close

Вход

Забыли?

вход по аккаунту

?

Delayed cerebral edema and fatal coma after minor head trauma Role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine.

код для вставкиСкачать
Delayed Cerebral Edema and Fatal Coma
after Minor Head Trauma: Role of the
CACNA1A Calcium Channel Subunit
Gene and Relationship with Familial
Hemiplegic Migraine
Esther E. Kors, MD,1 Gisela M. Terwindt, MD, PhD,1 Frans L.M.G. Vermeulen,2
Robin B. Fitzsimons, MBBS, BSc(Med), PhD, FRACP,3 Philip E. Jardine, MD, FRCPCH,4 Peter Heywood , MD,5
Seth Love, MBBCh, PhD, FRCP, FRCPath,6 Arn M.J.M. van den Maagdenberg, PhD,2 Joost Haan, MD, PhD,1,7
Rune R. Frants, PhD,2 and Michel D. Ferrari, MD, PhD1
Trivial head trauma may be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid
interval (“delayed cerebral edema”). Attacks of familial hemiplegic migraine (FHM) can be triggered by minor head
trauma and are sometimes accompanied by coma. Mutations in the CACNA1A calcium channel subunit gene on chromosome 19 are associated with a wide spectrum of mutation-specific episodic and chronic neurological disorders, including FHM with or without coma. We investigated the role of the CACNA1A gene in three subjects with delayed
cerebral edema. Two subjects originated from a family with extreme FHM, and one subject was the previously asymptomatic daughter of a sporadic patient with hemiplegic migraine attacks. In all three subjects with delayed severe edema,
we found a C-to-T substitution resulting in the substitution of serine for lysine at codon 218 (S218L) in the CACNA1A
gene. The mutation was absent in nonaffected family members and 152 control individuals. Haplotype analysis excluded
a common founder for both families. Neuropathological examination in one subject showed Purkinje cell loss with
relative preservation of granule cells and sparing of the dentate and inferior olivary nuclei. We conclude that the novel
S218L mutation in the CACNA1A calcium channel subunit gene is involved in FHM and delayed fatal cerebral edema
and coma after minor head trauma. This finding may have important implications for the understanding and treatment
of this dramatic syndrome.
Ann Neurol 2001;49:753–760
Trivial head trauma is sometimes complicated by severe, even fatal, cerebral edema and coma occurring after a lucid interval, a phenomenon referred to as delayed cerebral edema. The syndrome has received
particular attention in collision sports involving children and adolescents.1 Apart from young age, no other
risk factors are known.1 Snoek et al described a series
of 42 children who, after a lucid interval following minor head trauma, developed neurological symptoms
that were mostly transient and consisted mainly of disturbances of consciousness and sometimes convulsions.2 Three of the children, however, died as a result
of severe and uncontrollable brain swelling.
Minor head trauma is also a recognized trigger of
delayed migraine aura, also referred to as footballers
migraine.3,4 Particularly in children, these aura symptoms may be dramatic, including blindness, confusion,
and impaired consciousness. Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of
migraine with aura in which attacks are associated with
hemiparesis.5 Attacks of FHM can be triggered by minor head trauma, usually within 10 minutes,4 and may
be associated with loss of consciousness, as in basilar
migraine.6 About half of the reported FHM families
are linked to chromosome 19p13 and have missense
mutations in the CACNA1A gene. This gene encodes
From the 1Departments of Neurology and 2Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands; 322g
Macquarie Street, Sydney, Australia; 4Childrens Centre, 5Department of Neurology, and 6Department of Neuropathology, Frenchay
Hospital, Bristol, UK; and 7Department of Neurology, Rijnland
Hospital, Leiderdorp, The Netherlands.
Published online 24 March 2001.
Address correspondence to Dr Ferrari, Department of Neurology,
K5Q, Leiden University Medical Centre, PO Box 9600, 2300 RC
Leiden, The Netherlands. E-mail: M.D.Ferrari@lumc.nl
Received Aug 17, 2000, and in revised form Dec 29. Accepted for
publication Jan 2, 2001.
© 2001 Wiley-Liss, Inc.
