Epilepsia, 46(8):1256–1263, 2005
Blackwell Publishing, Inc.
C 2005 by the International League Against Epilepsy
Familial Temporal Lobe Epilepsy as a Presenting Feature
of Choreoacanthocytosis
∗ Abdullah Al-Asmi, ∗ An C. Jansen, ∗ AmanPreet Badhwar, ∗ François Dubeau,
∗ Donatella Tampieri, †Chaim Shustik, ∗ Suha Mercho, ∗ Ghislaine Savard, ‡Carol Dobson-Stone,
‡Anthony P. Monaco, ∗ Frederick Andermann, and ∗ §Eva Andermann
∗ Department of Neurology and Neurosurgery, McGill University, and the Montreal Neurological Hospital and Institute,
and †Department of Medicine (Hematology), McGill University and the Royal Victoria Hospital, Montreal, Quebec, Canada;
‡The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; and §Department of Human
Genetics, McGill University, Montreal, Quebec, Canada
Summary: Purpose: Choreoacanthocytosis (ChAc) is an autosomal recessive disorder caused by mutations in VPS13A on
chromosome 9q21 and characterized by neurodegeneration and
red cell acanthocytosis. Seizures are not uncommon in ChAc but
have not been well characterized in the literature. We report two
ChAc families in which patients presented with temporal lobe
epilepsy.
Methods: Detailed medical and family histories were obtained. EEG, video-telemetry, brain magnetic resonance imaging
(MRI) with volumetric studies of amygdala and hippocampus,
as well as neuropsychological testing were performed. Blood
smears were examined for acanthocytosis. Mutation analysis of
VPS13A was carried out in five patients.
Results: Six patients in three sibships were initially seen
with seizures. Age at seizure onset ranged from 22 to 38
years. Seizures preceded other clinical manifestations of ChAc
by ≤15 years. The epileptic aura consisted of a sensation of
déjà-vu, fear, hallucinations, palpitations, or vertigo. EEG with
video-telemetry showed epileptiform discharges originating either from one or both temporal lobes. Epilepsy was generally
well controlled, but some patients had periods of increased
seizure frequency requiring treatment with multiple antiepileptic
drugs (AEDs). Both families shared a deletion of exons 70–73
of VPS13A, extending to exons 6–7 of GNA14.
Conclusions: Temporal lobe epilepsy may be the presenting feature of ChAc and may delay its diagnosis. Epilepsy in
ChAc patients represents a challenge, because seizures may
at times be difficult to control, and some AEDs may worsen
the involuntary movements. Mutations in VPS13A or GNA14
or both may be associated with clinical features of temporal
lobe epilepsy. Key Words: Familial temporal lobe epilepsy—
Chorea-acanthocytosis—Movement disorders.
Acanthocytosis is a common feature of a genetically and
phenotypically heterogeneous group of neurodegenerative
disorders including McLeod syndrome, choreoacanthocytosis, and abetalipoproteinemia (1,2). Choreoacanthocytosis (ChAc; MIM 200150) or Levine–Critchley syndrome
is a rare familial neurodegenerative disorder, initially described in the late 1960s (3–5). Its clinical expression is
variable and includes orofacial and buccal dyskinesiae,
tics, chorea, dysarthria, parkinsonian features, cognitive
dysfunction, psychiatric manifestations, axonal neuropathy, increased creatine kinase (CK) levels, and seizures,
with onset of symptoms in the third to fifth decade (3–
9). Wet peripheral blood smears show acanthocytosis
(10).
Although ∼42% of ChAc patients have seizures (2),
the nature of the epileptic syndrome(s) associated with
this disorder is still not characterized in the literature.
In the majority of ChAc families, the disease is inherited as an autosomal recessive trait, caused by mutations
in the VPS13A (vacuolar protein sorting 13A, formerly
known as CHAC) gene on chromosome 9q21, encoding
for chorein (11,12). A mutation in the same gene has
been identified in an autosomal dominant ChAc family
(13).
Chorein may play an important role in protein sorting
and trafficking, with dysfunction impairing plasma membrane structure (11,12).
We report six patients from two French-Canadian kindreds with ChAc, who were first seen with temporal lobe
epilepsy.
Accepted April 5, 2005.
