Brief Communication

Journal of Child Neurology

25(7) 892-897
Congenital Ataxia, Mental Retardation, and ª The Author(s) 2010
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Dyskinesia Associated With a Novel DOI: 10.1177/0883073809351316
http://jcn.sagepub.com
CACNA1A Mutation

Lubov Blumkin, MD,1,2 Marina Michelson, MD,2,3

Esther Leshinsky-Silver,2,3,4 Sara Kivity, MD,1,2 Dorit Lev, MD,2,3 and
Tally Lerman-Sagie, MD1,2

Abstract
The CACNA1A gene encodes the pore forming alpha-1A subunit of neuronal voltage-dependant P/Q-type Ca2þ channels.
Mutations in this gene result in clinical heterogeneity, and present with either chronic progressive symptoms, paroxysmal events,
or both, with clinical overlap among the different phenotypes. The authors describe a seven year-old boy with mental retardation
and congenital cerebellar ataxia that developed dyskinesia at the age of a few months, and recurrent episodes of coma following
mild head trauma associated with motor and autonomic signs, from the second year of life. An extensive metabolic evaluation,
interictal electroencephalography (EEG), and muscle biopsy were normal. Brain magnetic resonance imaging (MRI) during one
of these episodes revealed edema of the right hemisphere and cerebellar atrophy. Genetic testing revealed a R1350Q mutation
in the CACNA1A gene. This is a novel de novo mutation.Congenital cerebellar ataxia can be a result of CACNA1A mutations,
especially when associated with recurrent unexplained coma.

Keywords
CACNA1A, coma, ataxia

Received August 20, 2009. Received revised September 15, 2009. Accepted for publication September 15, 2009.

The CACNA1A gene encodes the pore-forming alpha-1A
subunit of neuronal voltage-dependent P/Q-type Ca2þ
channels.1,2 Ca channels are abundantly expressed throughout
the nervous system with predominant expression in the cerebel-
lum and at the neuromuscular junction.1,3 The CACNA1A gene
contains glutamine-encoding CAG (cytosine-adenine-guanine)
triplet repeats. Expansion of the CAG repeats causes spinocer-
ebellar ataxia type 6, a dominantly inherited pure cerebellar
ataxia of late onset,4 but infantile onset of episodic symptoms
has been described.5 Different mutations of CACNA1A gene
result in familial hemiplegic migraine and episodic ataxia type
2.6 Some patients demonstrate an overlap between familial
hemiplegic migraine, episodic ataxia type 2, and spinocerebel-
lar ataxia type 6.7 Three patients with episodic ataxia type 2 and
fluctuating muscle weakness associated with mutations in
CACNA1A gene have been reported.8
Recently, the association of epilepsy with CACNA1A muta-
tions has been described.9-11 The seizures occurred either during
severe hemiplegic migraine attacks or as independent epileptic
events.
In 2000, Vahedi et al2 were the first to find a de novo
CACNA1A mutation in a patient with hemiplegic migraine
associated with coma. Fitzsimons and Wolfenden12
described, in 1985, a family with hemiplegic migraine who
developed brain edema and coma following minor head
trauma, and Kors et al13 found a CACNA1A mutation in this
family.13
We describe a patient with mental retardation and congeni-
tal cerebellar ataxia who developed a nonspecific dyskinesia at
the age of a few months, and recurrent episodes of coma fol-
lowing minor head trauma from the age of 1.5 years. Genetic
testing revealed a de novo CACNA1A mutation.
1
Pediatric Neurology Unit, Wolfson Medical Center, Sackler School of
Medicine, Tel- Aviv University, Holon, Israel
2
Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Sackler School of
Medicine, Tel- Aviv University, Holon, Israel
3
Institute of Medical Genetics, Wolfson Medical Center, Sackler School of
Medicine, Tel- Aviv University, Holon, Israel
4
Molecular Laboratory, Wolfson Medical Center, Sackler School of Medicine,
Tel- Aviv University, Holon, Israel
Corresponding Author:
Tally Lerman-Sagie, MD, Pediatric Neurology Unit, Wolfson Medical Center,
Holon, Israel 58100
Email: asagie@post.tau.ac.il