753
the ␣1A subunit of a neuronal calcium channel that is
primarily involved in mediating the release of neurotransmitters, including monoamines and glutamate.7–9
Chromosome 19 –linked FHM families report attacks
that are triggered by head trauma or are associated with
coma significantly more often than do non–chromosome 19 –linked families.10
Mutations in the CACNA1A gene are associated
with a wide spectrum of neurological phenotypes,
ranging from relatively mild episodic disorders, such as
migraine,11 FHM,7 and episodic ataxia,7 to more severe permanent symptoms, such as progressive cerebellar ataxia and severe cerebellar atrophy12,13 (see Fig 2).
In tottering and leaner mice, mutations in the mouse
homologue ␣1A subunit P/Q-type calcium channel
gene are associated with ataxia and epilepsy.14
Because of these clinical relationships and the remarkable diversity of neurological symptoms caused by
CACNA1A mutations, we postulated a role for this
gene in “delayed cerebral edema.” We therefore
screened the CACNA1A gene for mutations in three
patients who experienced severe, in one case even fatal,
cerebral edema and coma after a lucid interval following minor head trauma. Two subjects belonged to a
family with severe FHM, and one subject was the previously asymptomatic daughter of a sporadic patient
with hemiplegic migraine attacks.
Methods
The pedigrees of Families 1 and 2 are shown in Figure 1.
Family 1
Family 1 is an Australian family originally reported in
1985.15 The proband (III-13) had FHM attacks and recurrent coma associated with generalized hyperreflexia, decerebrate rigidity, pinpoint pupils, hyperpyrexia, cerebrospinal
fluid (CSF) pleocytosis, and hallucinations. On one occasion
he required respiratory support because of respiratory arrest
after cerebral angiography. His father (II-5) also had had recurrent febrile comas and psychotic episodes. His brother
(III-12) had mild mental retardation and FHM attacks,
which were typically triggered by trivial head injury. He once
became unconscious during an attack but recovered spontaneously after 4 days. All 3 patients had progressive cerebellar
ataxia, and computed tomographic (CT) scan revealed cerebellar atrophy. Two other family members (II-2 and II-6)
died at the age of 5 years during “meningo-encephalitis like
episodes with convulsions” following trivial head trauma in
1915 and 1926, respectively. Another sibling (III-10) had
impaired consciousness for several days following minor head
trauma in her twenties. She did not experience migraine attacks until her late forties, when severe headache was accompanied by increasingly slurred speech, ataxia, right-sided
numbness, and fever. She has mild long-standing cerebellar
ataxia that becomes worse for hours when she is tired and
selective atrophy of the superior cerebellar vermis evident on
CT scan. Notably, she has no history of FHM attacks. One
other, more distant family member (III-7) had childhood
migraine and currently has migraine attacks with preceding
fortification spectra but without hemiparesis or other neurological symptoms. Family members III-9 and III-11 were unaffected.
Family 2
Family 2 is a British family that has not previously been
reported. The proband (III-6), a 16-year-old female, had
been hypotonic since birth and was born with a convergent
squint. She may have had seizures shortly after birth, but
they were not well documented. Investigations at the age of
1 year, including an electroencephalogram and muscle biopsy, had normal results. Apart from recurrent falls until the
age of 4, she was healthy and did not suffer from any form
of migraine. To our knowledge, she never consulted a phy-
Fig 1. The pedigrees of Families (a) 1 and (b) 2. The arrow indicates the proband. Coma is indicated as a black box for males
and a circle for females. Familial hemiplegic migraine and ataxia is indicated by a vertical striped pattern, ataxia with or without
migraine by a horizontal striped pattern, and migraine only by a black half symbol. A question mark indicates hetero-anamnestic
information, and a plus indicates that DNA is available. The alleles of (in descending order) markers D19S221, D19S1150,
CAG-repeat, and D19S226 are shown for each tested individual. A box encloses the haplotype co-segregating with the disease.
