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Benign familial neonatal-infantile seizures Characterization of a new sodium channelopathy.

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Benign Familial Neonatal-Infantile
Seizures: Characterization of a
New Sodium Channelopathy
Samuel F. Berkovic, MD,1 Sarah E. Heron, BSc,2 Lucio Giordano, MD,3 Carla Marini, MD, PhD,1,4
Renzo Guerrini, MD,4 Robert E. Kaplan, MD,5 Antonio Gambardella, MD,6 Ortrud K. Steinlein, PhD,7
Bronwyn E. Grinton, BSc,1 Joanne T. Dean, BAppSc,1 Laura Bordo, BSc,8 Bree L. Hodgson, Dip Biomed Sci,2
Toshiyuki Yamamoto, MD, PhD,2 John C. Mulley, PhD,2 Federico Zara, PhD,8
and Ingrid E. Scheffer, MD, PhD1
We recently reported mutations in the sodium channel gene SCN2A in two families with benign familial neonatalinfantile seizures (BFNISs). Here, we aimed to refine the molecular-clinical correlation of SCN2A mutations in early
childhood epilepsies. SCN2A was analyzed in 2 families with probable BFNIS, 9 with possible BFNIS, 10 with benign
familial infantile seizures, and in 93 additional families with various early childhood epilepsies. Mutations effecting
changes in conserved amino acids were found in two of two probable BFNIS families, in four of nine possible BFNIS
families, and in none of the others. Our eight families had six different SCN2A mutations; one mutation (R1319Q)
occurred in three families. BFNIS is an autosomal dominant disorder presenting between day 2 and 7 months (mean,
11.2 ⴞ 9.2 weeks) with afebrile secondarily generalized partial seizures; neonatal seizures were not seen in all families.
The frequency of seizures varied; some individuals had only a few attacks without treatment and others had clusters of
many per day. Febrile seizures were rare. All cases remitted by 12 months. Ictal recordings in four subjects showed onset
in the posterior quadrants. SCN2A mutations appear specific for BFNIS; the disorder can now be strongly suspected
clinically and the families can be given an excellent prognosis.
Ann Neurol 2004;55:550 –557
Afebrile seizures in the first 12 months of life often are
associated with serious underlying structural brain disease or metabolic abnormalities, often with a guarded
prognosis.1,2 Two benign autosomal dominant epilepsy
syndromes are well recognized in the first year of life.
Benign familial neonatal seizures begins around day 3
and is caused by defects in potassium channel genes
KCNQ2 and KCNQ3 in many families.3– 6 Benign familial infantile seizures begins around 6 months of age.
It may be associated with paroxysmal dyskinesias in
later childhood and can also occur as a nonfamilial
form.7–10 No genes have been definitively identified
for benign familial infantile seizures; linkage to chromosomes 19 and 16 has been reported,11,12 and a mutation in the ATP1A2 gene on chromosome 1q21-23
was reported in one family in which there was partial
cosegregation of familial hemiplegic migraine and infantile seizures.13
In 1983, before the recognition of benign familial
infantile seizures, Kaplan and Lacey described a single
American family with an intermediate variant, benign
familial neonatal-infantile seizures (BFNIS), in which
seizure onset varied from 2 days to 3.5 months.14 In
2002, we reported two additional families with BFNIS
and described missense mutations in SCN2A, the gene
coding for the ␣2 subunit of the voltage-gated sodium
Here, we report a novel SCN2A missense mutation
in the original American BFNIS family and the clinical
and molecular findings in an additional five families.
From the 1Epilepsy Research Centre and Department of Medicine
(Neurology), University of Melbourne, Austin Health, Victoria,
Australia; 2Department of Genetic Medicine, Women’s and Children’s Hospital, Adelaide, South Australia; 3Division of Infantile
Neuropsychiatry, Civil Hospitals, Brescia; 4Child Neurology and
Psychiatry, IRCCS Stella Maris Foundation, Pisa, Italy; 5The Womens and Children’s Hospital of Buffalo, and University at Buffalo
School of Medicine and Biomedical Sciences, Buffalo, NY; 6 Institute of Neurology, University Magna Græcia, Catanzaro, Italy; 7Institute of Human Genetics, University Hospital Bonn, FriedrichWilhelms-University, Bonn, Germany; and 8Laboratory of Muscular
Biochemics and Neurogenetics, Gaslini: Institute, Italy.
