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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Chorea-Acanthocytosis

Synonyms: ChAc, Choreoacanthocytosis

, PhD, , DPhil, , PhD, , MD, , MB, ChB, PhD, , MD, and , MD, PhD.

Author Information
, PhD
Neurogenetics Group
Wellcome Trust Centre for Human Genetics
Oxford, United Kingdom
, DPhil
Neuroscience Research Australia and University of New South Wales
Sydney, Australia
, PhD
Division of Genetics and Cell Biology
San Raffaele Scientific Institute
Milan, Italy
, MD
Neurologische Klinik
Ludwig-Maximilians-Universität
Munich, Germany
, MB, ChB, PhD
Department of Neurology
James J Peters Veterans Affairs Medical Center
Mount Sinai School of Medicine
New York, New York
, MD
Neurologische Klinik
Ludwig-Maximilians-Universität
Munich, Germany
, MD, PhD
Neurogenetics Group
Wellcome Trust Centre for Human Genetics
Oxford, United Kingdom
Anthony.Monaco@well.ox.ac.uk
President, Tufts University
Medford, Massachusetts

Initial Posting: ; Last Update: January 30, 2014.

Summary

Disease characteristics. Chorea-acanthocytosis (ChAc) is characterized by a progressive movement disorder, cognitive and behavior changes, a myopathy that can be subclinical, and chronic hyperCKemia in serum. Although the disorder is named for acanthocytosis of the red blood cells, this feature is variable. The movement disorder is mostly limb chorea, but some individuals present with parkinsonism. Dystonia is common and affects the oral region and especially the tongue, causing dysarthria and serious dysphagia with resultant weight loss. Habitual tongue and lip biting are characteristic, as well as tongue protrusion dystonia. Progressive cognitive and behavioral changes resemble those in a frontal lobe syndrome. Seizures are observed in almost half of affected individuals and can be the initial manifestation. Myopathy results in progressive distal muscle wasting and weakness. Mean age of onset in ChAc is about 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. Life expectancy is reduced, with age of death ranging from 28 to 61 years.

Diagnosis/testing. The diagnosis of ChAc is based primarily on clinical findings, the presence of characteristic MRI findings, and evidence of muscle disease. CT and MRI reveal atrophy of the caudate nuclei with dilatation of the anterior horns of the lateral ventricles. MRI commonly shows T2-weighted signal increase in the caudate and putamen. Acanthocytes are present in 5%-50% of the red cell population. In some cases, acanthocytosis may be absent or may appear only late in the course of the disease. Increased serum concentration of muscle creatine kinase (CK) is observed in the majority of affected individuals. Muscle biopsy reveals central nuclei and atrophic fibers. VPS13A, which encodes chorein, is the only gene in which mutation is currently known to cause ChAc.

Management. Treatment of manifestations: Treatment is purely symptomatic, and may include: botulinum toxin for decreasing the oro-facio-lingual dystonia; feeding assistance; speech therapy; mechanical protective devices; splints for foot drop; phenytoin, clobazam, valproate, and levetiracetam for seizure management; antidepressant or antipsychotic medications; dopamine antagonists/depleters such as atypical neuroleptics or tetrabenazine; deep brain stimulation may be helpful in selected cases.

Surveillance: Monitoring of nutritional status and adaptation of diet to assure adequate caloric intake and to prevent aspiration; EEG every third year.

Agents/circumstances to avoid: Seizure-provoking circumstances and anticonvulsants that may worsen involuntary movements.

Genetic counseling. ChAc is inherited in an autosomal recessive manner. 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. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known. Prenatal testing is possible for families in which the pathogenic variants are known.

Diagnosis

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. While retinal detachment has been reported in two affected individuals from the same family, it is not clear that the retinal detachment was caused by ChAc [Ogawa et al 2013].

Neuroimaging. CT and MRI reveal atrophy of the caudate nuclei with dilatation of the anterior horns of the lateral ventricles [Gradstein et al 2005]. The caudate nucleus and putamen show significant and marked reductions in volume compared with controls [Walterfang et al 2011b]. There may be slight generalized cerebral cortical atrophy; frontal lobe atrophy has also been reported [Neutel et al 2012]. 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, and may occasionally demonstrate iron deposition [Lee et al 2011, Kaul et al 2013]. 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 pathogenic variant alleles (e.g., some missense substitutions); 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 pathogenic variants are currently known to cause ChAc.

Clinical testing

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

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
VPS13ASequence analysis 2Unknown 3
Deletion/duplication analysis 4Unknown 5

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected unless they are in homozygosis. For issues to consider in interpretation of sequence analysis results, click here.