754
Annals of Neurology
Vol 49
No 6
June 2001
sician concerning headache. At the age of 16, she was admitted to a hospital after head trauma, having been hit on her
head several times without losing consciousness. In the ambulance she was orientated and alert. In the emergency room
she appeared distressed and incoherent. Her initial Glasgow
coma score was 12/15, but after a witnessed, generalized seizure it dropped to 7/15 an hour after admission. She became
hypertonic with extensor plantar responses and was intubated
and ventilated. An initial cerebral CT scan revealed no abnormalities. The CSF white cell count was slightly elevated,
with normal protein and glucose levels. CSF pressure was not
measured. Cytologic studies and examination of a Gramstained preparation of the CSF revealed no evidence of infection. Over the following days, her neurological condition
deteriorated. Nine days after admission she was in a deep
coma and had developed a pyrexia of 39°C. She exhibited no
response to painful stimuli. She had fixed and dilated pupils
and was not breathing spontaneously. Repeat CT scan revealed mild cerebral edema. Three days later she died.
The older sister (III-5) of the proband was also hypotonic
after birth and had a squint. At the age of 4 years she was
still hypotonic and clumsy. In the following years, she started
to suffer from intermittent unsteadiness, which became a
slowly progressive problem, and now, at the age of 22, she is
developing dysarthria. At neurological examination she exhibited no pyramidal or extrapyramidal signs. Cerebral magnetic resonance imaging (MRI) has not been performed. She
has never suffered from any kind of migraine.
The father (II-3) of the proband has always been clumsy.
He suffered from attacks of headache often associated with
transient hemiplegia and confusion with marked pyramidal
signs, from which he recovered spontaneously. He presented
to medical attention with an episode lasting 2 weeks during
which he suffered intermittent headache, a fluctuating level of
consciousness, vivid hallucinations concerning his own death,
and marked hemiplegia. He recovered spontaneously without
needing artificial ventilation. MRI of the head was unremarkable during the attack. A single-photon emission computed
tomography scan showed hyperperfusion in the hemisphere
contralateral to the hemiplegia. Findings of a recent neurological examination were unremarkable except for horizontal nystagmus, mild dysarthria, and a mildly ataxic gait.
Neuropathological Examination
Multiple blocks from both cerebral hemispheres, the cerebellum, and the brain stem from the index case of Family 2
(III-6) were taken for histologic studies and paraffin sections
stained with hematoxylin-eosin, luxol fast blue–cresyl violet,
Palmgren silver impregnation, and phosphotungstic acid–hematoxylin. Sections were also immunostained for neurofilament protein, glial fibrillary acidic protein, and microtubuleassociated protein 2 (MAP-2).
Genomic DNA Samples
Blood samples were collected from II-5, III-7, III-9, III-10,
III-11, III-12, and III-13 of Family 1 and I-1, II-3, III-5,
III-6, and III-7 of Family 2. Genomic DNA was isolated
from leukocytes as described by Miller et al.16
Genotyping
Two extragenic polymorphic microsatellite DNA markers
from the Genethon linkage map, D19S221 and D19S226,
which flank the CACNA1A gene, were analyzed. In addition, two intragenic polymorphisms were analyzed: marker
D19S1150 in intron 7 and the CAG repeat in exon 47, using polymerase chain reaction (PCR) conditions as previously described.7
Single Strand Conformational Polymorphism (SSCP)
Analysis
For SSCP analysis, all 47 exons of the CACNA1A gene were
amplified using exon-specific primer sets and PCR conditions as previously described.7 In brief, PCR products were
radioactively labeled by incorporation of [␣32P] dCTP during PCR, denatured in formamide buffer and electrophoresed on a 8% polyacrylamide (19:1) gel containing 10%
glycerol at a constant power of 28 W. PCR products revealing aberrant banding patterns on SCCP gels were purified
using the QIAquick PCR Purification Kit (Qiagen Chatworth, LA). Subsequently, purified products were directly sequenced using the same PCR primers and the BigDye Terminator Cycle Sequencing Kit (PE Applied Biosystems
Foster City, CA, USA) on an ABI 377 DNA automated sequencer (PE Applied Biosystems Foster City, CA USA).
Carrier Detection
To identify carriers of the 928 C-to-T substitution, exon 5
was amplified by PCR using primers exon 5F (5⬘-CTTGGTGGCGGGGTTT-3⬘) and exon 5R (5⬘-CTGCCTAATCCTCCCAAGAG-3⬘) and genomic DNA as template.