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Blumkin et al
Case Report
A 7-year-old boy was referred to our clinic at the age of
3 years, for evaluation of global psychomotor delay and
dyskinesia.
Medical History
The patient was born, with a normal pregnancy and delivery, to
healthy nonconsanguineous parents. A 2-year-old sister is
healthy. The neonatal period was normal.
Development
Motor development was significantly delayed from the begin-
ning: he rolled over at 12 months, sat unsupported at 24 months,
and crawled at 36 months. He started walking with the aid of a
walker at the age of 6 years, and presently at the age of 7 years
he cannot yet walk independently. Receptive language is better
than expressive. Cognitive functions are estimated at the mild
mental retardation level (IQ 60). He shows abnormal executive
functioning and extreme inattention with communicative skills
appropriate for his age.
Dyskinesias
At the age of 4 months, episodes of upward gaze deviation
appeared when the child was held upright. Later, horizontal
rhythmic head movements appeared and eventually disap-
peared gradually. At the age of 2 years he developed simple
motor stereotypies: hand flapping and head banging. Since
the age of 3.5 years he has manifested rare brief episodes
of upward gaze deviation that increase during stress. Motor
activity (ie, eating, talking, playing with toys) provokes tone
changes, mirror or nonspecific involuntary movements, and
head and hand tremor.
Cerebellar abnormalities consisting of nystagmus, head
titubation, and abnormal pursuit became prominent during the
first year of life. Hypotonia, drooling, dysarthria, dysdiadocho-
kinesis, dysmetria, terminal kinetic tremor, and atactic gait
became more prominent with time.
He also developed pyramidal signs including brisk deep
tendon reflexes, nonsustained ankle clonus and bilateral
Babinski reflexes.
Episodic Coma
The patient has had 4 episodes of coma since the age of
1.5 years. These episodes were always triggered by mild head
trauma induced by a fall. The events lasted a few minutes to
days and were characterized by loss of consciousness or severe
apathy and sleepiness immediately or 2 to 3 hours following the
head trauma. Some episodes were accompanied by autonomic
signs such as high fever and recurrent vomiting. Motor
abnormalities were seen during these episodes consisting of
intermittent tonic upward gaze deviation, dyskinetic limb
893
Figure 1. Midsagittal T2-weighted image shows atrophy of the
vermis.
movements, and unilateral or generalized weakness. On reco-
vering from the coma the hemiplegia could persist for a month.
Motor seizures appeared during the comatose episodes and
consisted of a lateral or upward gaze deviation, hemi-clonic
or hemi-tonic convulsions. The patient was treated with intra-
venous phenytoin in one of the seizure episodes.
He was extensively evaluated and the following tests were
normal: complete blood count, glucose, liver and renal func-
tions, cholesterol, triglycerides, electrolytes, blood PH, bicar-
bonate, protein, albumin, creatine kinase, lactate, ammonia,
amino acids, carnitine, TSH, T4, very long chain fatty acids,
biotinidase, urine amino and organic acids, cerebrospinal fluid
protein, glucose, lactic acid, neurotransmitters, pterins, and
folate metabolites. Fragile X was excluded. A muscle biopsy
revealed no histological abnormalities and normal activity of
the mitochondrial respiratory chain complexes. Interictal elec-
troencephalograms were normal, an ictal one, during the last
episode, depicted right-sided paroxysmal discharges.
Recurrent brain computed tomography (CT) scans were nor-
mal. The first brain magnetic resonance imaging (MRI) at the
age of 8 months was normal (not shown). The second study was
done during the last episode of coma at the age of 6 years and
reveled cerebellar atrophy and mild right hemisphere edema
(Figures 1 and 2).
Sequence analysis of the CACNA1A gene revealed a het-
erozygous mutation in exon 25: c.4049G > A, p.Arg1350Gln.
It changes a positively charged amino acid of the S4 segment
in the highly conserved transmembrane domain to neutral
amino acid and, according to polyphen prediction software, it
is possibly damaging to the protein. The positively charged
amino acid acts as the voltage sensor, which detects changes
in the membrane electric field. To the best of our knowledge,
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894
Figure 2. Coronal T2-weighted image demonstrates cerebellar
atrophy and mild right hemisphere edema.
this mutation has not been previously reported. This is a de
novo mutation because it was not found in both parents.
Discussion
Our patient shows a unique clinical presentation due to a novel