Received Oct 14, 2003, and in revised form Dec 4. Accepted for
publication Dec 5, 2003.
Published online Mar 1, 2004, in Wiley InterScience
( DOI: 10.1002/ana.20029
Address correspondence to Dr Berkovic, Epilepsy Research Centre,
First Floor, Neurosciences Building, Repatriation Campus, Austin
Health, Heidelberg West, Victoria 3081, Australia. E-mail:
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
We also explore the specificity of SCN2A mutations for
BFNIS, by studying a variety of childhood epilepsies,
especially generalized epilepsy with febrile seizures plus
(GEFS⫹) because a small Japanese family with febrile
and afebrile seizures has been reported with an SCN2A
mutation.16 The clinical and molecular characterization
of a total of eight families with SCN2A mutations now
establishes BFNIS as an important sodium channelopathy of the early infantile period.
Subjects and Methods
Subjects and Clinical Evaluation
We studied three sets of subjects in addition to Families A
(Australian; Irish origin) and B (Canadian; Ashkenazi Jewish) described in our initial report on SCN2A mutations in
BFNIS.15 We sought clinical details regarding seizure onset,
clinical features, and seizure offset from mothers of affected
infants in addition to long-term follow-up information regarding seizures and developmental outcome. Hospital
records were obtained whenever possible to validate reported data.
PROBABLE BFNIS/SCN2A FAMILIES. Family C was the original American family reported as BFNIS in 1983.14 We followed up this family, extended the pedigree, and hypothesized that they had an SCN2A mutation. Family D was
reported previously as “benign familial infantile convulsions”
with onset around 3 months and mapped to chromosome 2q
in the region of SCN2A.17,18 Because of the early onset and
known linkage, we reevaluated the family clinically and
searched for a SCN2A mutation.
POSSIBLE BFNIS FAMILIES. Nine families had a familial epilepsy, with most individuals having seizures before 4 months
of age. In some families. neonatal seizures were observed.
familial neonatal seizures but did not have detected KCNQ2
or KCNQ3 mutations. Ten families were regarded as typical
benign familial infantile seizures with onset between 4 and 9
months in most affected individuals. We also studied 59
families with GEFS⫹ in whom mutations in SCN1A,
SCN1B, and GABRG2 were not detected and 32 unrelated
cases with benign childhood epilepsy with centrotemporal
This study was approved by the Human Research Ethics
Committees of Austin Health, Melbourne and the Women’s
and Children’s Hospital, Adelaide.
Molecular Genetic Analysis
Genomic DNA was analyzed for mutations in the coding
regions of SCN2A using single-stranded conformation analysis (SSCA), a rapid mutation screening technique. Any variants detected by SSCA subsequently were sequenced. One
individual from families that were negative on SSCA and
were thought to have probable or possible BFNIS was completely sequenced for the coding regions of SCN2A. Mutations detected in subjects were screened for in 50 anonymous
blood bank control samples.
Haplotyping and parentage testing were conducted using
highly polymorphic microsatellite repeat markers. Polymerase
chain reaction amplification from genomic DNA was conducted in the presence of 32P-dCTP. Products were separated on denaturing 5% polyacrylamide gels and visualized
by autoradiography. Details of primers and polymerase chain
reaction conditions are available from the authors.
SCN2A Mutation Analysis
Missense mutations in SCN2A resulting in changes in
evolutionarily conserved amino acids were found in six
families (Fig 1). Both families categorized as probable
BFNIS (Family C and D) and four of nine families
regarded as possible BFNIS (Families E, F, G, H) were
positive. The mutations identified in these families
were not found in the controls.
No mutations were found in 59 GEFS⫹ families.
Neither of the two families with exclusively neonatal
onset had SCN2A mutations. Of the 10 families with
benign familial infantile seizures, a change, A1822V,
was seen in two members of one family. One child in
the benign childhood epilepsy with centro-temporal
spikes group had a variant (T1200A). Neither variant
was detected in controls but due to the small number
of affected individuals, it is not possible to infer by
segregation analysis whether they are associated with
the phenotypes. Both amino acids are conserved in
mammalian neuronal sodium channels, but not in the
skeletal muscle subtype. In vitro effects on ion channel
properties must be demonstrated before they are regarded as possibly pathogenic.