PCR products were digested with BclI using standard protocols and electrophoresed on a 2% agarose gel. In nonaffected
individuals, only one band of 291 bp is visible, whereas in
heterozygous mutation carriers two additional bands of 203
and 88 bp are present. As a control, genomic DNA of 152
subjects from the general Dutch population with no history
of migraine or cerebellar ataxia was tested.
Results
Genotyping
Genetic linkage analysis to flanking and intragenic
CACNA1A markers did not result in a significant Lod
score due to the small size of the families, but haplotype analysis was compatible with involvement of this
locus in both families. Haplotype differences between
the two families excluded a common founder (see Fig
1). The number of CAG repeats in the family members was normal (ranging from 11 to 13, normal value
below 1712), excluding a possible moderate expansion,
as seen in episodic ataxia type 2 or spinocerebellar
ataxia type 6.
Mutation Analysis
Mutation analysis of the CACNA1A gene was performed using SSCP analysis on genomic DNA obtained from the probands of both families (III-13 in
Family 1 and III-6 in Family 2). All fragments present-
Kors et al: CACNA1A Mutation and Delayed Coma
755
ing a mobility variant were checked by direct sequencing. No previously described mutations were present,
but a new variant in exon 5 was found in both families, changing a C to a T at nucleotide position 928,
thereby replacing a hydrophilic serine for a hydrophobic leucine residue at codon 218 (S218L). The mutation is located in the small intracellular loop between
the fourth and fifth transmembrane segments of the
first domain of the ␣1A subunit (Fig 2). Segregation of
the mutation within the families was demonstrated by
restriction enzyme digestion because the S218L mutation introduces a BclI restriction site (Fig 3). In Family
1, the S218L mutation was found in subjects II-5, III10, III-12, and III-13 and in Family 2 in subjects II-3,
III-5, and III-6. It was not found in the nonaffected
family members, in the family member suffering from
migraine with aura (III-7 in Family 1), or in 152 normal control individuals.
Neuropathological Examination
Gross neuropathological examination of the brain of
the index case of Family 2 (III-6) revealed bilateral,
diffuse cerebral swelling with bilateral uncal herniation
and cerebellar tonsillar herniation and necrosis.
Apart from acute cerebral ischemic changes that
were thought to be due to the agonal rise in intracranial pressure, the principal histological abnormalities
were (1) cerebral edema, (2) long-standing sclerosis of
the right hippocampus, and (3) chronic degenerative
changes involving the cerebellar cortex. The edema diffusely affected cerebral white matter in both hemispheres and, to a lesser extent, the cerebellum. No histological abnormalities were discernible in parenchymal
Fig 2. Localization of the novel S218L mutation in the ␣1A
subunit of the P/Q-type calcium channel causing delayed cerebral edema and coma after a minor head trauma (arrow).
The mutation is located in the small cytoplasmic between the
fourth and fifth segments of the first domain of the protein. In
addition, the localization of all other known CACNA1A mutations and the associated clinical phenotypes is depicted.
FHM ⫽ familial hemiplegic migraine; EA-2 ⫽ episodic
ataxia type 2; Progr ⫽ progressive; SCA-6 ⫽ spinocerebellar
ataxia type 6.
756
Annals of Neurology
Vol 49
No 6
June 2001
blood vessels. The hippocampal sclerosis was characterized by loss of pyramidal neurons from the CA1 field
of the hippocampus, which exhibited dense fibrillary
astrocytosis. The degenerative changes in the cerebellum consisted of mild loss of Purkinje cells, with associated proliferation of Bergmann astrocytes and cortical
gliosis. Occasional “empty baskets” marked the sites of
Purkinje cell loss. There was marked swelling and deformity of the dendrites of many of the remaining Purkinje cells (Fig 4). Some of the dendrites had radiating
spike-like protrusions. The abnormal dendrites were
moderately argyrophilic, and most were immunopositive for MAP-2. Dystrophic swellings (so-called torpedoes) of some of the Purkinje cell axons were noted
within the granule cell layer. These changes were more
pronounced in the vermis than in the cerebellar hemispheres and tended to spare the depths of the sulci between the folia. The deep cerebellar nuclei, inferior olives, and basal ganglia were well preserved.