3. Mutations are dispersed throughout the gene (see Molecular Genetics).

4. Testing that identifies exonic or whole-gene 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.

5. Homozygous intragenic deletions spanning one or more exons have been described; see Molecular Genetics. Many such deletions will not be amplified by PCR prior to sequence analysis [Dobson-Stone et al 2005].

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

When clinical findings suggest the diagnosis of ChAc, the initial step is to evaluate the individual for elevated levels of serum creatine kinase (CK) and liver enzymes.

2.

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’).

3.

If a diagnosis of ChAc is further supported, western blot screening test may be carried out.

4.

In case of doubt or negative diagnosis by western blot, but strongly suggestive clinical findings, molecular genetic testing of VPS13A should be considered.

Clinical Description

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. Degenerative arthritis due to hyperkinetic movement has been reported, requiring surgical joint replacement [Stafford et al 2013].

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]. Disruptions to key frontostriatal loops secondary to pathology in the striatum and pallidum appear to predispose individuals to major neuropsychiatric conditions [Walterfang et al 2011a].

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 2011]. Walterfang et al [2011b] suggested that dorsal striatal neuron loss may occur early in the disease process, correlating with early neuropsychiatric and cognitive presentations of the disease, and subsequently follow a dorsal-ventral gradient.

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 2011]. There may be prolonged states of memory impairment and confusion most likely corresponding to non-convulsive seizures [Bader et al 2011].

Neuropathy and myopathy. Nerve and muscle involvement causes ankle areflexia in almost all affected individuals and muscle atrophy and weakness in at least half. Symptoms consistent with a neuromuscular syndrome suggestive of motor neuron disease have been reported [Miki et al 2010, Neutel et al 2012]. Sensory loss is usually slight or may only be detected as reduced vibration sense.

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

Phenotypic variability, even within a family, 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 pathogenic variants [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].
  • Retinal detachment was described in a Japanese family, but may be due to other causes [Ogawa et al 2013].
  • It is possible that an individual with ChAc could also suffer from another genetic disorder, particularly if the individual was the product of a consanguineous mating. An individual with ChAc was also diagnosed with multidrug resistance (MDR3) deficiency, caused by pathogenic variants in ABCB4; this individual presented with symptoms mimicking Wilson disease [Anheim et al 2010].

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 [Ismailogullari et al 2010].
  • 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 findings indicative of both neurogenic and myopathic atrophy [Liu et al 2012]. ‘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 neuropathologic 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. The kindred initially reported by Critchley et al [1967] has been confirmed by molecular genetic testing to harbor a pathogenic variant in VPS13A [Velayos-Baeza et al 2011]. The family reported by Levine et al [1968] in particular had atypical features, and proper evaluation with molecular techniques has not been made.

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.

Differential Diagnosis

Because of the protean manifestations of chorea-acanthocytosis (ChAc), a wide range of disorders needs to be considered in the differential diagnosis, including the general categories of parkinsonian syndromes, choreiform and other movement disorders, epilepsy disorders, and neuromuscular disorders [Danek et al 2005].

Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric disturbances. In addition to the almost identical choreiform movement disorder and imaging findings of HD and ChAc, the changes in personality and behavior are similar [Kutcher et al 1999]. Seizures are much more common in ChAc than in HD, where they are only reported in the juvenile form. Increased serum concentrations of CK or liver enzymes are usually not seen in HD. The mean age of onset of HD is 35 to 44 years; the median survival is 15 to 18 years after onset. Neuropathology in HD is more widespread and (in contrast to ChAc) also involves the cerebral cortex [Vonsattel & DiFiglia 1998]. The diagnosis of HD rests on the detection of an expansion of a CAG/polyglutamine tract in HTT (IT15). HD is characterized by autosomal dominant inheritance and anticipation, i.e., earlier disease onset in subsequent generations.

Wilson disease. Individuals who present with neuropsychiatric disease and elevated liver enzymes should be evaluated for Wilson disease, in addition to neuroacanthocytosis syndromes. Wilson disease is a disorder of copper metabolism with onset ranging from age three years to more than 50 years. The liver disease includes recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease. Neurologic presentations include movement disorders (tremor, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement). Psychiatric disturbance includes depression, neurotic behaviors, disorganization of personality and, occasionally, intellectual deterioration. Treatment by copper chelating agents or zinc can prevent the development of hepatic, neurologic, and psychiatric findings in asymptomatic affected individuals and can reduce findings in many symptomatic individuals.

