Choreoacanthocytosis (CHAC) is a rare disorder characterized by progressive neurodegeneration and red cell acanthocytosis, with onset in the third to fifth decade of life (Rubio et al., 1997).
See also McLeod syndrome (300842) for a phenotypically ... Choreoacanthocytosis (CHAC) is a rare disorder characterized by progressive neurodegeneration and red cell acanthocytosis, with onset in the third to fifth decade of life (Rubio et al., 1997). See also McLeod syndrome (300842) for a phenotypically similar disorder.
Walker et al. (2002) reported a family in which 3 members were affected with what the authors thought was autosomal dominant choreoacanthocytosis. The 56-year-old proband had initially been diagnosed with Huntington disease (143100). ... - Differential Diagnosis Walker et al. (2002) reported a family in which 3 members were affected with what the authors thought was autosomal dominant choreoacanthocytosis. The 56-year-old proband had initially been diagnosed with Huntington disease (143100). All 3 patients had 30 to 35% acanthocytosis on peripheral blood smear. However, in affected members of this family, Walker et al. (2003) identified trinucleotide repeat expansions in the junctophilin-3 gene (605268.0001), confirming a diagnosis of Huntington disease-like-2 (HDL2; 606438). Walker et al. (2003) suggested that HDL2 should be considered in the differential diagnosis of choreoacanthocytosis.
Critchley et al. (1967, 1968) described an adult form of acanthocytosis associated with neurologic abnormalities and apparently normal serum lipoproteins. The proband had onset in his mid-twenties of generalized weakness and involuntary movements, including grimacing, dystonia, and chorea. ... Critchley et al. (1967, 1968) described an adult form of acanthocytosis associated with neurologic abnormalities and apparently normal serum lipoproteins. The proband had onset in his mid-twenties of generalized weakness and involuntary movements, including grimacing, dystonia, and chorea. Orofacial movements were especially dramatic, and the patient had multiple bite lesions on his lips, tongue, and cheeks. The neurologic manifestations resembled those of the Gilles de la Tourette syndrome (137580) or Huntington disease (143100). Four of the proband's sibs had neurologic manifestations. A niece had acanthocytes and a neurologic disorder suggesting Friedreich ataxia (229300). Estes et al. (1967) and Levine et al. (1968) reported a family in which 19 persons in 4 generations had some degree of neurologic abnormalities, 15 with, and 4 without, acanthocytosis. Acanthocytes averaged from 1 to 20% of the total erythrocyte count, and there was no obvious association between the degree of acanthocytosis and the severity of the neurologic disability. There were no demonstrable quantitative defects of low density (beta) or high density (alpha) lipoproteins. Major neurologic symptoms included muscle weakness and atrophy, leg cramps, disturbances of coordination, hyporeflexia, chorea, and seizures. Inheritance was consistent with autosomal dominance. Levine et al. (1968) concluded that the disorder was neuronal. Critchley et al. (1970) reported a single case from England, a woman who showed self-mutilation of the tongue, lips, and cheeks. Another family was reported by Aminoff (1972). Wasting of girdle and proximal limb muscles, absent tendon reflexes, and disturbance of bladder function were other features. Cederbaum et al. (1971) and Bird et al. (1978) observed a consanguineous family in which 3 adult sibs developed progressive chorea and dementia similar to Huntington disease (143100), but with acanthocytes in the peripheral blood. No malabsorption or abnormalities of serum beta-lipoprotein were found. The proband was a 41-year-old male, and an affected brother and sister had died at ages 32 and 39 years. Postmortem examination showed marked neuronal loss and gliosis of the caudate and putamen. Two children of the proband were healthy. The authors suggested that the same disorder may have been present in the family of Critchley et al. (1967), although the pattern of inheritance in that family appeared to be autosomal dominant. In a patient with acanthocytosis and degeneration of the basal ganglia, Copeland et al. (1982) found an abnormally high level of a protein in the 100,000 MW range on 2-D O'Farrell gel electrophoresis of red cell membranes. This patient was from the family reported by Bird et al. (1978) (Motulsky, 1982). Yamamoto et al. (1982) reported 2 sibs with neuroacanthocytosis with normal serum lipoprotein levels. Features included orolingual tic-like movements associated with vocalization, biting of the lip and tongue, dysphagia, subtle parkinsonism, and chorea. Gross et al. (1985) reported a 46-year-old man of Hispanic Puerto Rican ancestry who had familial amyotrophic chorea with acanthocytosis (FACWA). At age 36 years, he developed progressive orofacial