Discussion
We describe the novel S218L missense mutation in the
CACNA1A calcium channel subunit gene in three subjects with minor head trauma–triggered delayed severe
cerebral edema and coma. Two subjects belonged to a
family with symptoms at the very extreme end of
FHM (II-5 and III-13 of Family 1). The third subject
(III-6 of Family 2) was the previously completely
asymptomatic daughter of a sporadic patient with
hemiplegic migraine (II-3). She had never experienced
migraine or hemiplegic phenomena before. Her father
(II-3) is the only family member who had episodes of
hemiplegic migraine. Thus, Family 2 could be regarded
as family with FHM, but only retrospectively and only
by assuming that the fatal event in index Patient II was
her first attack of hemiplegic migraine. We hypothesize
that the S218L CACNA1A mutation renders subjects
at risk for a disinhibited cytotoxic edematous response
to minor brain injury, mediated through dysfunction
of neuronal voltage-dependent P/Q-type calcium channels. Trauma-triggered “delayed cerebral edema” can
thus be added to the wide spectrum of episodic and
chronic progressive neurological disorders associated
with CACNA1A mutations. One might consider advising subjects with a positive family history for hemiplegic migraine or with demonstrated CACNA1A mutations to avoid sports in which head injury is common,
such as contact sports.
Impairment of consciousness is a known but rare associated symptom of hemiplegic migraine attacks.
Apart from the S218L mutation, five other CACNA1A
mutations have been associated with coma during at
least some FHM attacks: V714A,11 I1811L,11
T666M,17 Y138C,18,19 and R583Q20 (see Fig 2). In
addition, one family has been described in which FHM
was linked to chromosome 1q, and the proband, but
Fig 3. Mutation detection of the P/Q-type calcium channel ␣1A subunit gene in Families (a) 1 and (b) 2. The mutation is a
C-to-T substitution at codon 218, which results in a substitution of serine for leucine (S218L). Mutation S218L results in an additional BclI restriction site. In nonaffected individuals only one band of 291 bp is visible, whereas in heterozygous mutation carriers two additional bands of 203 and 88 bp are present (88-bp band not visible in figure).
not the other affected family members, had hemiplegic
migraine attacks associated with coma.21 In all these
families, however, the impairment of consciousness was
short-lived and never as dramatic as in our patients
with the S218L mutation; there also was no such dramatic delayed association with minor head trauma.
The clinical presentation of Patient III-6 of Family
2, with uncontrollable cerebral edema after a lucid interval following minor head trauma, resembles that of
three patients with delayed fatal detoriation in the se-
ries of otherwise benign concussion in 42 children described by Snoek et al2 and of the 17 cases of delayed
cerebral edema and coma in collision sports as reviewed
by McCrory and Berkovic.1 Among the various explanations for these dramatic events, a migrainous mechanism was suggested but not further investigated.
Screening for mutation in the mutation analysis of the
CACNA1A gene in these patients might be interesting.
Several pathophysiological mechanisms have been
implicated in post-traumatic hemispheric swelling due
Fig 4. (a) Section through cerebellar cortex. The molecular layer includes several swollen Purkinje cell dendrites (arrows).
Hematoxylin-eosin, ⫻100. (b) Palmgren silver impregnation of swollen Purkinje cell dendrites in the cerebellar molecular layer.
Spike-like processes radiate from one of the dendritic swellings (arrow), the center of which is relatively nonargyrophilic. ⫻200.
