OBSERVATION

Choreoacanthocytosis in a Mexican Family

José L. Ruiz-Sandoval, MD; Vı́ctor Garcı́a-Navarro, MD; Erwin Chiquete, MD, PhD; Carol Dobson-Stone, DPhil;
Anthony P. Monaco, MD, PhD; Lucı́a E. Álvarez-Palazuelos, MD; Juan J. Padilla-Martı́nez, MD;
Esperanza Barrera-Chairez, MD; Erika I. Rodrı́guez-Figueroa, MD; Guillermo Pérez-Garcı́a, MD

Background: Choreoacanthocytosis (CHAC) (Online
Mendelian Inheritance in Man accession No. 200150) is
a hereditary neurodegenerative syndrome characterized
by movement disorders, cognitive decline, myopathy, be-
havioral changes, and acanthocytosis and is caused by
mutations in the VPS13A gene.
Objective: To describe the cases of 2 Mexican women
with clinical and molecular characteristics compatible with
CHAC.
Design: Case reports.
Patients: Choreoacanthocytosis was identified in 2 Mexi-
can mestizo sisters with healthy consanguineous par-
ents. Clinical manifestations began at different ages.
Results: The onset of signs and symptoms of CHAC in
the proband was at age 32 years and was characterized
by balancing problems followed by chorea, compulsive
lip and tongue biting with buccolingual self-mutilation,
dysarthria, dysphagia, and weight loss. The first clinical
manifestations in the proband’s sister occurred at age 45
years and included multiple motor and verbal tics, with
coprolalia, followed by lip and tongue biting, self-
mutilation, and chorea. The clinical findings in both sis-
ters were remarkable for acanthocytosis that developed
late, when neurologic changes were already evident. Mu-
tation screening of the VPS13A gene revealed homozy-
gosity for the frameshift mutation c.3556_3557dupAC
in exon 33. Currently, the proband’s sister, in whom neu-
rologic defects developed 13 years after onset of CHAC
in the proband, is the least affected.
Conclusions: The same mutation of the VPS13A gene
can be expressed differently in the same family. This ob-
servation confirms the notion that there is considerable
heterogeneity in the clinical manifestation of CHAC.
Arch Neurol. 2007;64(11):1661-1664

Author Affiliations:
Departments of Neurology
and Neurosurgery
(Drs Ruiz-Sandoval,
Garcı́a-Navarro, Chiquete,
Álvarez-Palazuelos,
Padilla-Martı́nez, and
Rodrı́guez-Figueroa),
Hematology (Dr Barrera-
Chairez), and Genetics
(Dr Pérez-Garcı́a), Hospital
Civil de Guadalajara “Fray
Antonio Alcalde,” Universidad
de Guadalajara, Guadalajara,
Jalisco, Mexico; Prince of Wales
Medical Research Institute and
University of New South Wales,
Randwick, Australia
(Dr Dobson-Stone); and
Wellcome Trust Centre for
Human Genetics, University of
Oxford, Oxford, England
(Dr Monaco).
C
HOREOACANTHOCYTOSIS
(CHAC) is a type of
neuroacanthocytosis, a
heterogeneousgroupofhe-
reditarysyndromescharac-
terized by the association of neurologic ab-
normalities with acanthocytic red blood
cells.1,2 Choreoacanthocytosis is mainly an
autosomal recessive disorder caused by a
variety of mutations in the VPS13A gene
(Online Mendelian Inheritance in Man ac-
cession No. 200150; available at http://www
.ncbi.nlm.nih.gov/omim/). The exact patho-
physiologic mechanisms remain largely
unknown, and no obvious genotype-
phenotype correlation has been described
to date.3 The clinical manifestation in-
cludes progressive movement disorders
(primarily chorea but occasionally parkin-
sonism), clinical or subclinical myopathy,
cognitive decline, compulsive behavior, and
acanthocytosis of the red blood cells.3,4 Dys-
tonia is frequent, affecting the oral region
and causing dysarthria and dysphagia with
resultant weight loss. Seizures occur in al-
most 50% of patients.3 Clinical manifesta-
tions of CHAC overlap considerably with
those seen in chorea with the McLeod phe-
notype (McLeod syndrome), an X-linked
neuroacanthocytosis in which erythro-
cyte protein abnormalities have been much
studied.4
A detailed description of neuropatho-
logic findings in 2 Mexican patients af-
fected with CHAC was published in 1989.5
Since then, to our knowledge, no further
descriptions of Mexican patients with
CHAC have been published in the scien-
tific literature. The purpose of the pres-
ent report is to report the cases of 2 sis-
ters with the clinical phenotype of CHAC,
with the mutation c.3556_3557dupAC in
the VPS13A gene causing the disorder.
REPORT OF CASES
CASE 1
The proband, a 42-year-old woman with
healthy parents in a consanguineous re-
lationship (first-degree cousins) was 32
years old when the first clinical manifes-
tations appeared. These included fre-
quent falls and abrupt, undulant, asym-
metric involuntary movements of the