CACNA1A gene mutation. He presented with the known clin-
ical phenotype of recurrent episodes of coma following mild
head trauma and associated with seizures, and paroxysmal
motor and autonomic signs. However, he also manifested
unusual symptoms consisting of congenital ataxia, interictal
dyskinesia, and mental retardation with onset in the first years
of life.
Typically, disorders due to CACNA1A mutations present
with either chronic progressive symptoms, paroxysmal events,
or both, with much clinical overlap among the different
phenotypes1-13 (OMIM #183086 spinocerebellar ataxia,type
6; #108500 episodic ataxia, type 2; #141500 familial hemiple-
gic migraine, 1).
The age at clinical presentation has wide variability.
Spinocerebellar ataxia type 6 due to CAG repeats expansion,
presents with slowly progressive cerebellar ataxia and isolated
cerebellar atrophy usually beginning between 20 to 66 years
old. An inverse correlation is found between the CAG-repeat
number and the age at onset.14 Clinical variants with a parox-
ysmal course, such as episodic ataxia type 2 and benign parox-
ysmal torticollis of infancy, usually start earlier.7,15,16
Paroxysmal attacks of torticollis can be observed in infants
as young as 3 months.16 The mutations in episodic ataxia type
2 are mostly truncation, although missense mutations and even
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Journal of Child Neurology 25(7)
a CAG-repeat expansion have been reported.1,17Familial hemi-
plegic migraine is an additional phenotype characterized by
paroxysmal events of hemiplegia associated with migrainous
headaches and exclusively associated with missense mutations
of the CACNA1A gene.1,7 T666M is the most common CAC-
NA1A mutation, highly associated with the hemiplegic
migraine/progressive cerebellar ataxia phenotype.7,18
Recurrent coma related to CACNA1A mutation is a
rare phenotype and has been reported by several
authors.2,7,12,13,18-20 It can be the first symptom of the dis-
ease.12,13,18 Such severe attacks occur mostly in young individ-
uals at a mean age of 21 +16 years.18 The attacks are
characterized by a severe encephalopathy (confusion or coma),
high fever, prolonged hemiplegia, and sometimes seizures.
Brain neuroimaging demonstrates brain edema, although it can
be normal in the beginning of the attack. An ictal electroence-
phalography (EEG) demonstrates intermittent theta and delta
activity, predominantly over the affected hemisphere, and
cerebrospinal fluid shows sterile lymphocytic pleocyto-
sis.2,7,12,13,18-20 These signs can last weeks, and most patients
recover fully.18 The attack can be triggered by mild head
trauma, diagnostic procedures like cerebral or coronary
angiography, or physical activity.2,7,12,13,18-20 In a study by
Ducros et al, the most frequent mutation in patients with recur-
rent coma was T666M.18 However, there is no strict genotype-
phenotype correlation in CACNA1A disorders.13
The pathogenic mechanism of severe brain edema and
coma in patients with CACNA1A mutation is poorly under-
stood. There is not enough neuropathological data in these
patients except rare cases of death during the comatose episo-
des.13,19Tottene et al studied the functional consequences of
mutation S218L on human Ca2þ channels expressed in human
embryonic kidney cells and in neurons from S218L knock-in
mouse.21The study showed that the S218L mutation produces
a shift to lower voltages of the single channel activation,
which are insufficient to open the wild-type channel. In addi-
tion, this mutation affects the kinetics of inactivation of the
channel because of a much smaller extent of inactivation dur-
ing long depolarization and a much faster rate of recovery
from inactivation. They further demonstrated an increase of
spontaneous release at the neuromuscular junction and
enhanced glutamate release from cortical neurons in culture.
The authors assumed that these findings explained why a
weak depolarizing stimulus, such as minor head trauma,
which is without consequences in healthy individuals, is able
to initiate cortical spreading depression in familial hemiplegic
migraine-1 patients. They suggested that a longer duration of
cortical spreading depression, together with prolonged activa-
tion of NMDA receptors, can cause excessive accumulation of
intracellular Ca2þ or production of nitric oxide, arachidonic
acid, and reactive oxygen species, leading to damage of the
blood-brain barrier and enhancement of vasogenic and cyto-
genic edema.21
Recurrent episodes of ‘‘migraine coma’’ following mild
head trauma appeared in our patient at the very early age of
1.5 years. Severe hypotonia, drooling, nystagmus, head
 Table 1. Patients With CACNA1A Mutation, Comatose Episodes, and Developmental Abnormalities