Kors et al: CACNA1A Mutation and Delayed Coma
757
to cytotoxic edema, including traumatic depolarization
(TD).22 In TD, depolarization of the neuronal cell
membrane potential and activation of voltagedependent ion channels are triggered by mechanical
strain on the brain. This depolarization results in massive ionic fluxes across the plasma membrane and
calcium-dependent exocytotoxic release of excitatory
neurotransmitters, such as glutamate and aspartate, further reinforcing the ionic perturbation and eventually
causing cellular swelling.23 The ionic perturbation, the
shift of the cell membrane potential, and the pivotal
role of excitatory amino acid release and K⫹ in TD23
are also important mechanisms involved in cortical
spreading depression (CSD). CSD is believed to be the
underlying mechanism of the aura in migraine and
FHM.24 This view is supported by a recent observation
that the N-methyl-D-aspartate antagonist ketamine reduced the neurologic deficits in some FHM patients.25
Diffusion MRI in a sporadic patient with hemiplegic
migraine carrying the Y1384C CACNA1A missense
mutation showed reversible hemispheric edema and decrease of cerebral water mobility during a long-lasting
attack of hemiplegic migraine associated with coma.19
Hemispheric swelling was also observed in the patients
described here.
The CACNA1A gene encodes for the main, ionconducting, pore-forming ␣1A subunit of voltagedependent P/Q-type neuronal calcium channels,7
which modulate neurotransmitter release.26 Like all
other known CACNA1A mutations causing FHM, the
S218L mutation is a missense mutation. The serine
residue at position 218 is highly conserved both between the various calcium channel pore-forming subunits and across all species (Fig 5). This observation
suggests that an amino acid change at this position
would severely affect the function of the channel.
Other missense mutations causing FHM were all
found to cause either gain or loss of function.27,28,29 In
tottering mice, mutations in the Cacna1a gene change
the threshold for CSD30 and the release of acetylcholine at the neuromuscular junction.31 Both in lethargic
mice, which have mutations in the Cacnb4 gene encoding the auxiliary ␤4 subunit of P/Q-type calcium channels, and in tottering mice, the thalamic release of glutamate is impaired.32 Thus, mutations in P/Q-type
calcium channel subunit genes affect neurotransmitter
release. This effect on neurotransmitter release may
have profound implications for the mechanisms involved in TD and CSD and could lead to an exaggerated edematous response to minor head trauma or
other trigger factors. If a calcium channelopathy is indeed an underlying mechanism in “delayed cerebral
edema,” treatment with acetazolamide might prove effective. This nonspecific carbonic anhydrase inhibitor
has shown to be effective in a number of other cerebral
Fig 5. Alignment of relevant parts of a diverse set of pore-forming calcium channel subunits. The arrow indicates the serine residue
on codon 218 (dark gray box). Both human dihydropyridine-sensitive (L-type) and -nonsensitive (non–L–type) calcium channel
subunits are included. In addition, various orthologous channels of human CACNA1A and CACNA1B are presented. Variations
from the human CACNA1A are indicated by light gray boxes. Amino acid residues that are not variable are indicated by a horizontal line at the bottom of the figure. The following accession numbers were used for the alignment: human CACNA1A
(X99897), CACNA1B (M94172), CACNA1C (L04569), CACNA1D (M76558), CACNA1E (L29384), CACNA1F
(AJ224874), and CACNA1S (L33798); mouse CACNA1A (U76716); rat CACNA1A (M64373); rabbit CACNA1A (X57688);
Drosophila melanogaster DMCA1A (P91645); and Discopyge ommata DOE-4 (P56698).
758
Annals of Neurology
Vol 49
No 6
June 2001
channelopathies, including the CACNA1A disorder episodic ataxia type 2.33
The pathological features of the cerebellar degeneration associated with a missense mutation in the
CACNA1A gene have not been reported previously.
Neligan et al noted multiple infarcts in the cerebral
cortex and basal ganglia of a patient with FHM who
had died 4 months after experiencing a respiratory arrest.34 Ataxia was not recorded for this patient, and
genetic status is unknown. Histologic studies of the
cerebellum revealed widespread loss of Purkinje cells,
but this was attributed by the authors to the single anoxic episode. Although the patient whose brain was examined neuropathologically in the present study (III-6
of Family 2) had not manifested hemiplegic migraine,
her father has typical clinical features of this disorder.