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 A B C

Figure 1. Patient with choreoacanthocytosis. A, Note self-mutilation of the lips owing to orofacial dyskinesia. B, Peripheral blood smear exhibits acanthocytes
(Wright-Giemsa, original magnification, ⫻100). C, Coronal view of T1-weighted magnetic resonance image shows atrophy of the caudate nuclei.

atine kinase (395 U/L; reference range, 22-269 U /L) and

G G C A A C A C T G T T C A G heterozygous ε3/ε4 genotype of apolipoprotein E. There
were no remarkable results for ␣-tocopherol, cobala-
∗ ∗
Case 1 min, ceruloplasmin, and copper concentrations in plasma
or for lipoprotein electrophoresis and iron kinetics. As-
sessment of peripheral nerve conduction velocity re-
G G C A A C A C T G T T C A G vealed a severe polyneuropathic axonal sensorimotor de-
fect. Brain imaging assessment included computed
Case 2 ∗ ∗
tomography and magnetic resonance imaging, which dem-
onstrated global atrophy, especially of the caudate nu-
clei (Figure 1). Magnetic resonance spectroscopy of the
G G C A A C T G T T C A G G brain showed no meaningful results.
Control
CASE 2

The proband’s 54-year-old sister experienced the onset

Figure 2. Sequence chromatograms show the VPS13A c.3556_3557dupAC
of signs of CHAC at age 45 years, characterized by mul-
mutation found in patients 1 and 2. Asterisks indicate the inserted bases. tiple motor and verbal tics, both simple and complex; para-
noid behavior; coprolalia; and lip and tongue biting with
trunk, neck, and upper limbs, associated with compul- buccolingual self-mutilation. She refused to undergo neu-
sive lip and tongue biting. At age 35 years, she began to rologic evaluation and complied poorly with therapy.
experience episodes of anxiety and depression. Three years Given the awareness of the diagnosis of CHAC in her sis-
later, there was dysphagia to solid foods, dysarthria, and ter, no other diagnostic procedures were performed ex-
orofacial dyskinesia, with buccolingual self-mutilation cept for PBS and mutation screening of the VPS13A gene.
(Figure 1) and consequent weight loss of 12 kg. At age She is walking at home but with frequent falls and de-
40 years, she could not walk because of hypotonia of the pendence on her family.
legs. The dysphagia worsened, and she was able to swal-
low only liquids and semisolid foods. Multiple pharma- MOLECULAR GENETIC ASSESSMENT
cologic approaches, including benzodiazepine, oral non-
deposit form of haloperidol, biperiden hydrochloride, In patient 1, DNA was screened for VPS13A mutations
trihexyphenidyl hydrochloride, clonazepam, levodopa, by denaturing high-performance liquid chromatogra-
fluoxetine hydrochloride, and vitamin B complex therapy, phy followed by direct sequencing, as described else-
were sequentially initiated in an attempt to control symp- where.6 We confirmed the presence of the mutation in
toms, but with limited response. Two years later, at age patient 2 by direct sequencing. Both patients were ho-
42 years, she became emaciated, anarthric, and reactive mozygous for a frameshift mutation in exon 33
to the environment, performing only simple com- (c.3556_3557dupAC) (Figure 2), a genetic change first
mands. The lower cranial nerves were patently affected, detected in a family from the United States (family
with lingual atrophy and paralysis. The arms and legs were CHAC4).7 Patients 1 and 2 have 2 sisters (one of them
flaccid, paretic, and hyporeflexic. Given the clinical sus- with compulsive alcoholism) and 2 brothers, all older than
picion of CHAC, several peripheral blood smear (PBS) 30 years, who are otherwise healthy (Figure 3). Serial
preparations were analyzed, initially yielding nonsignifi- PBS preparations from the case patients’ siblings and neph-
cant results. However, as a consequence of the fortu- ews have been analyzed, yielding unremarkable results
itous finding of erythrocyte acanthocytosis in her sister to date. Genetic counseling has been provided, but given
several months later, a new PBS was analyzed, which re- the recessive inheritance of this syndrome, the family has
vealed 40% acanthocytes (Figure 1). Other significant refused genotyping unless another member with symp-
laboratory findings included elevated MB fraction of cre- toms of CHAC is identified.