Address correspondence and reprint requests to Dr. E. Andermann
at Neurogenetics Unit, Montreal Neurological Hospital and Institute,
3801 University Street, Montreal, Quebec, Canada H3A 2B4. E-mail:
eva.andermann@mcgill.ca
Present address of Dr. Al-Asmi: Department of Medicine, Sultan
Qaboos University, Al-Khoud (Muscat), Oman.
Dr. Jansen and Ms. Badhwar contributed equally to this work.
1256
METHODS
Detailed medical and family histories, as well as medical records of affected family members, were obtained.
Six patients were examined and investigated. Three had
continuous EEG and video-telemetry recording. Four had
volumetric studies of the hippocampus and amygdala. In
five patients, blood smears were tested for the presence
of acanthocytes, and peripheral blood was drawn for genetic studies. These tests were not performed in patient
3, who died before the family was investigated in detail.
The probands in both families were screened for mutations in VPS13A by denaturing high-performance liquid
chromatography. Presence of the EX70 73del allele was
confirmed in each affected family member by polymerase
chain reaction (PCR) amplification across the deletion
breakpoint junction.
RESULTS
Patients 1 to 4 come from two consanguineous sibships
in the same kindred, originating from the Lac St-Jean region of Quebec, an area with a small founding population.
Four additional family members had epilepsy, and many
had movement disorders, especially tics, and psychiatric
problems, including panic attacks, obsessions, aggressive
conduct, and depression. The second family originated
from Portneuf County in the province of Quebec and, although no consanguinity was evident, three of the four
grandparents were born in the same village.
The clinical features and results of investigations are
summarized in Table 1. A pedigree of each family is shown
in Fig. 1.
Patient 1
The proband of family 1, a 47-year-old college graduate,
started having seizures at age 26 years. Her aura consisted
of a rising epigastric sensation and déjà-vu. This was at
times followed by loss of contact with oral and manual
automatisms, occasionally resulting in secondary generalization. Initially, she had only two or three attacks per
year. At age 27 years, phenobarbital (PB) was introduced,
but was substituted with carbamazepine (CBZ) at age 34
years because of side effects including memory impairment and drowsiness. She developed abnormal orofacial
movements at age 37 years. The abnormal movements
were initially thought to be due to CBZ toxicity, and she
was started on gabapentin (GBP). Seizure frequency increased, and CBZ was reintroduced. At age 40 years, CBZ
was switched to lamotrigine (LTG). Although seizures
were better controlled, she continued to have frequent
auras. This led to the addition of clobazam (CLB), with
excellent seizure control and some improvement in the involuntary movements. At age 44 years, significant deterioration of her seizure control, movement disorder, behavior, and memory led to the addition of topiramate (TPM),
1257
followed by increased dysarthria and dysphagia. LTG and
TPM were then replaced by phenytoin (PHT). Two months
later, she reported significant improvement in her movements, with little change in seizure severity or frequency.
She showed a childish demeanor, inappropriate smiling,
apathy, distractibility, indifference, and concrete thinking.
Cranial nerves were normal, except for slight impairment
of ocular saccades and pursuit. She had abnormal sighing.
Speech was hesitant and dysarthric, with a spastic quality.
She had orofacial and lingual dyskinesia, as well as intermittent mild to moderate choreiform movements of trunk
and limbs, which she incorporated into apparently purposeful gestures. She had motor impersistence of tongue
protrusion and of handgrip. Gait was abnormal, with occasional buckling of the knees and tripping, decreased
associated movements, but no ataxia.
During continuous EEG and video-telemetry recording,
six of her habitual seizures, all of right temporal origin,
were recorded. Interictal recording showed infrequent independent bitemporal epileptiform discharges, as well as
intermittent theta and delta activity over the same regions.
The background alpha rhythm was at 8 Hz, reacting well
to eye opening and closure.
MRI showed bilateral caudate atrophy and signalintensity changes in the striatum. Volumetric studies revealed right hippocampal atrophy and normal amygdalar
volumes.
Her full-scale IQ scores (WAIS-R) were in the lowaverage range, with a minimal discrepancy between Verbal and Performance IQ scores, in favor of the Verbal. She
was left-handed, with atypical left-ear advantage on dichotic listening. Attention, concentration, and memory for
verbal and nonverbal material and visuoperceptual ability were severely deficient. Word fluency and Wisconsin
Card Sorting tests were suggestive of poor frontal lobe
function. Bimanual sequential tapping and motor pinch
were impaired.
