported by Critchley et al [1967] [Walker et al, in preparation]. The family reported by Levine et al [1968] in particular had atypical features, and proper evaluation with molecular techniques is still missing.

Other outdated terms include “chorea-amyotrophy-acanthocytosis syndrome” and ‘familial amyotrophic chorea with acanthocytosis.’

Prevalence

The number of individuals with ChAc known worldwide is estimated at 500-1000. Reports have come from practically all ethnic backgrounds.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with chorea-acanthocytosis (ChAc), the following evaluations are recommended:

• Swallowing assessment
• Electroencephalography to allow for early detection of signs indicating an increased risk for epileptic seizures and consideration of use of antiepileptic drugs
• Neuropsychological assessment to identify and address possible psychosocial complications
• Electromyography and nerve conduction testing to document the extent of neuromuscular disease
• Physical therapy evaluation to identify and address areas of possible benefit

Treatment of Manifestations

Botulinum toxin may be helpful in increasing the oro-facio-bucco-lingual dystonia that interferes with eating [Schneider et al 2006].

Assistance with feeding is often necessary to prevent aspiration [Aasly et al 1999].

With progression to mutism, evaluation for computer-assisted speech systems is appropriate [Aasly et al 1999].

Mechanical protective devices may be needed for complications such as teeth grinding, head banging, and repeated falls. Use of a mouth guard has been reported to reduce psychiatric symptoms [Fontenelle & Leite 2008].

Splints can be tried for foot drop. Since the equinovarus deformity has a dystonic component, local injections of botulinum toxin have been used.

Phenytoin, clobazam, valproate and levetiracetam are reported to be effective for seizure control.

Use of psychiatric medications such as antidepressant or antipsychotic medications is based on conventional approaches.

Use of dopamine antagonists/depleters such as atypical neuroleptics or tetrabenazine as for chorea or Tourette syndrome should also be offered, although affected individuals should be carefully monitored for side effects of parkinsonism and depression [Borchardt et al 2000].

Prevention of Secondary Complications

The following are advised:

• Prevention of falls
• Keeping an object such as a handkerchief in the mouth to diminish damage to lips and tongue from involuntary biting

Surveillance

The following are appropriate:

• Monitoring of nutritional status and adaptation of diet to assure adequate caloric intake
• EEG approximately every third year

Agents/Circumstances to Avoid

Avoid the following:

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

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Neurosurgical approaches have been reported in single anecdotal cases:

• Ablative procedures. Staged bilateral posteroventral pallidotomy supposedly improved feeding in one affected individual [Fujimoto et al 1997]. The outcome was not reported for unilateral ventral lateral thalamic coagulation and other ablative procedures [Cavalli et al 1995].
• Deep brain stimulation
  • Stimulation of the internal globus pallidus was judged ineffective [Wihl et al 2001]; however, newer studies have shown a benefit [Ruiz et al 2009].
  • Bilateral thalamic stimulation successfully reduced incapacitating trunk spasms, re-established ambulation, and improved feeding in one affected individual [Burbaud et al 2002].
  • Deep brain stimulation has been carried out in few individuals with variable success. Prospective data are as yet missing and this therapy has to be considered experimental at present.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

The atypical dopamine antagonist clozapine was at least temporarily effective in a single observation [Wihl et al 2001].

The antiepileptic drug levetiracetam was effective in eliminating trunk jerks, blinking, and head nodding in a single case [Lin et al 2006].

Dopamine decreased dystonia in one individual but was ineffective in his sister [Kobal, personal communication].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Chorea-acanthocytosis (ChAc) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The unaffected parents are obligate carriers (heterozygotes) and have an alteration in one copy of VPS13A.
• Consanguinity of affected individuals' parents has been noted in a number of reports [Sorrentino et al 1999, Bohlega et al 2003, Al-Asmi et al 2005].
• Current knowledge indicates that carriers are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has 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.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

• The offspring of an individual with ChAc are obligate heterozygotes (carriers) for a disease-causing mutation in VPS13A.
• The risk that the offspring of an individual with ChAc will develop ChAc depends on the other parent's carrier status and/or the occurrence of a de novo mutation in the other parent’s VPS13A allele.

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

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Possible autosomal dominant ChAc. Some families with a clinical syndrome compatible with ChAc and apparent autosomal dominant transmission have been reported. It is not known if these disorders are linked to the VPS13A locus [Levine et al 1968, Marson et al 2003].

• Saiki et al [2003] identified a novel mutation in the last nucleotide of exon 57 of VPS13A in affected sibs in a family with apparent autosomal dominant ChAc. However, definite conclusions about mode of inheritance could not be made, as DNA was not available from the presumptively affected father.
• Pseudodominant inheritance of ChAc was observed in a family in which the affected mother was homozygous for a VPS13A mutation [Bohlega et al 2003 (family 1)].