dyskinesia, dysarthria, dysphagia, and chorea of the trunk and limbs. Generalized tonic-clonic seizures appeared at age 40. Examination at age 46 showed the abnormal movements, as well as atrophy and weakness of the limb muscles and areflexia. Laboratory studies showed acanthocytosis on peripheral blood smear and increased serum creatine kinase. Family history revealed a brother who was less severely affected. The index patient also had increased free sialic acid, which the authors attributed to tissue destruction; the brother did not have this finding. Gross et al. (1985) noted the phenotypic similarity to the family reported by Estes et al. (1967). Hardie et al. (1991) reviewed neuroacanthocytosis on the basis of 19 cases, 12 familial and 7 nonfamilial. The mean age at onset was 32 years (range, 8-62) and the clinical course was usually progressive with cognitive impairment, psychiatric features, and organic personality changes in over half the cases. More than one-third of the cases had seizures. Orofaciolingual involuntary movements and pseudobulbar disturbance commonly caused dysphagia and dysarthria. Chorea was seen in almost all cases, and dystonia, tics, and akinetic-rigid features also occurred. CT imaging showed cerebral atrophy, but caudate atrophy was seen less commonly. Postmortem examination in 1 case revealed extensive neuronal loss and gliosis affecting the striatum, pallidum, and substantia nigra. Kartsounis and Hardie (1996) reviewed the clinical features of 19 reported cases of neuroacanthocytosis and found that the most consistent neurologic findings were impairment of frontal lobe function and psychiatric morbidity, in a pattern suggesting subcortical dementia. See Kay (1991) for a discussion of band 3 protein (109270) abnormalities in autosomal recessive choreoacanthocytosis. In 3 patients with neuroacanthocytosis, Rinne et al. (1994) demonstrated reduced neuronal density in the substantia nigra. As in Parkinson disease, the ventral lateral region was most severely affected, but with a slightly more diffuse distribution. Sorrentino et al. (1999) described late appearance of acanthocytes in the course of chorea-acanthocytosis. The patient was a 37-year-old man whose parents were second cousins. Onset was reported to be at the age of 20 years with personality changes, sexual disinhibition, aggressiveness, and sporadic orofaciolingual dyskinesias. Persistent choreic movements of the head, shoulders, trunk, and limbs appeared later. At 28 years, he developed sporadic, generalized tonic-clonic seizures which disappeared after the age of 33 years. At that time, neurologic examination showed self mutilation of tongue and lip, dysarthria, mild diffuse muscle atrophy, and lack of deep tendon reflexes. Blood smears failed to show acanthocytes. Three years later when he was restudied for progression of neurologic manifestations, a fresh Wright stain revealed 51% acanthocytes. Requena Caballero et al. (2000) described a 34-year-old male, son of consanguineous parents, who had a progressive neurologic illness characterized by seizures, tics, choreic movements, and mood changes. Acanthocytosis was present in the blood, and serum beta-lipoprotein was normal. No KX (314850) changes of McLeod syndrome were found. Serial neuroimaging studies demonstrated progressive caudate atrophy. Elevated creatine kinase and muscle biopsy showed a nonspecific myopathy. Genetic study demonstrated linkage of the disorder to the 9q21 region. Lossos et al. (2005) reported 3 unrelated Jewish patients with choreoacanthocytosis confirmed by genetic analysis (605978.0006; 605978.0007). One of the patients had trichotillomania beginning in adolescence, 2 decades before diagnosis of CHAC. She also experienced postpartum exacerbation of CHAC. Another patient showed increased serum creatine kinase and hepatosplenomegaly approximately 10 years before other symptoms of CHAC developed. Gradstein et al. (2005) described the eye movement abnormalities in 3 patients with CHAC. All had degeneration of the basal ganglia on MRI typical of CHAC. Their eye movement findings suggested brainstem involvement as an additional site of neurodegeneration outside the basal ganglia in CHAC. All 3 patients were later reported by Dobson-Stone et al. (2002) to have mutations in the VSP13A gene. Ruiz-Sandoval et al. (2007) reported 2 Mexican mestizo sisters, born of consanguineous parents, with choreoacanthocytosis associated with a homozygous VPS13A mutation (605978.0009). The proband had onset at age 32 years and showed severe progression of the disorder; at age 42, she was emaciated, anarthric, and reactive only to simple commands. In contrast, her sister had onset at age 45 years and primarily showed motor and verbal tics, paranoid behavior, and depression. Ruiz-Sandoval et al. (2007) noted the clinical heterogeneity of the disorder in this family despite the patients having the same mutation.