Nerve-conduction studies and electromyogram (EMG)
were in keeping with a mild axonal neuropathy; somatosensory evoked potentials and muscle biopsy were
normal. She had no retinitis pigmentosa, nystagmus, or
Kayser–Fleischer rings.
Genetic testing for Huntington disease, oculopharyngeal muscular dystrophy, and myoclonus epilepsy associated with ragged-red fibers (MERRF) was negative.
Maximal serum creatine kinase (CK) level was 1,237 U/L
(normal range, 40–150 U/L). Blood smears prepared from
fresh blood showed 4% acanthocytes (abnormal levels,
>1–2%) and a few echinocytes.
Patient 2
Patient 2 is the 40-year-old maternal first cousin of the
proband, with a college degree in architectural technology. Pregnancy, delivery, and developmental milestones
were normal. Seizures started at age 26 years. Attacks
Epilepsia, Vol. 46, No. 8, 2005
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EPILEPSY IN CHOREOACANTHOCYTOSIS
1
2
3
4
5
6
No
No
No
No
Yes
No
Parkinsonism
Neuropsychological testing
No
No
No
No
No
No
Dystonia
21
14
22
16
11
4
Yes
Yes
Yes
Yes
Yes
No
Movement
disorder
Yes
Yes
No
Yes
Yes
Yes
Dysarthria
Disease
duration (y)
39
32
36
38
36
–
Onset
age (y)
Tics
Yes
Yes
No
Yes
Yes
Yes
44
37
37
38
n/a
n/a
Yes
Yes
Yes
Yes
Yes
Yes
Seizures
Psychiatric disorders
26/right temporal
26/bitemporal
22/unknown
23/left temporal
30/right temporal
38/unknown
Onset age/origin
Tongue
Normal - age 41
Normal - age 37
Normal - age 37
n/a
Normal - age 35
Normal - age 41
Brain CT
Brain MRI
Yes - EMG
Yes - EMG
Yes - EMG
No - EMG
Yes - exam
Yes - exam
Neuropathy
Yes
Yes
No
No
Yes
No
Vocalizations
Caudate atrophy, R HA
Caudate atrophy
Caudate atrophy
Caudate atrophy
Asymmetric TH
n/a
No
No
No
No
No
No
Myopathy
Biting/protrusion
Thrusting
Normal
Normal
Biting
Normal
Bitemporal epileptiform
Bitemporal epileptiform
Bitemporal slowing
Right temporal epileptiform
Bitemporal R>L
Slow background rhythm
Interictal EEG findings
Emotional flattening, planning problems
Emotional flattening, planning problems
Confusion, paranoid ideation, flat mood, verbally aggressive
Disinhibition, impulsivity, emotional lability
Major depression with paranoid psychosis, flat mood
None
Drooling
Jaw posturing, eye blinking, sighing, shrugging shoulders, rapid retrocollis
Throat clearing, clicking, lip smacking, sucking, grinding teeth
Rapid tic-like movements involving trunk and right arm
Eye blinking, vocal and facial tics
Perioral movements - tics or athetotis
No
Age at testing (y)
Yes
Yes
No
Yes
Yes
No
Dysphagia
FS IQ low average range, impaired memory, frontal lobe dysfunction
FS IQ low average range, impaired memory, frontal lobe dysfunction
FS IQ low average range, impaired memory, frontal lobe dysfunction
FS IQ borderline range, impaired memory, frontal lobe dysfunction
n/a
Memory problems
Yes
No
Yes
Yes
Yes
No
Chorea
47
40
44
39
41
42
Age last
examined (y)
n/a, not available; (y), years; EEG, electroencephalography; –, not applicable; R, right; L, left; EMG, electromyogrophy; FSIQ, full scale IQ; TH, temporal horn; HA, hippocampal atrophy.
Patient
1
2
3
4
5
6
Patient
26
26
22
23
30
38
First
symptoms (y)
A. AL-ASMI ET AL.
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Epilepsia, Vol. 46, No. 8, 2005
1
2
3
4
5
6
Patient
TABLE 1. Clinical features and results
1258
Family 1
1259
Family 2
P6 P5
P1
=
P3
P4
P2
Male
Female
Consanguineous
marriage
Deceased
Chorea-acanthocytosis
FIG. 1. Pedigrees.
were primarily nocturnal, occurring 3 to 4 times per year.