Families Positive for SCN2A Mutations
This American family
was of English origin. One new affected infant has
been born since the original 1983 report.14 She had a
cluster of approximately 16 afebrile seizures during
days 3 to 5 of life. Initially, these were thought to be
“hiccoughs,” but, as they became longer, they comprised a choking noise, tonic body extension, eyelid
fluttering followed by apnea, and bilateral jerking lasting about 30 seconds. Seizures were controlled on phenobarbital with a recurrence at 4 months in the setting
of low phenobarbital levels. Twelve other family members were known to be affected with ages of onset varying from day 2 to 3 months. Another individual was
said to have had late hypocalcemic neonatal seizures;
records were unavailable and she could not be recontacted to test for the SCN2A mutation.
Family D was a previously reported Sicilian family17,18 that has 17 affected
individuals. Access to the family was limited and medical records were not available. Seizures were said to
begin at around 3 months in all affected infants, but
Berkovic et al: Benign Familial Seizures
Fig 1. Pedigrees of six families with benign familial neonatal-infantile seizures (BFNIS) and SCN2A mutations.
precise onsets could not be determined. Some children
had single or a few seizures, others had seizures for
months, and multiple seizures were reported on single
days in certain children. Seizures ceased by 12 months
in all individuals.
Family E from Northern Italy (Brescia) has two affected individuals. The
7-month-old proband had seizure onset at 3 months
and 3 days with clonic jerking of the eyelids and lower
lip, lasting a few seconds. A week later, afebrile seizures
recurred in a cluster and he was hospitalized. Video-
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electroencephalogram (EEG) documented a secondarily
generalized partial seizure (Fig 2). He was commended
on phenobarbital. In the following month, three more
single seizures and a few clusters of four to five seizures
per day occurred. He has been seizure-free since 5
months of age.
His 27-year-old mother had seizures from 5
months to 1 year of age. Seizures were characterized
by a brief tonic contraction of the four limbs and
cyanosis. The mutation was found in the proband
and mother. The mother’s parents did not have the
mutation, and parentage was confirmed by analysis of
Fig 2. Ictal electroencephalogram (EEG) from an infant (Family E) at age 3 months. The seizure was characterized by clonic jerking of both eyelids and mouth on the right side, staring, perioral cyanosis, tonic contraction of the legs, and generalized twitching.
The EEG shows onset in the left temporal region; it remains unilateral for over a minute (top two panels) and then becomes bilateral and stops 3.5 minutes after onset (note different sensitivities).
19 microsatellite repeat markers, indicating a de novo
mutation as the origin of the BFNIS phenotype in
this family.
Family F from central
Italy (Pisa) has four affected individuals. The 10-yearold proband had a brief febrile seizure at 5.5 months,
followed by a cluster of afebrile tonic-clonic seizures 2
days later with seizures approximately every 6 hours for
2 days. Interictal EEG at 6 months was normal. A
1-minute seizure comprising generalized rigidity and
bilateral arm jerking was recorded with the ictal EEG
showing rhythmic bilateral 100 to 200␮V spikes followed by high-amplitude generalized delta waves, but
the onset was not documented. Magnetic resonance
imaging (MRI) of the brain was normal. He was
treated with phenobarbital for 2 years and had no further seizures.
His 16-year-old brother had three simple febrile sei-
zures between 7 and 11 months of age. He was treated
with valproic acid for 2 years. At 9 years, he had a
choroid plexus papilloma removed and was given carbamazepine. An interictal EEG recording at 9 years
showed rare, brief generalized spike-wave complexes.
Their 40-year-old mother had several generalized convulsions between 4 and 8 months of age. Computed
tomography scan and EEG recording at the age of 30
years for migraine were normal. The 36-year-old maternal aunt had two afebrile convulsions at 7 to 8
months. The maternal grandmother had the SCN2A
mutation but had no known history of seizures.