Brain MRI Family

during history
Perinatal Age of onset of comatose Other Paroxysmal Cerebellar comatose CACNA1A of
Reference Patients period Motor delay episodes episodes: HM, EA MR Cerebellar signs atrophy episode mutation migraine
Fitzsimons III-12 Normal Did not walk until age 2 to 13 years: coma after head Since childhood, þ þ þ NI S218L þ
and Wolfen- 3 years trauma, hemiparesis usually after mild
den12; Kors head trauma
et al13
Vahedi et al2 1 Normal Did not sit until age 2.5 years; 7 years: stupor for 7 days, - þ þ þ Cortical De novo -
did not walk until age fever, hemiplegia for 10 days edema T1385C
7 years
Kors et al13 II-3 Normal Clumsy Adulthood: one episode of Headache attacks - Nystagmus dys- - - S218L þ
fluctuating level of conscious- with hemiplegia arthria, ataxic
ness, headache, hallucinations, and confusion gait
hemiplegia NI about age of
onset
III-6 Normal Hypotonic since birth; 16 years after head trauma: - - - - Mild cerebral S218L -
recurrent falls until age loss of consciousness, CSF edema
4 years pleocytosis, fever, brain edema
Death after 12 days
Wada et al7 III-3 Normal Walking from age 3 years 4 years: coma, fever, hemiple- - þ Nystagmus, þ ND T666M þ
gia, dystonic posture dysarthria,
ataxia
III-1 Walking from age 2 years, 7 years: coma, fever, hemiple- Hemiplegic - þ þ ND T666M þ
6 months gia for 3 weeks migraine from
12 years
Curtain et al20 1 Normal Always regarded as clumsier 5 years after mild head trauma: - - þ Cerebral Cerebral S218L -
than her sibs, this produced coma, fever, episodic chorea atrophy edema
numerous falls in early for a few months
childhood
de Vries 1 Normal At age 17 years is still not 2 years: atonic episodes fol- - þ Ataxia, athetotic - Hemispheric De novo -
et al24 able to walk lowed by loss of consciousness limb move- edema G5361T
ments,
tetraparesis
2 Normal þ 3 years, atonic episodes Hemiplegic epi- þ Ataxia - Normal De novo -
accompanied by loss of con- sodes from age G5361T
sciousness for 1 hour 10 years
Our patient 1 Normal Walks with walker from age 1.5 years after mild head Episodes of eye þ Severe cerebel- þ Brain hemi- De novo
7 years trauma: coma, fever, dyskinesia deviation and lar deficit, dys- spheric R1350Q
for a few days dyskinesia from kinesia, pyrami- edema
age 4 months dal signs

HM ¼ hemiplegic migraine; EA ¼ episodic ataxia; MR ¼ mental retardation; MRI ¼ magnetic resonance imaging; NI ¼ no information;ND ¼ not done; CSF ¼ cerebrospinal fluid; N ¼ normal; (-) ¼ no; (þ) ¼ yes.