Diagnosis depends on the detection of low serum copper and ceruloplasmin concentrations and increased urinary copper excretion. Pathogenic variants in ATP7B are causative. Inheritance is autosomal recessive [Gow et al 2000].

McLeod neuroacanthocytosis syndrome (MLS) is a multisystem disorder with central nervous system (CNS), neuromuscular, and hematologic manifestations in males that overlap considerably with those seen in ChAc [Danek et al 2001]. CNS manifestations are typical of neurodegenerative basal ganglia disease including movement disorder, cognitive impairment, and psychiatric symptoms. Neuromuscular manifestations include a mostly subclinical sensorimotor axonopathy, muscle weakness, or atrophy. The hematologic manifestations are red blood cell acanthocytosis, compensated hemolysis, and the McLeod blood group phenotype resulting from absent expression of the Kx erythrocyte antigen and reduced expression of the Kell blood group antigens. This latter finding distinguishes MLS from ChAc, in which Kell blood group antigen expression is normal. Heterozygous females have mosaicism for the Kell blood group antigens and RBC acanthocytosis but only rarely have CNS and neuromuscular manifestations. Pathogenic variants in XK are causative. Inheritance is X-linked.

Pantothenate kinase-associated neurodegeneration (PKAN) is characterized by progressive dystonia and basal ganglia iron deposition with onset usually before age ten years. Commonly associated features include dysarthria, rigidity, and pigmentary retinopathy. About 25% of individuals have an ‘atypical’ presentation with onset after age ten years, prominent speech defects, psychiatric disturbances, and more gradual progression of disease. Acanthocytes are often seen in PKAN [Hayflick et al 2003, Pellecchia et al 2005]. ‘HARP syndrome’ (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) is allelic with PKAN [Ching et al 2002, Houlden et al 2003].

The 'eye of the tiger' is a characteristic MRI finding identified on transverse images of the globus pallidus as a central region of hyperintensity surrounded by a rim of hypointensity. In greater than 98% of individuals with neurodegeneration with brain iron accumulation and the 'eye of the tiger' sign on MRI at least one PANK2 pathogenic variant is identified. Inheritance is autosomal recessive.

See also Neurodegeneration with Brain Iron Accumulation Disorders Overview.

Huntington disease-like 2 (HDL2) typically presents in midlife with a picture similar to ChAc and HD, with a relentlessly progressive triad of movement, emotional, and cognitive abnormalities progressing to death over ten to 20 years [Margolis et al 2004]. JPH3 is the only gene known to be associated with HDL2 [Holmes et al 2001]. In the presence of a clinical syndrome consistent with HDL2, 41 or more CTG trinucleotide repeats in JPH3 is considered diagnostic of HDL2. HDL2 is inherited in an autosomal dominant manner; to date, it has only been reported in individuals of African ancestry. Acanthocytosis is found in a few individuals with HDL2 [Walker et al 2003].

Abetalipoproteinemia (ABL) and hypobetalipoproteinemia (HBL) share acanthocytosis with ChAc and MLS, as well as the presence of dysarthria, neuropathy, and areflexia, but differ in their hallmark findings of pigmentary retinopathy, vitamin E deficiency, steatorrhea, and absence of basal ganglia movement disorder. ABL and HBL are caused by pathogenic variants in the genes encoding the microsomal triglyceride transfer protein and apolipoprotein B, respectively. ABL is inherited in an autosomal recessive manner. HBL has clinical manifestations in both the homozygous and heterozygous states. Neurologic findings include the following:

  • A progressive spinocerebellar degeneration
  • A demyelinating sensorimotor and axonal peripheral neuropathy with hyporeflexia, diminished vibration and position sense, ataxia of gait, dysmetria, and dysarthria
  • Rarely, pyramidal tract signs
  • Rarely, cranial nerve involvement

Tourette syndrome is often diagnosed during initial stages of ChAc [Saiki et al 2004]. Its picture of motor and vocal tics, obsessive-compulsive behavior, and impaired impulse control can be similar to part of the ChAc spectrum.

Lesch-Nyhan syndrome, an X-linked recessive disorder caused by decreased activity of the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT), is characterized by neurologic dysfunction, cognitive and behavioral disturbances, and uric acid overproduction (hyperuricemia). The most common presenting features are hypotonia and developmental delay, which are evident by age three to six months. Affected individuals are delayed in sitting; most never walk. Within the first few years, extrapyramidal involvement (e.g., dystonia, choreoathetosis, opisthotonus) and pyramidal involvement (e.g., spasticity, hyperreflexia, and extensor plantar reflexes) become evident. Persistent self-injurious behavior (biting the fingers, hands, lips, and cheeks; banging the head or limbs) is a hallmark of the disease.