Auras consisted of seeing the face of the devil making
fun of him, and these were usually followed by generalized tonic–clonic seizures. CBZ caused skin rash, PHT
led to gum hypertrophy, and valproic acid (VPA) caused
weight gain. Tics worsened with LTG and did not improve
with risperidone and haloperidol. They did, however, improve with benztropine, quetiapine, and lorazepam (LZP).
Seizures are currently well controlled with a combination
of PHT, VPA, and clonazepam (CZP).
Vocal and buccal tics started at age 32 years and included grimacing; pursing, and biting his lips, tongue, and
cheeks; grinding teeth; throat-clearing; clucking, sucking
noises; and explosive sounds. He had a tendency to protrude his tongue, to frown and blink. He had dysphagia for
solids and liquids and difficulty chewing. The abnormal
movements were always present, but increased with anxiety and fatigue. He was able to suppress them transiently,
but this always resulted in a rebound increase.
During 24-h continuous EEG video-telemetry recording, he had two of his habitual seizures, one of right temporal and the other of left temporal origin. Interictal activity consisted of infrequent independent bitemporal spikes.
Background rhythm showed 10-Hz normal alpha.
Serial MRIs showed progressive atrophy of the head of
the caudate nucleus bilaterally, resulting in focal dilatation
of the frontal horns of the lateral ventricles (Fig. 2). A
progressively increasing amount of iron storage occurred
at the level of the pallidal nuclei and anterior commissures.
Volumetric studies of hippocampi and amygdalae were
normal.
Full-scale IQ score was in the low-average range. Mild
word-finding deficit was noted on a naming task. Frontal
lobe functions (Wisconsin Card Sorting, Word Fluency,
and Stroop test) showed adequate mental flexibility but
significant deficiency in problem solving.
EMG and nerve-conduction studies were in keeping
with mild sensorimotor peripheral neuropathy. Maximal
serum CK level was 285 U/L. Peripheral blood wet smear
showed 3–5% acanthocytes.
FIG. 2. Magnetic resonance imaging findings in choreoacanthocytosis. Axial magnetic resonance images at the level of
the striatum in patient 2, showing the atrophic caudate nuclei
(arrows) with secondary dilatation of the anterior horn of the lateral
ventricles.
Patient 3
Patient 3 was the 44-year-old brother of the proband.
Seizures started at age 22 years and were characterized
by an aura of vertiginous sensation and nausea, usually
followed by loss of contact and secondary generalization. Because PHT and PB were insufficient to control
the seizures, CBZ and VPA were added. At age 38 years,
status epilepticus developed, and GBP was added. He then
remained seizure free until age 41 years, when he had a
flurry of convulsive seizures following a small reduction
of CBZ. He died at age 44 years, most likely of suffocation
during a seizure.
At age 28 years, he was diagnosed to have systemic
lupus erythematosus (SLE), based on arthritis, facial skin
lesions, and elevated anti-DNA and antinuclear antibody
(ANA) levels. Repeated biopsy of the facial skin lesion failed to show evidence of cutaneous lupus. He was
treated with plaquenil and maintenance prednisone at various dosages. At age 31 years, he had nonautoimmune
hemolytic anemia and splenomegaly. No causes for anemia were found, but he underwent splenectomy with subsequent improvement in hemoglobin levels.
He had long-standing abnormal brisk involuntary movements, described as ticlike, involving the trunk and the
right arm. At age 36 years, choreiform movements, affecting mainly the upper limbs, were noted. No vocal tics
were reported.
EEGs showed bitemporal slow waves in the theta range
with right-sided predominance, but interictal epileptic discharges were absent. MRI of the brain showed caudate
atrophy. Volumetric studies of the temporal structures
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EPILEPSY IN CHOREOACANTHOCYTOSIS
A. AL-ASMI ET AL.
were not performed. Neuropsychological assessment at
age 37 years revealed Verbal and Performance IQ scores
in the low-average range. Attention, concentration, and
constructional skills were poor. Memory was deficient for
immediate and delayed recall in both verbal and nonverbal modalities. Verbal fluency, mental flexibility, abstract
thinking, and planning were deficient, pointing to frontal
lobe dysfunction. Serial drawing showed perseveration.
Spoken language was normal, except for stuttering when
stressed. Written language and simple calculations were
poor. Fine-motor performance was deficient.