The 48-year-old paternal uncle had possible perinatal asphyxia, followed by normal development. At 13
months of age, atypical absences appeared. Seizures occurred up to three times per month in childhood and
comprised loss of awareness with perilabial cyanosis
and hypotonia. Generalized spike-wave discharges were
seen on EEG. He was treated with phenobarbital; sei-
Berkovic et al: Benign Familial Seizures
zures stopped at 7 years and treatment was withdrawn
at 13 years. Two distant paternal cousins had febrile
FAMILY G (MUTATION (L1003I). There were three affected individuals in Family G, an Italian family from
Tuscany. The 2.5-year-old proband had a seizure at 15
days with sudden loss of consciousness, rigidity, cyanosis, and staring, lasting 20 to 30 seconds followed by
sleep. Two similar episodes occurred at 2 months and
treatment with phenobarbital was begun. At 4 months,
a cluster of approximately 100 afebrile seizures occurred over 4 days requiring rectal diazepam. No further seizures occurred. The interictal EEG was normal.
An ictal EEG showed rhythmic spikes in the right central region evolving to a rhythmic discharge at the vertex followed by bilateral slow activity. Clinically, he
showed diffuse rigidity and upward eye deviation followed by clonic jerks.
His 10-year-old sister had two afebrile seizures at 6
months within 24 hours. She was treated with phenobarbital. At 7.7 months, she had a low-grade temperature with an ear infection, and a cluster of four brief
seizures occurred over 1 day. An interictal EEG and
MRI were normal. Treatment was changed to carbamazepine and she was treated for 5 years. No further
seizures occurred.
Their 38-year-old father had three to four afebrile
convulsions at age 6 months comprising rigidity, cyanosis, and loss of consciousness, lasting one to several
minutes. His interictal EEG was normal.
FAMILY H (MUTATION (R1319Q). Family H, an Italian
family from Calabria, has four affected individuals and
one unaffected carrier. The 6-year-old proband had
afebrile seizures from age 3.5 months characterized by
head and eye deviation (not always the same in each
attack) followed by generalized stiffening and bilateral
limb jerking. At the onset, seizures lasting 45 to 180
seconds occurred in clusters every day and were
promptly controlled with phenobarbital. Brain MRI
was normal. Interictal EEG recordings in the active
phase showed bilateral parietooccipital sharp waves and
subsequently were normal. He was of age until 2 years
of age and has been seizure-free since.
His 9-year-old female cousin had an essentially identical electroclinical pattern with onset at 4 months.
One seizure was captured with onset in the left centrooccipital region followed by a diffuse discharge. She
was treated with phenobarbital until 3 years of age
with no further seizures. At follow-up, repeated EEG
recordings were always normal. Details on the proband’s father and grandfather were sketchy; seizure onset was at around 5 months and the course was benign.
All affected individuals were developmentally normal.
Families E, F, and H had the same mutation
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(c.3956G3 A; R1319Q). Although all three families
were Italian, they were not known to be related after
detailed genealogical analysis. Haplotypes of six markers closely linked to the SCN2A locus were different in
the three families (data not shown), confirming independent origin of the mutation.
Epileptology of Benign Familial Neonatal-Infantile
Seizure with SCN2A Mutations
Our two previously published families, plus the six reported here, make a total of eight families with 56 affected individuals. All pedigrees were consistent with
autosomal dominant inheritance, although in Family F
bilineal inheritance of epilepsy genes may have complicated the phenotypes in the proband’s nuclear family.
We identified only two individuals with mutations
who had no known history of seizures; one was elderly
and no information about her infancy was available.
This together with pedigree inspection (see Fig 1) suggests that the penetrance is very high.
None of the affected individuals had a significant
perinatal history, and all had normal developmental
milestones and neurological examinations. The precise
age of onset was known for 27 affected individuals
from the 8 families; it varied from day 2 to 7 months
of age (mean, 11.2 ⫾ 9.2 weeks; median, 13 weeks).
Seven began in the first week of life, a further three
between 1 week and 1 month, twelve between 1 and 4
months, and the remaining five cases between 5 and 7
Seizures were predominantly afebrile secondarily
generalized partial seizures. Focal motor manifestations
were usually noted first, typically head and eye deviation, with tonic and clonic movements subsequently.
Seizures were recorded in the laboratory in individuals
from five families and focal features at onset were documented in four families. Although some seizures were
reported as brief (approximately 20 seconds), they
could be relatively long with convulsive phases lasting
up to 4 minutes. Apnea and staring were prominent
features in some seizures. The frequency of seizures
varied greatly, with some individuals having only a few
attacks without treatment and others having clusters of
many per day. Where seizures were active, they were
easily controlled by antiepileptic medication.
