Chorea-Acanthocytosis

Clinical 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.

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.

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

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 500-1,000. Reports have come from practically all ethnic backgrounds.

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

Clinical 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 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.

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].