HPRT enzyme activity that is less than 1.5% normal in cells from any tissue (e.g., blood, cultured fibroblasts, or lymphoblasts) establishes the diagnosis of Lesch-Nyhan syndrome.

Other disorders. Several other rare genetic movement disorders may be confused with ChAc. These include dentatorubral-pallidoluysian atrophy (DRPLA), benign hereditary chorea, infantile neuroaxonal dystrophy and other disorders that may mimic HD [Ross et al 1997, Xiang et al 1998, Kambouris et al 2000, Curtis et al 2001, Fernandez et al 2001, Richfield et al 2002, Xu et al 2004, Paisan-Ruiz et al 2009].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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

Medical genetics consultation may be considered.

Treatment of Manifestations

Botulinum toxin may be helpful in increasing the oro-facio-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. Behavioral compulsions, particularly those resulting in self-harm, should be aggressively treated with antidepressant medications that target obsessive-compulsive symptoms.

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].

Deep brain stimulation of the globus pallidus pars interna may improve chorea and dystonia [Miquel et al 2013].

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 and to prevent aspiration
  • 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

Deep brain stimulation was initially investigated in a few affected individuals with variable success [Wihl et al 2001, Burbaud et al 2002, Ruiz et al 2009]. A recent multicenter retrospective study by Miquel et al [2013] indicates that this therapy may be effective for several symptoms.

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].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

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 pathogenic variant 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 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 relatives usually requires prior identification of the pathogenic variants in the family. In those instances in which the diagnosis of ChAc has been confirmed by western blot analysis, but the specific pathogenic variants are unknown, haplotyping (i.e., linkage analysis) could be used.

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].

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variants have been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be available for families in which the pathogenic variants have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Advocacy for Neuroacanthocytosis Patients
    32 Launceston Place
    London W8 5RN
    United Kingdom
    Phone: 020 7409 0092
    Fax: 020 7495 4245
    Email: glenn@naadvocacy.org; ginger@naadvocacy.org
  • Huntington's Disease Society of America (HDSA)
    HDSA has material on their site to assist in caretaking issues for adult onset progressive neurologic diseases.
  • Neuroacanthocytosis Database (Registry)
    Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
    Königstrasse 46
    Stuttgart D-70173
    Germany
    Phone: 49 731 500 63100
    Fax: 49 731 500 63082
    Email: benedikt.bader@med.uni-muenchen.de

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Chorea-Acanthocytosis: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Chorea-Acanthocytosis (View All in OMIM)

200150CHOREOACANTHOCYTOSIS; CHAC
605978VACUOLAR PROTEIN SORTING 13, YEAST, HOMOLOG OF, A; VPS13A

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, 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, although VPS13C variants have been associated with susceptibility for type 2 diabetes [Saxena et al 2010, Strawbridge et al 2011]. 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], and for multiple aspects of prospore membrane morphogenesis [Park & Neiman 2012]. 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.

The homologous protein in the ciliate Tetrahymena thermophila, TtVPS13A, was detected in a mass spectrometry analysis of the phagosome proteome [Jacobs et al 2006] and then shown to localize in the phagosome membrane and to be necessary for efficient phagocytosis [Samaranayake et al 2011]. Therefore, it is possible that chorein and/or other members of the human protein family are involved in autophagy.

Chorein has been reported to localize in the termini of extended neurites in rat PC12 cells and it has been proposed that it may be involved in dopamine release and exocytosis of dense-core vesicles [Hayashi et al 2012]. More functional experiments are required to assess chorein's biologic 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 GABAA receptor-anchoring protein) and GABRG2 (GABAA 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].

Gene structure. VPS13A is organized in 74 exons over a chromosomal region of about 240 kb. Several transcript variants are known, transcript variant A (NM_033305.2) (exons 1-68, 70-73) being the main expressed form. Alteration/absence of transcript A-encoded chorein is sufficient to cause ChAc [Dobson-Stone et al 2002]. At least two other 3'-end alternative splicing forms are expressed: transcript variant B (exons 1-68, 69) and transcript variant D (1-68, 68b); the approximate sizes of these three mRNA forms are 11.2, 10 and 9.6kb for transcript variants A, B and D, respectively. Other splicing variants, probably minor forms, have also been detected [Velayos-Baeza et al 2004]. See Table A, Gene Symbol for detailed information on transcript variants.

