Alternative titles; symbols
SNOMEDCT: 26848004, 66881004; ORPHA: 2388; DO: 0050766;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q21.2 | Choreoacanthocytosis | 200150 | Autosomal recessive | 3 | VPS13A | 605978 |
A number sign (#) is used with this entry because of evidence that choreoacanthocytosis (CHAC) is caused by homozygous or compound heterozygous mutation in the VPS13A gene (605978), which encodes chorein, on chromosome 9q21.
Choreoacanthocytosis (CHAC) is an autosomal recessive 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.
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).
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. 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). Absence of the McLeod blood group (XK; 314850) phenotype (300842) was noted.
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 VPS13A 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.
Spitz et al. (1985) reported 2 brothers from a consanguineous family with motor and vocal tics, parkinsonism, distal muscular atrophy, and acanthocytosis. The neurologic features became most apparent in their thirties. Villegas et al. (1987) reported 2 affected sibs whose parents were normal. The patients did not have anemia or signs of hemolysis.
Vance et al. (1987) reported 4 affected patients from 3 families, and concluded that the inheritance was most likely autosomal recessive. Two of the 3 propositi were initially diagnosed as having Huntington disease. MRI showed atrophy of the caudate and putamen. Obligate heterozygotes did not show acanthocytosis. The authors noted that the disorder may be more frequent in Japan than elsewhere (Kito et al., 1980; Nagashima et al., 1979; Yamamoto et al., 1982). Vance et al. (1987) reviewed the literature and concluded that of 9 families in which there were 2 or more affected members, 2 were probably autosomal dominant and 7 were autosomal recessive.
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.
Rubio et al. (1997) performed linkage studies of 11 families segregating for CHAC that were of diverse geographic origin. They found linkage in all families to a 6-cM region of 9q21 that is flanked by the recombinant markers GATA89a11 and D9S1843. A maximum 2-point lod score of 7.1 at theta = 0.0 was achieved for D9S1867. The results of these studies were confirmed by homozygosity-by-descent analysis in offspring from consanguineous marriages. Together, these data provided strong evidence for the involvement of a single locus for CHAC.
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.
Sakai et al. (1985) suggested the term 'Levine-Critchley syndrome' as the best designation for this disorder. They considered the term choreoacanthocytosis inappropriate because tics, dystonia, or parkinsonism may dominate the clinical picture (Spitz et al., 1985). 'Neuroacanthocytosis' was also considered inappropriate because it might include the Bassen-Kornzweig syndrome (200100). Jankovic et al. (1985) noted that there are 2 other neuroacanthocytoses: one associated with hypobetalipoproteinemia (615558) and another that is part of the McLeod syndrome.
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. The pattern of inheritance appeared to be autosomal dominant. However, Walker et al. (2023) stated that descendants of the family reported by Levine et al. (1968) had been found to carry mutations in the XK gene, indicating that they had McLeod syndrome; see 300842.
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