We found the pathological abnormalities to be of similar distribution to those in spinocerebellar ataxia type
6 (SCA-6) but less severe.35,36 In cases of SCA-6 that
have been studied neuropathologically, the principal
abnormality has been Purkinje cell loss with relative
preservation of granule cells and sparing of the dentate
and inferior olivary nuclei, the basal ganglia, and other
parts of the brain. As in the present case, the cerebellar
cortical abnormalities in SCA-6 tend to be more
marked in the vermis than in the hemispheres. Prominent dendritic abnormalities have not been noted in
descriptions of SCA6, although the dendritic abnormalities in the current study resemble those in several
other types of cerebellar cortical degeneration, including Menkes’ disease.37 A potential complicating factor
in the interpretation of the neuropathological findings
in the cerebellum in the present case is the development of agonal ischemic changes associated with the
brain swelling. These changes were, however, relatively
acute and could not account for the loss of Purkinje
cells, development of dystrophic axonal swellings, or
cerebellar gliosis. Furthermore, the effects of ischemia
on Purkinje cells do not include the formation of swollen and misshapen dendrites and tend to be most severe in the depths of sulci between folia, the least severely affected part of the cerebellar cortex in our case.
In conclusion, the novel S218L mutation in the
P/Q-type neuronal calcium channel ␣1A subunit gene
CACNA1A and possibly other similar CACNA1A mutations are involved in a delayed disinhibited, sometimes even fatal, cytotoxic cerebral edematous response
to minor head trauma after a lucid interval. This finding could offer new avenues for the understanding and
treatment of this dramatic syndrome.
This work was supported by the Netherlands Organisation for Scientific Research (NWO, no. 903–52-291), Migraine Trust, and Asclepiacie Association.
References
1. McCrory PR, Berkovic SF. Second impact syndrome. Neurology 1998;50:677– 683.
2. Snoek JW, Minderhout JM, Wilmink JT. Delayed detoriation
following mild head injury in children. Brain 1984;107:15–36.
3. Matthews WB. Footballer’s migraine. Br Med J 1972;2:326 –
327.
4. Solomon S. Posttraumatic migraine. Headache 1998;38:772–
778.
5. International Headache Society. Classification and diagnostic
criteria for headache disorders, cranial neuralgias and facial
pain. Cephalalgia 1988;8(suppl 7):1–96.
6. Haan J, Terwindt GM, Ophoff RA, et al. Is familial hemiplegic
migraine a hereditary form of basilar migraine? Cephalalgia
1995;15:477– 481.
7. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial
hemiplegic migraine and episodic ataxia type-2 are caused by
mutations in the Ca2⫹ channel gene CACNL1A4. Cell 1996;
87:543–552.
8. Catterall WA. Structure and function of neuronal Ca2⫹ channels and their role in neurotransmitter release. Cell Calcium
1998;24:307–323.
9. Hill MP, Brotchie JM. Control of glutamate release by calcium
channels and kappa-opioid receptors in rodent and primate striatum. Br J Pharmacol 1999;127:275–283.
10. Terwindt GM, Ophoff RA, Haan J, et al. Familial hemiplegic
migraine: a clinical comparison of families linked and unlinked
to chromosome 19. Cephalalgia 1996;16:153–155.
11. Terwindt GM, Ophoff RA, Haan J, et al. Variable clinical expression of mutations in the P/Q-type calcium channel gene in
familial hemiplegic migraine. Neurology 1998;50:1105–1110.
12. Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant
cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the 1A-voltage-dependent calcium channel. Nat
Genet 1997;15:62– 69.
13. Tournier-Lasserve E. CACNA1A mutations: hemiplegic migraine, episodic ataxia type 2, and the others. Neurology 1999;
53:3– 4.
14. Fletcher CF, Lutz CM, O’Sullivan TN, et al. Absence epilepsy
in tottering mutant mice is associated with calcium channel defects. Cell 1996;87:607– 617.
15. Fitzsimons RB, Wolfenden WH. Migraine coma: meningitic
migraine with cerebral oedema associated with a new form of
autosomal dominant cerebellar ataxia. Brain 1985;108:555–
557.
16. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16.
17. Ducros A, Denier C, Joutel A, et al. Recurrence of the T666M
calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum
Genet 1999;64:89 –98.
18. Vahedi K, Denier C, Ducros A, et al. CACNA1A gene de novo
mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 2000;55:1040 –1042.
19. Chabriat H, Vahedi K, Clark CA, et al. Decreased hemispheric
water mobility in hemiplegic migraine related to mutation of
CACNA1A gene. Neurology 2000;54:510 –512.