Over the years, serum CK levels were consistently elevated, in the range of 300 to 1,660 U/L (normal range, 22–
198 U/L). Initially, these were attributed to lupus myositis. Nerve-conduction studies revealed mild sensorimotor
axonal polyneuropathy, with no evidence of myopathy.
Acanthocyte levels and mutation analysis were not performed because the diagnosis of ChAc in the family was
made only after the patient died.
Patient 4
Patient 4 is the 40-year-old sister of the proband, who
was employed as a social worker. Seizures started at age
23 years, with an aura of déjà-vu, fear, palpitations, and
urinary urgency, at times followed by loss of contact. Attacks were short lasting and occurred daily. She was initially treated with CBZ and CLB, later changed to GBP
and VPA, but full seizure control was never achieved.
At age 33 years, frequent panic attacks developed, and
her behavior changed. She displayed motor restlessness,
and winked and laughed inappropriately. Facial and vocal tics, hyperkinetic dysarthria, and dystonic oro-lingualfacial-laryngeal movements were noted since age 38 years.
During repeated 24-h continuous EEG video-telemetry
studies, 12 seizures were recorded, all originating from the
left temporal lobe, except one with apparent bitemporal
onset. Interictal recordings were mostly normal, but on
two occasions showed slow or epileptiform activity over
the right anterior temporal region.
MRI of the brain showed caudate atrophy. Volumetric
studies of hippocampi and amygdala were within normal
limits. However, the left hippocampus was smaller than
the right.
Intellectual functions were within the borderline range,
which presented a notable decline from the estimated
premorbid level of functioning. Memory for both verbal
and nonverbal material was severely impaired. Confrontational naming was extremely poor.
EMG and nerve-conduction studies were normal. Her
peripheral fresh blood smear showed acanthocytes.
Patient 5
The proband of the second family, a 41-year-old man,
was the product of a normal pregnancy and delivery. The
family history was positive for mental retardation in two
maternal aunts, schizophrenia in a paternal uncle, and reEpilepsia, Vol. 46, No. 8, 2005
active depression in his father. He finished high school
and had 2 years of educational training, with average results. He worked as a mechanic until age 34 years. At
age 16 years, he had a minor head injury. He was first
seen with nocturnal generalized tonic–clonic seizures at
age 30 years. Later, his seizures were characterized by
an aura of rising epigastric sensation, followed by loss of
consciousness and falls. He was treated successfully with
CBZ. At age 36 years, he had a generalized tonic–clonic
seizure with a prolonged postictal period for which reason, CBZ was replaced by PHT and CLB. For unknown
reasons, the antiepileptic treatment was then discontinued,
leading to a cluster of seizures at age 38 years, at which
point CBZ was reintroduced in combination with CZP. He
has had only a few minor seizures since.
Since age 36 years, he progressively deteriorated, and
facial dyskinesia, tremor of hands and head, gait difficulties with frequent falls, dysarthria, dysphagia, and drooling developed. At age 40 years, he has marked hypophonia
and severe dysarthria. Movement disorders include perioral movements, some of which resemble tics, as well as
athetosis and choreiform movements of trunk and limbs,
pill-rolling tremor, and parkinsonian features. He has selfmutilation of tongue and lips. Gait is wide-based with impaired balance.
Early EEGs showed epileptiform activity originating
from the right temporal region, as well as slowed background activity. Recent EEGs were normal or showed mild
intermittent disturbance of cerebral activity over the right
temporal lobe.
MRI of the brain at age 37 years showed minimal
asymmetry of the temporal horns, with the right being
larger than the left. Volumetric studies were not performed.
Blood smears showed 5.5% acanthocytes.
Patient 6
Patient 6, the 42-year-old brother of patient 5, started
having seizures at age 38 years. His aura consisted of a
sensation of confusion, followed by extension of the right
arm with secondary generalization. Postictally, he could
remain confused for weeks. Attacks tended to be clustered,
and no clear triggers were known. At age 40 years, he
had status epilepticus, complicated by rhabdomyolysis,
in the context of viral illness and low AED levels. He
has experienced ∼10 attacks over a 4-year period. He was
treated with PHT in monotherapy until age 41 years, when
CBZ was added. He tolerated his medication well and
continued to work as a clerk in a grocery store. He recently
started to experience memory problems. At age 42 years,
he has hypersalivation, nonfluent speech, especially when
stressed, and absent deep tendon reflexes.
