Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation.

Abstract

Autosomal dominant episodic ataxia type 2 (EA2) results from mutations of the CACNA1A gene. We describe EA2 with unusual features in a father and daughter with a novel CACNA1A mutation coding for Y248C. Both patients showed severe cerebellar atrophy in MRI and clinical signs of progressive spinocerebellar atrophy type 6. Most disabling were the very frequent episodes of ataxia with migraine (with aura in the father and without aura in the daughter) and nystagmus in our patients. Additionally, they suffered from ictal hyperhidrosis with acute hypothermia of the extremities. Lastly, the father presented with interictal chronic diarrhea not associated to a known primary gastrointestinal disorder. Both ictal hyperhidrosis and interictal diarrhea ameliorated upon acetazolamide intake, the typical treatment for EA2. The significance of these findings is discussed and the phenotype correlated to previously reported cases.

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Case study
Episodic ataxia type 2 showing ictal hyperhidrosis
with hypothermia and interictal chromic diarrhea
due to a novel CACNA1A mutation
D.I. Zafeirioua,*, F. Lehmann-Hornb, E. Vargiamia, E. Teflioudia,
A. Ververia, K. Jurkat-Rottb,*
a1st Department of Pediatrics, Aristotle University of Thessaloniki, Egnatia St. 106, 54622 Thessaloniki, Greece
bDepartment of Applied Physiology, University of Ulm, Germany
a r t i c l e i n f o
Article history:
Received 11 December 2007
Received in revised form
15 February 2008
Accepted 17 February 2008
Keywords:
Episodic ataxia type 2
CACNA1A gene
Acetazolamide
Migraine
Diarrhea
Hyperhidrosis
a b s t r a c t
Autosomal dominant episodic ataxia type 2 (EA2) results from mutations of the CACNA1A
gene. We describe EA2 with unusual features in a father and daughter with a novel
CACNA1A mutation coding for Y248C. Both patients showed severe cerebellar atrophy in
MRI and clinical signs of progressive spinocerebellar atrophy type 6. Most disabling were
the very frequent episodes of ataxia with migraine (with aura in the father and without
aura in the daughter) and nystagmus in our patients. Additionally, they suffered from ictal
hyperhidrosis with acute hypothermia of the extremities. Lastly, the father presented with
interictal chronic diarrhea not associated to a known primary gastrointestinal disorder.
Both ictal hyperhidrosis and interictal diarrhea ameliorated upon acetazolamide intake,
the typical treatment for EA2. The significance of these findings is discussed and the
phenotype correlated to previously reported cases.
ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.
1.Introduction
Episodic ataxia type 2 (EA2) is an autosomal dominant disor-
der characterized by paroxysmal ataxia and interictal nystag-
mus. The paroxysmal ataxia attacks may be accompanied by
vertigo, nausea, dysarthria, diplopia, tinnitus, dystonia, hemi-
plegia, and headache. Attacks can be triggered by stress, exer-
tion, caffeine, alcohol, and phenytoin and relieved by
acetazolamide. During the interictal period, patients may ini-
tially be asymptomatic, but eventually develop limb ataxia,
postural imbalance, myasthenia-like weakness, and interictal
gaze-evoked or downbeat nystagmus. Cerebellar atrophy with
progressive ataxia and forms of migraine are frequently pres-
ent in EA2.1,2
EA2 arises from mutations in the alpha 1A-subunit of the
brain P/Q-type calcium channel, Cav2.1, encoded by the
CACNA1A gene on chromosome 19p13.3
mainly result in premature truncations, however, missense
mutations have been described. Two allelic disorders with
phenotypic overlaps are hemiplegic migraine caused by
Cav2.1 missense mutations3and spinocerebellar ataxia type
6 (SCA6) caused by a polyglutamine expansion in the channel
EA2 mutations
* Corresponding authors. Tel.: þ30 2310 241845; fax: þ30 23920 63186.
E-mail address: jeff@med.auth.gr (D.I. Zafeiriou).
1090-3798/$ – see front matter ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejpn.2008.02.011
Official Journal of the European Paediatric Neurology Society
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european journal of paediatric neurology xxx (2008) 1–3
Please cite this article in press as: Zafeiriou DI et al., Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and
interictal chromic diarrhea due to a novel CACNA1A mutation, European Journal of Paediatric Neurology (2008), doi:10.1016/
j.ejpn.2008.02.011