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The original gene symbol designation, CHAC, was changed to VPS13A to acknowledge its similarity with VPS13/SOI1 in yeast. Three other human genes belong to the same family: VPS13B, VPS13C, and VPS13D, on chromosomes 8q22, 15q21, and 1p36 respectively [Velayos-Baeza et al 2004]. VPS13B (COH1) is altered in individuals with Cohen syndrome (OMIM 216550), a rare autosomal recessive disorder characterized by non-progressive psychomotor retardation and microcephaly, retinal dystrophy, and characteristic facial features [Kolehmainen et al 2003]. No human disorders have yet been associated with VPS13C or VPS13D. All four human VPS13 genes have multiple splicing variants.

Little is known about the function of chorein. Amino acid sequence analysis failed to identify conserved domains, motifs, or identifiable structural features [Rampoldi et al 2001]. Vps13p, chorein's yeast homologue, is required for proper intracellular trafficking of certain trans-Golgi network (TGN) proteins [Brickner & Fuller 1997]. It is reasonable to hypothesize a role for chorein similar to that of its yeast counterpart. Indeed, chorein may control one or more steps in the cycling of proteins through the TGN to early and late endosomes, lysosomes, and the plasma membrane. Functional experiments are required to assess chorein's biological function in mammalian systems.

A mouse model of chorea-acanthocytosis (ChAc) has been developed. Mice with a deletion of VPS13A exons 60 and 61 show acanthocytosis and late-onset motor disturbance (gait disturbance and early fall from the rotarod, but no involuntary movements). This contrasts with humans, who typically present with chorea as the major motor symptom. Brain pathology indicated apoptotic cells in the striatum. Levels of homovanillic acid, a dopamine metabolite, were reduced in the midbrain [Tomemori et al 2005]. These mice have also been described to have levels of gephyrin (a GABA_A receptor-anchoring protein) and GABRG2 (GABA_A receptor γ2 subunit) immunoreactivity in the striatum and hippocampus that are significantly higher than those in wild type mice, suggesting that loss of chorein may lead to a compensatory upregulation of these proteins to prevent striatal degeneration [Kurano et al 2006].

Normal allelic variants. VPS13A is organized in 74 exons over a chromosomal region of about 240 kb. Several splicing variants are known, variant A (exons 1-68, 70-73) being the main expressed form. Alteration/absence of variant A-encoded chorein is sufficient to cause ChAc [Dobson-Stone et al 2002]. At least two other 3'-end alternative splicing forms are expressed: variant B (exons 1-68, 69) and variant D (1-68, 68b); the approximate sizes of these three mRNA forms are 11.2 (variant A), 10 (B) and 9.6 (D) kb. Other splicing variants, probably minor forms, have also been detected [Velayos-Baeza et al 2004]. See Entrez Gene for detailed information on transcript variants.

Pathologic allelic variants. Table 2 (pdf) lists the mutations in VPS13A. A similar table can be found in Velayos-Baeza et al [2008].

Normal gene product. Variant A encodes a 3174-amino acid protein. Variants B and D would encode 3095- and 3069-amino acid proteins, respectively.

Abnormal gene product. Most mutations in VPS13A are predicted to lead to absence of chorein. The basic defect of the acanthocytic membrane has not yet been determined [Terada et al 1999]. Melone et al [2002] found increased levels of tissue transglutaminase, a cross-linking enzyme involved in assembly of macromolecular structures in two individuals with clinically diagnosed ChAc. The authors suggested that increased cross-linking activity could cause cellular membrane distortions. Such distortions in muscle cells and erythrocytes could lead, respectively, to the increase in serum creatine kinase and the acanthocytosis observed in ChAc.

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Suggested Reading

1. Bader B, Danek A, Walker RH. Chorea-acanthocytosis. In: Walker RH, ed. The Differential Diagnosis of Chorea. Chap 6. Oxford, UK: Oxford University Press; 2010:122-48.
2. Walker RH, Danek A, Dobson-Stone C, Guerrini R, Jung HH, Lafontaine AL, Rampoldi L, Tison F, Andermann E. Developments in neuroacanthocytosis: expanding the spectrum of choreatic syndromes. Mov Disord. 2006;21:1794–805. [PubMed: 16958034]
3. Walker RH, Jung HH, Dobson-Stone C, Rampoldi L, Sano A, Tison F, Danek A. Neurologic phenotypes associated with acanthocytosis. Neurology. 2007;68:92–8. [PubMed: 17210889]
4. Walker RH, Saiki S, Danek A, eds. Neuroacanthocytosis Syndromes II. Berlin, Germany: Springer-Verlag; 2008.

Author Notes

A Danek and B Bader offer chorein Western blot testing on a research basis. Please email benedikt.bader@med.uni-muenchen.de or download instructions for blood sampling and shipping from www.euro-hd.net/html/na/network/docs/.

Revision History

• 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 to live Web site
• 10 January 2005 (ad) Revision: Differential Diagnosis; Testing
• 16 July 2004 (me) Comprehensive update posted to live Web site
• 14 June 2002 (me) Review posted to live Web site
• 7 March 2002 (lr) Original submission