Seizures with fever were noted in a minority of cases
during the course of the seizure disorder and, with the
exception of two siblings from Family F, were never
the presenting feature. Of note was that these two boys
inherited the SCN2A mutation from their mother, but
on the father’s side there was a history of febrile seizures and generalized epilepsy.
All cases stopped having seizures by 12 months of
age with no documented recurrences in later childhood, adolescence, or adult life.
Interictal EEGs in the active phase were either nor-
mal or showed focal epileptiform discharges in the posterior or central regions. Later EEGs were always normal. Ictal recordings in four subjects showed onset in
the posterior quadrants (see Fig 2); one subject had
bilateral discharges during the seizure, but the onset
was not recorded. Brain imaging was normal in eight
cases; one case had a choroid plexus papilloma, which
was regarded as incidental.
Molecular studies now separate BFNIS from the other
two autosomal dominant epilepsies of the first year of
life. Another six BFNIS families with SCN2A mutations, together with the two previously published families,15 enables a clear electroclinical profile to be established for this disorder.
The three syndromes have overlapping clinical features that previously masked their separation into separate clinical entities (Table). Seizures often occur in
clusters of numerous attacks over a day or a few days.
The seizures are usually partial seizures that secondarily
generalize with prominent motor manifestations; recorded seizures typically originate from posterior head
regions. Benign familial neonatal seizures and benign
familial infantile seizures were classified previously as
generalized epilepsy syndromes19; this subsequently was
questioned because of seizure recordings showing focal
ictal onsets.3 Our data show that BFNIS also shares
this feature of posterior focal seizure onset.
Age of onset is an important factor in distinction of
these syndromes and the clinical-molecular correlation
is strong. Benign familial neonatal seizures with potassium channel mutations has a very narrow age of onset
within and between families. Nearly all cases begin
within the first week of life, if corrected for gestational
age. Rare single cases with onset after one month are
reported, but not as a consistent pattern within a family.3 In contrast, benign familial infantile seizures characteristically begins at approximately 6 months of age;
outliers outside the 3 to 9-month window are uncommon, although it is emerging that this syndrome is
clinically heterogeneous.7,11,12,21,22 BFNIS with
SCN2A mutations is intermediate; ages of onset vary
within families, from the neonatal period to 6 months,
with most cases clustering around the ages of 2 to 3
months. Diagnosis of BFNIS cannot be made on one
case but should be considered if all cases within a family begin before 6 months and strongly suspected if onset is always before 5 months, with a mixture of neonatal and early-infantile onsets. Although the first three
families described with this condition had individuals
with both neonatal and infantile onsets,14,15 families
D, E, F, and H reported here had no subjects with
known neonatal onset.
Clinical recognition of BFNIS is important for
proper management, especially to avoid overinvestigation and overtreatment. The occurrence of seizure clusters in this age group may raise the question of a metabolic disorder, cortical malformation, or infantile
spasms. However, the seizure patterns and associated
findings in these syndromes is quite different from
BFNIS, so clinical distinction is easy. Moreover, a
careful family history from parents and grandparents
may quickly support the diagnosis, allay concerns in
medical staff and family alike, and allow confident
prediction of an excellent outcome.
None of our 56 cases had seizures after 12 months
of age. This is important data for family counseling.
The outcome is similarly excellent in benign familial
infantile seizures, although later occurrence of paroxysmal dyskinesias occurs in some families that map to the
chromosome 16 locus. In contrast, occasional later seizures are a feature of some patients with benign familial neonatal seizures. The reason for the spectacular remission of seizures is unknown; it may relate to
developmental regulation of the ion channel subunits
concerned or of other genes.
Despite the report of a small bilineal Japanese family with GEFS⫹ and an SCN2A mutation,16 our findings provide little support for an association between
SCN2A and GEFS⫹. We failed to find SCN2A mutations in 59 GEFS⫹ subjects. In our BFNIS cohort,
Table. Features of Autosomal Dominant Epilepsies of the First Year of Life
Benign Familial
Benign Familial
Neonatal Seizures
Onset (mean ⫾ SD)
Typical onset range
Seizure onset
Childhood/adult seizures
Other clinical features
3 ⫾ 2 days
1 day to 1 mo
Probably focal
Yes, in ⬃15% of cases
Myokymia (rare)
11 ⫾ 9 weeks
2 days to 6 mo
Chromosomal loci
20, 8
Potassium channels KCNQ2 KCNQ3
Sodium channel SCN2A
Benign Familial
Infantile Seizures
6 ⫾ 2 mo
3 to 9 mo
Paroxysmal dyskinesias in
some families
16, 19
Table was compiled from references 3–7, 11, 12, 20 –22 and unpublished data.