20. Battistini S, Stenirri S, Piatti M, et al. A new CACNA1A gene
mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology 1999;53:38 – 43.
21. Echenne B, Ducros A, Rivier F, et al. Recurrent episodes of
coma: an unusual phenotype of familial hemiplegic migraine
with linkage to chromosome 1. Neuropediatrics 1999;30:214 –
217.
22. Bauer R, Walter B, Fritz H, Zwiener U. Ontogenetic aspects of
Kors et al: CACNA1A Mutation and Delayed Coma
759
23.
24.
25.
26.
27.
28.
29.
30.
760
traumatic brain edema: facts and suggestions. Exp Toxicol
Pathol 1999;51:143–150.
Katayama Y, Maeda T, Koshinaga M, et al. Role of excitatory
amino acid-mediated ionic fluxes in traumatic brain injury.
Brain Pathol 1995;5:427– 435.
Lauritzen M. Pathophysiology of the migraine aura: the spreading depression theory. Brain 1994;117:199 –210.
Kaube H, Herzog J, Kaufer T, et al. Aura in some patients with
familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000;55:139 –141.
Randall A, Benham CD. Recent advances in the molecular understanding of voltage-gated Ca(2⫹) channels. Mol Cell Neurosci 1999;14:255–272.
Kraus RL, Sinnegger MJ, Glossmann H, et al. Familial hemiplegic migraine mutations change alpha 1A Ca2⫹ channel kinetics. J Biol Chem 1998;273:5586 –5590.
Kraus RL, Sinnegger MJ, Koschak A, et al. Three new familial
hemiplegic migraine mutants affect P/Q-type Ca(2⫹) channel
kinetics. J Biol Chem 2000;275:9239 –9243.
Hans M, Luuisetto S, Williams ME, et al. Functional consequences of mutations in the human alpha A calcium channel
subunit linked to familial hemiplegic migraine. J Neurosci
1999;19:1610 –1619.
Ayata C, Shimizu-Sasamata M, Lo EH, et al. Impaired neurotransmitter release and elevated threshold for cortical spreading
Annals of Neurology
Vol 49
No 6
June 2001
31.
32.
33.
34.
35.
36.
37.
depression in mice with mutations in the alpha1A subunit of
P/Q type calcium channels. Neuroscience 2000;95:639 – 645.
Plomp JJ, Vergouwe MN, Van den Maagdenberg AM, et al.
Abnormal transmitter release at neuromuscular junctions of
mice carrying the tottering alpha(1A) Ca(2⫹) channel mutation. Brain 2000;123:463– 471.
Caddick SJ, WangC, Fletcher CF, et al. Excitatory but not inhibitory synaptic transmission is reduced in lethargic
(Cacnb4(Lh)) and tottering (Cacna1atg) mouse thalami. J Neurophysiol 1999;81:2066 –2074.
Bain PG, O’Brien MD, Keevil SF, Porter DA. Familial periodic
cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. Ann Neurol 1992;31:147–154.
Neligan P, Harriman DG, Pearce J. Respiratory arrest in familial hemiplegic migraine: a clinical and neuropathological study.
Br Med J 1977;2:732–734.
Tsuchiya K, Ishikawa K, Watabiki S, et al. A clinical, genetic,
neuropathological study in a Japanese family with SCA 6 and a
review of Japanese autopsy cases of autosomal dominant cortical
cerebellar atrophy. J Neurol Sci 1998;160:54 –59.
Ishikawa K, Watanabe M, Yoshizawa K, et al. Clinical, neuropathological, and molecular study in two families with spinocerebellar ataxia type 6 (SCA6). J Neurol Neurosurg Psychiatry
1999;67:86 – 89.
Ellison D, Love S. Neuropathology: a reference text of CNS
pathology. London: 1998.
Документ
Категория
Без категории
Просмотров
1
Размер файла
2 053 Кб
Теги
channel, migraine, delayed, subunit, relationships, cerebral, minor, trauma, hemiplegic, edema, head, fatal, cacna1a, coma, familiar, role, genes, calcium
1/--страниц
Пожаловаться на содержимое документа