Computed tomography scan of the brain was normal
and EEGs showed no epileptic discharges. Fresh blood
smears showed 5–10% acanthocytes, as well as spherocytes.
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1260
Genetic results
Five of six affected individuals in both families (test not
performed in patient 3) were found to be homozygous for
a gross deletion spanning exons 70–73 of VPS13A, as well
as exons 6–7 of the contiguous seven-exon gene encoding
for alpha 14 subunit of the guanine nucleotide-binding
protein (GNA14, OMIM ∗ 604397) that lies in a tail-totail arrangement with VPS13A. Furthermore, all patients
with this deletion shared a common haplotype in the same
region.
DISCUSSION
Choreoacanthocytosis is a rare familial neurodegenerative disorder with a heterogeneous phenotype. Its clinical presentation may vary among different families, as
well as among members of the same family (14). Seizures
are among many neurologic manifestations of ChAc. Although they usually occur after the onset of involuntary
movements or late in the course of the disease (2,5,10),
seizures can be the presenting symptom in ChAc (14–
17) and may delay the diagnosis. The seizure onset in
all our patients preceded other clinical manifestations by
≤15 years (median, 13; mean, 10.8).
In family 1, it took 11 years to reach the diagnosis in
the proband, and 6 years in her cousin, patient 2, who had
previously been diagnosed to have Tourette syndrome.
Patient 3 was diagnosed to have systemic lupus erythematosus. However, it is likely that his clinical presentation was more in keeping with ChAc. He had nonautoimmune hemolytic anemia and splenomegaly, which have
also been described in other ChAc patients (5,18). Patient 5
was considered to have Wilson disease for years before he
was diagnosed to have ChAc. To our knowledge, only five
ChAc patients are reported in the English literature, with
seizure onset before the onset of involuntary movements
(14,16,17,19,20).
The nature of the epileptic syndrome(s) in ChAc is not
well characterized in the literature, although ∼42% of patients have seizures at one point in the course of their disease (2,10). All six patients in our series had either no or
infrequent epileptiform discharges originating either from
one or independently from both temporal lobes. Telemetry showed right temporal seizure onset in patient 1 and
5, left temporal onset in patient 3, and bitemporal independent foci in patient 2. Interictal temporal epileptiform
abnormalities were seen in patients 1, 2, 4, and 5. Patient
3 had slow activity over both temporal regions.
Although the seizures in these patients were eventually
controlled, they tried on average more than four different
AEDs before achieving control, and they subsequently
remained on average taking more than two AEDs. The
need for multidrug therapy for the treatment of epilepsy
in ChAc patients has previously been described (14,17).
Medical management of epilepsy in ChAc patients is
complicated by the fact that the comorbid involuntary
1261
movements may be worsened by some of the AEDs. AEDs
are known to have a potential influence on involuntary
movements in patients with underlying movement disorders (21–25). This was found with CBZ and LTG for
patient 1 and with LTG for patient 2. CBZ is known to induce various movement disorders, not necessarily related
to toxic levels (21,22,24). This can occur in an idiosyncratic and transient fashion and does not always necessitate drug discontinuation (21). Reversible LTG-induced
tic disorder has also been reported (25). For patient 2, tics
improved after replacement of LTG with VPA.
Epilepsy surgery is not an option in ChAc patients,
mainly because of the progressive nature of the underlying disease.
The occurrence of temporal lobe epilepsy in ChAc families adds ChAc to the list of single-gene disorders associated with a familial temporal lobe epilepsy (FTLE)
phenotype. The FTLEs can be divided into mesial (FMTLE) and lateral (FLTLE) forms (26). In FMTLE, two
subgroups have been described: those with benign outcome (27,28) with frequent déjà-vu and overrepresentation of migraine, and those with clinical features that are
indistinguishable from those of sporadic MTLE, including
patients with refractory seizures, history of febrile convulsions, and frequent hippocampal atrophy (29,30). Two
explanations exist for the different FMTLE phenotypes:
the benign phenotype was found in population-based twin
studies (27,28), whereas the more severe phenotype was
identified in hospital-based series of patients investigated
for epilepsy surgery (29,30). Both these phenotypes have
been found in the same families, suggesting that they are
not necessarily genetically distinct. However, evidence
exists for involvement of more than one gene (31) and
possibly complex inheritance (32) in most families with
FMTLE. Hippocampal atrophy has been demonstrated in
family members of FMTLE patients who have not developed seizures, suggesting that hippocampal atrophy per se
might also have a genetic basis (33).