Berkovic et al: Benign Familial Seizures
only one individual had febrile seizures alone, whereas
his brother (see Fig 1, Family F) had febrile seizures
followed by a cluster of afebrile seizures typical of
BFNIS. This pattern is unlike GEFS⫹ where afebrile
seizures rarely cluster, and in GEFS⫹ later onset of
seizures is usual.23,24 Moreover, these siblings had a
family history through their father of febrile seizures
and generalized epilepsy, implicating other epilepsy
genes in their seizure disorders. Thus, although seizures with fever occasionally do occur in BFNIS, they
do not continue into the second or later years of life
and thus do not conform to the usual clinical pattern
of either simple febrile seizures or GEFS⫹.
All SCN2A mutations were missense mutations (Fig
3). The structure–function relationships of various domains of the sodium channel are beginning to be unraveled; there are four homologous transmembrane domains, each with six segments. Segment 4 in each
domain contributes to the voltage sensor, segments 5
and 6 and the linker between them form the pore and
the inactivation gate is between domains III and IV.25
The mutations were spread throughout the coding regions and a unified effect on function cannot presently
be predicted; this will have to await functional studies.
Similarly, GEFS⫹ can be caused by missense mutations
spread throughout the SCN1A gene.26 –28 One site
(R1319) appeared to be a “hot spot,” with three families having independently arising mutations, confirmed
by haplotype analysis. There was no apparent correlation of clinical features with the molecular lesions, except that all families with infantile onset (range, 3–7
months) and no known neonatal-onset cases had mutations leading to an arginine-glutamine substitution in
the voltage sensor of the protein: R223Q (Family D)
on segment S4 of domain I and R1319Q (Family E, F,
H) on segment S4 of domain III.
The penetrance of SCN2A mutations was high, yet
in four pedigrees there were only two generations
known to be affected. In at least one case (Family E),
this was caused by a de novo mutation. This suggests
that there may be a significant rate of spontaneous mutation of this gene to cause BFNIS. In two families,
however, older generations were not available to test
this hypothesis whereas in Family F, the grandmother
carried the mutation but was not known to be affected.
An alternative explanation to de novo mutation for
small pedigrees is that older generations were affected
in infancy, but their early history was not known. De
novo mutations in SCN2A could explain some of the
early-onset cases of benign partial epilepsy in infancy
and benign infantile convulsions,8 –10,21,22 but such
cases were not examined in our study.
Review of our pedigrees with autosomal dominant
epilepsies beginning in the neonatal period or early infancy suggests that the molecular defect can now be
found in a significant proportion of families. For families with only neonatal seizures, we found KCNQ2
mutations in 9 of 11 families, with none having the
rarer KCNQ3 abnormalities (S.E. Heron and J.C. Mulley, unpublished data). For families with possible or
probable BFNIS on clinical grounds, we have eight
families with confirmed SCN2A mutations and five for
whom no mutations were found. There were no distinguishing clinical features identified in the negative
families. It is possible that these families have SCN2A
mutations in a nontranslated sequence or that other
genes are responsible. Understanding the molecular basis of these families as well as identifying the elusive
Fig 3. Structure of the SCN2A protein, with the four transmembrane domains shown. The positions of the six missense mutations
are indicated by the arrows. Note, three families had the mutations R1319Q (thick arrow), and the other five families had unique
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genes for benign familial infantile seizures are the next
major challenges to complete the clinicomolecular classification of the autosomal dominant epilepsies of the
first year of life. Just as molecular diagnosis has redefined classification of many neurogenetic disorders such
as muscular dystrophies and become a lynchpin of diagnosis, the same may soon be true of these epilepsies.
This work was supported by the National Health and Medical Research Council of Australia (144C05, S.F.B., I.E.S.; 207703,
J.C.M.), Bionomics Ltd. (J.C.M.; S.F.S.), the Pierfranco and Luisa
Mariani Foundation (F.Z.), and Comitato Telethon Foundation
We thank Drs R. Romero, M. Shevell, E. Andermann and A.F.