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carboxy terminus.4We describe the clinical and genetic
features of two related patients with EA2 sharing a novel mu-
tation of the CACNA1A gene.
2. Case report
Our patients, a 7-year old daughter and her 35-year old father
were identified through a neurodevelopmental clinic. EA2
manifested at first and third year of life, respectively.
Ictal symptoms in both cases consisted of recurrent epi-
sodes of cerebellar ataxia accompanied by spontaneous hori-
zontal gaze-evoked nystagmus and migraine headache,
occasionallytriggeredbyphysicalstress(i.e.sleepdeprivation)
or emotional stress. The ictal migraine of the father addition-
ally showed facial hypoesthesia and left-sided hemiplegia
especially of the upper extremity. Both patients had ictal hy-
perhidrosis of the face and the extremities (especially of the
arms) which led to acute hypothermia of the extremities
with temperatures down to 35.5?C, however without signs of
cold-induced vasoconstriction (i.e. blue nails of fingers and
toes or signs of atrophy in the fingertips). The hyperhidrosis
was present for almost the whole duration of these episodes,
while heart rate and blood pressure were at the upper normal
limit for age. These episodes lasted 8–10 h, occurred every 2–3
weeks, and were resolved by sleep in both patients without
ever evolving to delirium or unconsciousness. None of the
patients had ictal vertigo, brainstem symptomatology or other
extracerebellar signs.
Interictally, both patients reported typical episodes of pure
migraine according to the IHS criteria: migraine with aura in
the father (mean frequency of the attacks twice a month
with a mean duration of 2 h) and simple migraine without
aura in the daughter (mean frequency once a month with
a mean durationof 1.5 h), which were unresponsive to parace-
tamolormephenamicacid andresolvedonlyaftervomitingor
fallingasleep.Therewasa significant overlapto theSCA6phe-
notype both morphologically, with severe cerebellar atrophy
in cranial MRI (Fig. 1) and clinically (mild baseline nystagmus
and mild slowly progressive baseline trunk ataxia without
fluctuations). The father also suffered from interictal chronic
abdominal cramping pain and diarrhea with liquid excre-
ments almost 2–3 times a day, which were not caused by a pri-
mary gastrointestinal disorder (i.e. Morbus Crohn and colitis
ulcerosa), which was excluded.
Genomic DNA was isolated from peripheral blood with
patients’ informed consent and CACNA1A was analyzed for
mutations. In exon 5, a novel base change, A743G (Fig. 2), cod-
ing for Y248C at the junction of S5 and the pore loop of domain
I of Cav2.1, was identified in both patients but not in the unaf-
fected mother. The amino acid substitution was not present in
149 control samples and is conserved all the Cav2 family, i.e.
Cav2.1, Cav2.2, and Cav2.3, in human, mouse, and rabbit spe-
cies. Testing for the CAG elongation coding for the polyglut-
amine expansion responsible for SCA6 was negative (R
Christodoulou, Institute of Genetics, Cyprus).
Acetazolamidewasgiventothedaughterinadoseof250 mg/
dandtothefatherinadoseof500 mg/d.Thistreatmentreduced
the frequency of attacks by more than 75% (follow-up period 15
months),withasimultaneousdecreaseoftheseverityanddura-
tion of the attacks; there were no more episodes of hemiplegic
migraine in the father, while the daughter experienced a de-
crease in her migraine attacks as well. Additionally, under treat-
ment, the hyperhidrosis disappeared completely in both father
and daughter. Lastly, acetazolamide decreased the frequency
of diarrhea in the father from 2.7 times per day to once every 3
weeks in the 6 months follow-up period.
3. Discussion
Y248C fulfills several criteria for a causative mutation, i.e. it is
notpresentin alargenumberofcontrols anditaffectsa highly
conserved residue in a channel known to be related to EA2. In
contrast to the majority of EA2 mutations which are nonsense
mutations, Y248C codes for a single amino acid exchange.
However, Y248C shares the association to the pore loop of do-
main I just like the Cav2.1 missense mutations H253Y, C271Y,
and G293R all of which cause EA2 also.5–7Like C271Y and
G293R,6,7Y248C shows prominent cerebellar atrophy and
Fig. 1 – MRI of 7-year-old daughter (a) and 37-year-old father (b) demonstrating atrophy of the cerebellar vermis
(predominately the anterior part) on T2-weighted imaging corresponding to the clinical SCA6-like phenotype.
european journal of paediatric neurology xxx (2008) 1–3
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Please cite this article in press as: Zafeiriou DI et al., Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and
interictal chromic diarrhea due to a novel CACNA1A mutation, European Journal of Paediatric Neurology (2008), doi:10.1016/
j.ejpn.2008.02.011

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SCA6-like symptoms even at the very young age of 7 years.
Therefore, the functional defect of Y248C may be similar to
that of C271Y and G293R which showed reduced Cav2.1 ex-
pression due to deficient channel membrane targeting, and
evidence of protein misfolding leading to reduced channel
function.6We concludethat the outermost amino acid residue
of S5, Y248, may contribute to the orientation of the pore loop
of domain I, and that the reduction of channel conductance
and channel trafficking together accelerates cerebellar atro-
phy. Therefore, the Cav2.1 pore mutations including Y248C
differ clearly from the many Cav2.1 nonsense mutations lead-
ing to a loss-of-function EA2 pathomechanism by haploinsuf-
ficiency only.
The phenotype in our patients differs from previous
reports by two features. One is the ictal hyperhydrosis with
hypothermia. While the presence of Cav2.1 channels in
sudomotoric synapses has not been demonstrated yet, these
sympathetic synapses are of the subthreshold kind8similar
synapses of which do express Cav2.1.9The fixed association
of hyperhidrosis with the EA2 attacks and the improvement
by EA2 medication, acetazolamide, strengthen a possible
association between Y248C and this symptom. The second
feature that is different in our patients is the interictal diar-
rhea. As the mechanism for neurotransmitter release of ace-
tylcholine in gastrointestinal submucosal neurons requires
Cav2.1,10it is thinkable that diarrhea may be associated with
the Cav2.1 mutation Y248C as well. This hypothesis is sup-
ported by the lack of other explanation for the diarrhea and
the observation that the symptoms improved under acetazol-
amide treatment, the classic EA2 therapy. We recommend to
examine the presence of these symptoms in EA2 patients
and, if present, to try acetazolamide for relief.
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Fig. 2 – Sequence of exon 5 around base A743 in control (a:
top) and patient (b: bottom). Note the A-to-G base change in
the patient which changes the triplet TAT to TGT coding for
a tyrosine to cysteine at position 248.
european journal of paediatric neurology xxx (2008) 1–3
3
ARTICLE IN PRESS
Please cite this article in press as: Zafeiriou DI et al., Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and
interictal chromic diarrhea due to a novel CACNA1A mutation, European Journal of Paediatric Neurology (2008), doi:10.1016/
j.ejpn.2008.02.011