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titubation, and abnormal pursuit—symptoms compatible with
congenital ataxia—appeared during the first year of life before
the onset of these episodes. The initial differential diagnosis
was disorders causing congenital ataxia.
The congenital ataxias are rare disorders characterized by
marked hypotonia, developmental delay followed by the
appearance of ataxia.22 They are predominantly nonprogres-
sive and can be caused by a developmental cerebellar abnorm-
ality due to different genetic defects, or can be a result of
different perinatal causes such as intrauterine infection, perina-
tal vascular event, or others.22,23 Congenital ataxia has not been
previously diagnosed in patients with CACNA1A mutations
although early developmental delay has been described.
We have found 70 cases of recurrent coma with hemiparesis
and autonomic signs related to genetically confirmed CAC-
NA1A mutations in the English literature.2,7,12,13,18-20,24,25
There is data regarding perinatal history and early development
in only 13 cases. Early motor development was delayed in 9
cases, with no history of perinatal problems,2,7,12,13,20,24 and
in 6 cases early symptoms were consistent with congenital
ataxia2,7,12,24 (Table 1). Kors et al reported a patient with a
CACNA1A mutation, a relative of patients with episodic coma,
who had hypotonia and clumsiness until the age of 4 years but
no paroxysmal episodes.13 We could not find any genotype-
phenotype correlation between patients with or without devel-
opmental problems, as well as an association with a family
history of migraine, age of onset of comatose episodes, and
severity and frequency of these episodes. It is interesting that
although most patients demonstrate a progressive cerebellar
atrophy, some patients, including our own, did not depict any
cerebellar abnormality on the initial brain MRI despite the clear
cerebellar signs.13,20,24 This can be attributed to microscopic
changes in the cerebellar cells that have previously been
described in patients with congenital ataxias.22Patients with
other CACNA1A mutation phenotypes and a paroxysmal
course can demonstrate interictal cerebellar deficits with no
cerebellar atrophy on brain MRI.26 These findings indicate a
functional cerebellar defect before the onset of the neurodegen-
erative process or a low sensitivity of conventional neuroima-
ging in diagnosis of early cerebellar damage.
It is not well understood how mutations in CACNA1A cause
clinical symptoms of developmental delay and early cerebellar
dysfunction compatible with congenital cerebellar ataxia.
Expression of CACNA1A is particularly high in Purkinje and
granule cells.27 Mice that completely lack this neuronal cal-
cium channel are born alive but have severe ataxia and die soon
after birth.27 Careful neuroanatomical studies in mice with
calcium-channel mutations have shown a failure of appropriate
arborization of Purkinje cells and migration of granule cells.
These findings are consistent with the dystrophic swellings in
granule cells found by Kors et al in the brain of a patient who
died during a comatose episode.13
Ictal dyskinesia has been reported in patients with CAC-
NA1A mutations and coma. However, interictal dyskinesia
starting in the first year of life is very rare. Interictal chor-
eoathetosis has been described by de Vries et al24 and dystonia
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Journal of Child Neurology 25(7)
has been reported in 2 patients with episodic ataxia 2 in their
fifth decade.28
Mental retardation has been previously described in patients
harboring CACNA1A mutations.6,19,29 It is infrequent in
patients with familial hemiplegic migraine29 but can be com-
mon in patients with recurrent coma. Cognitive dysfunction has
been described in 12/21 patients.2,7,12,13,19,20,24,25,30 The sever-
ity of mental dysfunction varies from profound/severe mental
retardation2,20 to mild or even normal cognitive function, but
less than in other family members.12,30 Different types of muta-
tions have been found with no genotype-phenotype correlation.
It is not clear whether mental retardation is secondary to
repeated neuronal damage caused by the attacks of hemiplegic
migraine with or without coma, or is an underlying neuronal
abnormality due to dysfunction of the CACNA1A calcium chan-
nel. Analysis of the published cases and medical history of our
patient argues in favor of the latter option. In most patients with
CACNA1A mutations, the cognitive dysfunction appeared
before the onset of the hemiplegic and comatose attacks29 and
a few patients never had any paroxysmal episodes at all.29 On the
other hand, Kors et al described 3 relatives with CACNA1A
mutation who developed cognitive decline in a stepwise fashion,
with gradual deterioration after onset of the comatose attacks.19
We can conclude that patients with CACNA1A mutations and
paroxysmal episodes can have early onset developmental delay
and subsequent mental deterioration.
Conclusions
CACNA1A mutations present with a wide clinical spectrum.
Congenital ataxia, mental retardation, and dyskinesia can be
the presenting signs of CACNA1A mutations. Paroxysmal epi-
sodes associated with impaired consciousness, autonomic fea-
tures, and mixed motor signs should raise the suspicion of
CACNA1A mutations. In these cases, a family or individual
history of migraine attacks is not mandatory.
Declaration of Conflicting Interests
The authors declared no conflicts of interest with respect to the author-
ship and/or publication of this article.
Funding
The authors received no financial support for the research and/or
authorship of this article.
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