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 COMMENT
We present the case reports of 2 sisters with the rare CHAC
syndrome. To our knowledge, this is the second report
of this disorder in Mexicans.5,7 Although the same mu-
tation of the VPS13A gene was responsible for the dis-
ease, the clinical expression differed between the 2 sis-
ters for age at onset, appearance of neurologic findings,
and severity of disease. These findings confirm that clini-
cal heterogeneity seems to be the rule in CHAC.8,9 It is
possible that gene environment or complex interactions
among products of different genes are responsible for the
variable expression of this syndrome. The exact deter-
minants of the clinical spectrum of CHAC will be clari-
fied when the function of the product encoded by the
VPS13A gene is known.
The VPS13A gene (formerly CHAC gene) is located at
chromosome locus 9q21, spanning a 250-kb region with
at least 73 exons.10 This gene encodes the chorein pro-
tein, which is thought to have a role in the dynamic change
of cellular structures.10 Choreoacanthocytosis occurs
worldwide in individuals of different ethnic back-
grounds, and various mutations in VPS13A cause the dis-
order.8 Inheritance is primarily autosomal recessive, but
autosomal dominant inheritance has also been de-
scribed.11 The clinical manifestations of CHAC develop
between the third and fifth decades of life, primarily be-
ginning with balancing problems and hyperkinetic cho-
reic movements. Hypokinetic forms are infrequent and
usually develop late in the course of the disease.3,12 In our
patients, we documented the hyperkinetic form of CHAC.
Cognitive changes occur in more than half of affected in-
dividuals and consist of depression, suicide ideation, ob-
sessive-compulsive disorder, and symptoms of frontal lobe
involvement. In the 2 cases described herein, the pro-
band’s sister exhibited paranoid and schizophrenic be-
havior including isolation, coprolalia, and depression, as
in Guilles de la Tourette syndrome.
The hematologic feature acanthocytosis in the con-
text of neurologic abnormalities was first described by
Estes et al13 in 1967. Acanthocytes can constitute from
5% to 50% of erythrocytes in a PBS from a patient with
CHAC. This hematologic finding may appear late in
the course of the disease, and the possibility of a posi-
tive result depends on the laboratory method used.14
Isotonically diluted blood can yield higher acantho-
cyte levels than standard dry blood smear prepara-
tions; thus, use of isotonically diluted erythrocytes
combined with unfixed wet blood preparations would
yield a normal level of less than 6.3% acanthocytes
relative to total erythrocytes. This method is recom-
mended in screening for serious acanthocytosis in
movement disorders because it is inexpensive and easy
to perform.14
Other nonspecific laboratory findings in CHAC in-
clude elevated plasma activity of creatine kinase and lac-
tic dehydrogenase.3,15 Computed tomographic and mag-
netic resonance images can demonstrate atrophy of the
caudate nuclei, and positron emission tomographic or
single-photon emission computed tomographic images re-
veal hypoactivity of the basal ganglia and occasionally of
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I
1 2
II
1 2 3 4
P
5 6 7 8
III
1 2 3 4
Figure 3. Family pedigree. Arrow indicates the proband (P); circles, females;
squares, males; solid symbols, individuals affected with choreoacanthocyto-
sis; and slashes, deceased members.
the frontal cortex.16 The differential diagnosis of CHAC
includes McLeod syndrome, abetalipoproteinemia,
Hallervorden-Spatz syndrome, Wilson disease, Guilles de
la Tourette syndrome, Huntington disease, Lesch-Nyhan
syndrome, and dentatorubral and pallidoluysian degen-
eration, among several other conditions.12 To date, there
is no effective treatment of CHAC, and death usually oc-
curs as a consequence of emaciation and prostration.
In conclusion, CHAC occurs worldwide, with vari-
able clinical expression, even in individuals from the same
family and, thus, sharing the same mutation of the VPS13A
gene. Our observation suggests that complex gene-
environment or gene-gene interactions may influence the
phenotype of CHAC. Because PBS analysis is inexpen-
sive and readily available, it can be performed serially in
patients who are at risk of the disease; especially those
with movement disorders and first-degree relatives hav-
ing a confirmed diagnosis of CHAC.
Accepted for Publication: January 31, 2007.
Correspondence: José L. Ruiz-Sandoval, MD, Depart-
ment of Neurology and Neurosurgery, Hospital Civil de
Guadalajara “Fray Antonio Alcalde,” Hospital 278, Guad-
alajara, Jalisco, Mexico 44280 (jorusan@mexis.com).
Author Contributions: Study concept and design: Ruiz-
Sandoval and Rodrı́guez-Figueroa. Acquisition of data:
Garcı́a-Navarro, Dobson-Stone, Monaco, Alvarez-
Palazuelos, Padilla-Martı́nez, and Pérez-Garcı́a. Analy-
sis and interpretation of data: Chiquete, Monaco, and
Barrera-Chairez. Drafting of the manuscript: Ruiz-
Sandoval, Chiquete, Dobson-Stone, Alvarez-Palazuelos,
Padilla-Martı́nez, Barrera-Chairez, and Rodrı́guez-
Figueroa. Critical revision of the manuscript for impor-
tant intellectual content: Ruiz-Sandoval, Garcı́a-Navarro,
Dobson-Stone, and Monaco. Administrative, technical, and
material support: Garcı́a-Navarro, Chiquete, Barrera-
Chairez, Rodrı́guez-Figueroa, and Pérez-Garcı́a. Study su-
pervision: Ruiz-Sandoval and Monaco.
Financial Disclosure: None reported.
Additional Contributions: Lea A. Filippone, BA, assisted
in mutation detection.
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cytosis: a new syndrome. Arch Neurol. 1968;19(4):403-409.
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