In the 11 CHAC families reported by Rubio et al. (1997), Rampoldi et al. (2001) identified 16 different mutations in the gene encoding chorein (see, e.g., 605978.0001).
In 4 affected patients from 3 Japanese kindreds with ... In the 11 CHAC families reported by Rubio et al. (1997), Rampoldi et al. (2001) identified 16 different mutations in the gene encoding chorein (see, e.g., 605978.0001). In 4 affected patients from 3 Japanese kindreds with CHAC, Ueno et al. (2001) identified homozygosity for a deletion in the VPS13A gene (605978.0003). The unaffected parents were heterozygous for the deletion. Haplotype analysis indicated a founder effect. Among 43 patients with choreoacanthocytosis, Dobson-Stone et al. (2002) identified 57 different mutations distributed throughout the CHAC gene (see, e.g., 605978.0004). In 7 patients, only 1 heterozygous mutation was found; in 4 patients, no disease mutations were found. The authors noted that small gene deletions or rearrangements may not have been detected in these patients. In 2 affected sibs from a Japanese family with choreoacanthocytosis with apparent autosomal dominant inheritance, Saiki et al. (2003) identified heterozygosity for mutation in the CHAC gene (605978.0005). In an erratum, the authors stated that an error in sequencing had occurred and the inheritance pattern should have been reported as autosomal recessive (pseudodominant). Dobson-Stone et al. (2005) identified a homozygous 37-kb deletion in the VPS13A gene (605978.0008) in affected members of 3 French Canadian families with choreoacanthocytosis. Haplotype analysis indicated a founder effect.
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....
DiagnosisClinical DiagnosisChorea-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. TestingAcanthocytosis. 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 TestingGene. VPS13A is the only gene in which mutation is currently known to cause ChAc. Clinical testingSequence analysis of genomic DNA and associated intron junctions. 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-AcanthocytosisView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityVPS13ASequence analysisSequence variants 2 UnknownClinical Deletion /duplication analysis 3Deletion of exon(s) or of the whole geneUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.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: 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.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in VPS13A.
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....
Natural HistoryMean 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].
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]. ...
Differential DiagnosisBecause 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. 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, and chronic liver disease. Neurologic presentations include movement disorders (tremors, 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 with 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. Mutations in ATP7B are causative. Inheritance is autosomal recessive [Gow et al 2000].McLeod 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, and 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. Mutations in XK are causative. Inheritance is X-linked. Pantothenate kinase-associated neurodegeneration (PKAN) (formerly Hallervorden-Spatz syndrome) 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 mutation 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 lack of basal ganglia movement disorder. ABL and HBL are caused by mutations 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. The 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].
To establish the extent of disease in an individual diagnosed with chorea-acanthocytosis (ChAc), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsBotulinum 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 ComplicationsThe following are advised:Prevention of fallsKeeping an object such as a handkerchief in the mouth to diminish damage to lips and tongue from involuntary biting SurveillanceThe following are appropriate:Monitoring of nutritional status and adaptation of diet to assure adequate caloric intake EEG approximately every third year Agents/Circumstances to AvoidAvoid 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 InvestigationNeurosurgical 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.OtherThe 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].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDVPS13A9q21.2Vacuolar protein sorting-associated protein 13AVPS13A homepage - Mendelian genesVPS13AData 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) View in own window 200150CHOREOACANTHOCYTOSIS; CHAC 605978VACUOLAR PROTEIN SORTING 13, YEAST, HOMOLOG OF, A; VPS13AMolecular Genetic PathogenesisThe 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 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]. 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.