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Chorea-acanthocytosis (ChAc) is a form of neuroacanthocytosis (see this term) and is characterized clinically by a Huntington disease-like phenotype with progressive neurological symptoms including movement disorders, psychiatric manifestations and cognitive disturbances.
ORPHA:2388Classification level: Disorder
Prevalence and incidence are not known, but it is estimated that there are around 1,000 cases worldwide. ChAc appears to be more prevalent in Japan, possibly due to a founder effect, and clusters have been found elsewhere in geographically isolated communities (e.g. French-Canadian population).
Onset is in early adulthood and the initial presentation is often subtle cognitive or psychiatric symptoms. However, patients may have developed related psychiatric disorders several years before neurological manifestations. In at least 1/3 of patients, seizures, typically generalized, are the first manifestation. In some cases, seizures may precede the appearance of movement disorders by as much as a decade. During the course, most patients develop a characteristic phenotype including chorea, a very peculiar ''feeding dystonia'' with tongue protrusion, orofacial dyskinesias, limb dystonia, involuntary vocalizations, dysarthria and involuntary tongue- and lip-biting. Gait may have a ''rubber man'' appearance with truncal instability and sudden, violent trunk spasms. Most patients develop generalized chorea and some degree of parkinsonism. Impairment of memory and executive functions is frequent. Psychiatric manifestations are common and may present as schizophrenia-like psychosis or obsessive compulsive disorder (OCD). Myopathy and axonal neuropathy are usually mild. Clinical neuromuscular manifestations include areflexia, sensorimotor neuropathy, and variable weakness and atrophy. ChAc usually progresses slowly over 15-30 years, but sudden death, presumably caused by seizures or autonomic involvement, may occur.
ChAc is caused by various mutations in the VPS13A gene (9q21), coding for chorein. No obvious genotype-phenotype correlations have been observed.
Diagnosis may be challenging. Presence of self-mutilating lip and tongue biting, or other self-mutilation is strongly suggestive of ChAc. Determination of acanthocytosis in peripheral blood smears may be negative and does not rule out the disorder. Serum CK is mostly elevated. Patients have absent chorein expression in erythrocytes on Western blot. Confirmatory DNA analysis of the VPS13A gene is difficult due to its size and heterogeneity of mutation sites. Electroneurography may demonstrate sensorimotor axonal neuropathy while electromyography shows neurogenic as well as myopathic changes. Electroencephalographic findings are not specific. Neuroradiologically, there is progressive striatal atrophy affecting especially the head of the caudate nucleus as well as impaired striatal glucose metabolism similar to that seen in HD.
The differential diagnoses depend on the presenting symptoms and include McLeod neuroacanthocytosis syndrome, Huntington's disease, Huntington-like disorders, juvenile Parkinson's disease and Tourette's syndrome (see these terms).
Routine methods for prenatal testing can be applied.
ChAc is an autosomal recessive disorder and genetic counseling is recommended. The chances of a sibling developing ChAc are 1:4. If the causative genetic defect is known, presymptomatic diagnosis in siblings at disease risk may be offered.
Management and treatment
No curative or disease-modifying treatments are currently available and management is purely symptomatic.
The course is usually relentlessly progressive and overall prognosis is poor. Sudden death may be due to seizures, or possibly autonomic dysfunction. There may be gradual generalized weakness with fatal aspiration pneumonia or systemic infections.