FLTLE is characterized by auditory auras, ictal aphasia, and at times visual hallucinations. The seizures are
easily controlled and often remit spontaneously. Developmental abnormalities in the neocortical aspect of the
temporal lobes have been described, with no clear signs
of hippocampal atrophy (34). Mutations in LGI1 on chromosome 10q24 have been identified in several families
(35–38).
Although our ChAc patients have many symptoms of
TLE, they do not clearly fit any of the FTLE syndromes
previously described. The prognosis in our families was
worse than is usually the case in FTLE. Seizures were more
difficult to control, and cognitive functioning deteriorated,
resulting in loss of autonomy.
It still remains unclear why epilepsy develops in
ChAc patients, and the anatomic substrate for the
epilepsy in ChAc requires further study. Unlike many
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EPILEPSY IN CHOREOACANTHOCYTOSIS
A. AL-ASMI ET AL.
neurodegenerative disorders with diffuse histopathologic
changes and generalized seizures, ChAc causes focal
epilepsy, most frequently of temporal lobe origin. Autopsy
studies in ChAc showed that the abnormal histopathologic
findings in the central nervous system were mainly confined to the striatum, where the putamen and caudate nuclei showed moderate to severe atrophy, correlating with
the involuntary movements. Lesions or focal changes in
the temporal lobe structures have never been mentioned
in autopsy studies of ChAc patients with epilepsy (39–
42). MRI showed discrete temporal lobe asymmetry in
three of our six ChAc patients (patients 1, 4, and 5), and
only one had significant hippocampal atrophy. It is possible that ChAc represents another example of pseudotemporal epilepsy (43). Furthermore, a subcortical origin of
the epileptic activity cannot be entirely excluded. Further
studies of the expression pattern and function of chorein,
the VPS13A gene product, might shed light on the epileptogenesis of ChAc.
Apart from the relatively long time between onset of
seizures and the development of involuntary movements,
the phenotype in our ChAc patients was similar to that in
the patients previously reported (1,2,10,16).
Parental consanguinity, the finding of a common haplotype, and a shared deletion mutation in both families, all
suggest a founder effect in the French-Canadian population. Routine testing for the exon 70 to exon 73 deletion of
VPS13A in suspected ChAc cases may therefore be worthwhile in this population. Mutations in VPS13A or GNA14
or both may be associated with the clinical features of
FTLE. To date, no clear evidence links the GNA14 gene
either to ChAc or to TLE. Because five of five patients
with deletions of exons 70 to 73 of VPS13A and exons 6
and 7 of GNA14 had seizures as compared with only 42%
in ChAc patients with mutations of VPS13A alone (2),
we hypothesize that this particular deletion may be more
strongly associated with the epilepsy phenotype. The high
prevalence of epilepsy in patients with deletions of both
VPS13A and GNA14 may suggest a contiguous gene syndrome, as seen, for example, in Miller–Dieker syndrome
(44) and tuberous sclerosis with polycystic kidney disease
(45).
In conclusion, ChAc is a familial neurodegenerative
disorder with various clinical presentations, which may
represent a clinical diagnostic challenge, especially when
presentation is atypical. The diagnosis should be considered in patients who have both seizures and a movement
disorder, have one and later develop the other, or have a
family history of both movement disorders and epilepsy.
We have shown that patients with ChAc have a tendency
to develop TLE and that this may be the presenting feature. The treatment of epilepsy in ChAc patients represents
another challenge, because seizures may at times be intractable, and some AEDs may worsen the involuntary
movements.
Epilepsia, Vol. 46, No. 8, 2005
Acknowledgment: We thank Dr. A. Sano for performing haplotype analysis on patient 4, and Dr. E. Kobayashi for her helpful comments on the familial temporal lobe epilepsies. A.J. was
funded by the Fondation Belge de la Vocation/Belgische Stichting Roeping, and she is currently a recipient of a postdoctoral
fellowship from the Savoy Foundation for Epilepsy Research.
C.D.-S. was supported by a Wellcome Trust Prize Studentship.
A.P.M. is a Wellcome Trust Principal Research Fellow. E.A. was
a recipient of an operating grant from the Canadian Institutes of
Health Research (CIHR).
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EPILEPSY IN CHOREOACANTHOCYTOSIS