Pathogenic allelic variants. Pathogenic variants are dispersed throughout the gene and comprise missense, frameshift, nonsense, splice site, duplication, and deletion mutations [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, Miki et al 2010, Tomiyasu et al 2011, Velayos-Baeza et al 2011, Walker et al 2012a, Neutel et al 2012, Shin et al 2012, Ogawa et al 2013, Chen et al 2013]. A list of many of these pathogenic variants can be found in Velayos-Baeza et al [2008]. Most of the recent pathogenic variants are described in Tomiyasu et al [2011].

Most of the reported large deletions have been described in homozygosis, often constituting founder mutations [Ueno et al 2001, Dobson-Stone et al 2005]. Individuals with suspected ancestry from regions with these founder mutations or where other large deletion/duplications have been described can undergo targeted analysis to detect such pathogenic variants in heterozygosis.

Noting the high incidence of psychiatric disorders (e.g., mood disorder, schizophrenia) among patients with neuroacanthocytosis, Shimo et al [2011] sequenced VPS13A in patients with mood disorder; they found three nonsynonymous, two synonymous, and six intron variants that were absent from controls. These authors propose that these variants may be associated with susceptibility to mood disorder.

Normal gene product. Transcript variant A encodes a 3174-amino acid protein (NP_150648.2). Variants B and D encode 3095- and 3069-amino acid proteins, respectively. See Entrez Gene.

Abnormal gene product. Most pathogenic variants 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.

Erythrocyte membrane changes in ChAc have been proposed to result from altered Lyn kinase activity [De Franceschi et al 2011]. The authors detected increased tyrosine phosphorylation of the cytoskeletal components β-spectrin and adducin and the integral membrane protein band 3 in RBCs from individuals with ChAc, which would alter the composition of the junctional complexes involved in anchoring the membrane to the cytoskeleton. Using a computational approach, several other kinases have been postulated as being involved in generation of acanthocytes in ChAc and MLS [De Franceschi et al 2012]. Protein levels of β-adducin isoform 1 were markedly decreased in erythrocyte membranes from a ChAc patient [Shiokawa et al 2013].

Foller et al [2012] found an altered signaling of PI3K, Rac1 and PAK1, and a higher fraction of depolymerized actin in ChAc erythrocytes, indicating an impaired assembly of the junctional complex. An effect of reduced chorein levels in actin depolymerization has also been reported in vascular endothelial cells [Alesutan et al 2013]. Shiokawa et al [2013] reported a reduction of b-actin levels in ChAc RBCs.

Siegl et al [2013] reported reduced physiologic responses (drug-induced endovesiculation and lysophosphatidic acid-induced phosphatidylserine exposure and calcium uptake) of RBCs from individuals with neuroacanthocytosis (ChAc, MLS, PKAN), and suggested an ‘acanthocytic state’ of the red cell where alterations in functional and interdependent membrane properties arise together with an acanthocytic cell shape.

Regulation of secretion and aggregation of blood platelets has recently been proposed [Schmidt et al 2013]. The authors detected altered cytoskeletal structures in platelets from patients with ChAc, as well as reduced levels of PI3K and PAK1, involved in regulation of the actin network, and of VAMP8, required for granule secretion.

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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. Prohaska R, Sibon OC, Rudnicki DD, Danek A, Hayflick SJ, Verhaag EM, Vonk JJ, Margolis RL, Walker RH. Brain, blood, and iron: perspectives on the roles of erythrocytes and iron in neurodegeneration. Neurobiol Dis. 2012;46:607–24. [PMC free article: PMC3352961] [PubMed: 22426390]
  3. 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]
  4. 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]
  5. Walker RH, Saiki S, Danek A, eds. Neuroacanthocytosis Syndromes II. Berlin, Germany: Springer-Verlag; 2008.

Chapter Notes

Author Notes

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

The authorship for the different versions of this review has been as follows:

  • Original posting (2002). Luca Rampoldi, Carol Dobson-Stone, Adrian Danek, Anthony P Monaco
  • First update (2004). Carol Dobson-Stone, Luca Rampoldi, Antonio Velayos Baeza, Adrian Danek, Anthony P Monaco
  • Second update (2006). Carol Dobson-Stone, Luca Rampoldi, Antonio Velayos Baeza, Ruth H Walker, Adrian Danek, Anthony P Monaco
  • Third update (2010). Carol Dobson-Stone, Luca Rampoldi, Benedikt Bader, Antonio Velayos Baeza, Ruth H Walker, Adrian Danek, Anthony P Monaco
  • Fourth update (2014). Antonio Velayos Baeza, Carol Dobson-Stone, Luca Rampoldi, Benedikt Bader, Ruth H Walker, Adrian Danek, Anthony P Monaco

Revision History

  • 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 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
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