Bleasel for clinical data on their patients and D. Jezek and Dr R.
Wallace for assistance in obtaining DNA samples.
1. Chevrie JJ, Aicardi J. Convulsive disorders in the first year of
life: neurological and mental outcome and mortality. Epilepsia
2. Matsumoto A, Watanabe K, Suguira M, et al. Long-term prognosis of convulsive disorders in the first year of life: mental and
physical development and seizure persistence. Epilepsia 1983;
3. Plouin P, Anderson VE. Benign familial and non-familial neonatal seizures. In: Roger J, Bureau M, Dravet C, Genton P,
Tassinari CA, Wolf P, eds. Epileptic syndromes in infancy,
childhood and adolescence. 3rd ed. London: John Libbey,
4. Singh NA, Charlier C, Stauffer D, et al. A novel potassium
channel gene, KCNQ2, is mutated in an inherited epilepsy of
newborns. Nat Genet 1998;18:25–29.
5. Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science 1998;279:
403– 406.
6. Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a
novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 1998;18:53–55.
7. Vigevano F, Fusco L, Di Capua M, et al. Benign infantile familial convulsions. Eur J Pediatr 1992;151:608 – 612.
8. Fukuyama Y. Borderland of epilepsy, with special references to
febrile convulsions and so-called infantile convulsions. Seishin
Igaku (Tokyo) 1963;5:211–223.
9. Watanabe K, Yamamoto N, Negoro T, et al. Benign complex
partial epilepsies in infancy. Pediatr Neurol 1987;3:208 –211.
10. Watanabe K, Negoro T, Aso K. Benign partial epilepsy with
secondarily generalized seizures in infancy. Epilepsia 1993;34:
635– 638.
11. Szepetowski P, Rochette J, Berquin P, et al. Familial infantile
convulsions and paroxysmal choreoathetosis: a new neurological
syndrome linked to the pericentromeric region of human chromosome 16. Am J Hum Genet 1997;61:889 – 898.
12. Guipponi M, Rivier F, Vigevano F, et al. Linkage mapping of
benign familial infantile convulsions (BFIC) to chromosome
19q. Hum Mol Genet 1997;6:473– 477.
13. Vanmolkot KR, Kors EE, Hottenga JJ, et al. Novel mutations
in the Na⫹, K⫹-ATPase pump gene ATP1A2 associated with
familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 2003;54:360 –366.
14. Kaplan RE, Lacey DJ. Benign familial neonatal-infantile seizures. Am J Med Genet 1983;16:595–599.
15. Heron SE, Crossland KM, Andermann E, et al. Sodiumchannel defects in benign familial neonatal-infantile seizures.
Lancet 2002; 360: 851-2. Erratum: Lancet 2002;360:1520.
16. Sugawara T, Tsurubuchi Y, Agarwala KL, et al. A missense mutation of the Na⫹ channel alpha II subunit gene Na(v)1.2 in a
patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci USA 2001;98:6384 – 6389.
17. Giordano L, Accorsi P, Valseriati D, et al. Benign familial infantile convulsions: natural history of a case and clinical characteristics of a large Italian family. Neuropediatrics 1999;30:
99 –101.
18. Malacarne M, Gennaro E, Madia F, et al. Benign familial infantile convulsions: mapping of a novel locus on chromosome
2q24 and evidence for genetic heterogeneity. Am J Hum Genet
19. Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:
389 –399.
20. Dedek K, Kunath B, Kananura C, et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the
KCNQ2 K⫹ channel. Proc Natl Acad Sci USA 2001;98:
21. Vigevano F, Bureau M. Idiopathic and/or benign localizationrelated epilepsies in infants and young children. In: Roger J,
Bureau M, Dravet C, Genton P, Tassinari CA Wolf P, eds.
Epileptic syndromes in infancy, childhood and adolescence. 3rd
ed. London: John Libbey, 2002:153–160.
22. Caraballo RH, Cersosimo RO, Espeche A, Fejerman N. Benign
familial and non-familial infantile seizures: a study of 64 patients. Epileptic Dis 2003;5:45– 49.
23. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogeneous clinical phenotypes. Brain 1997;120:479 – 490.
24. Singh R , Scheffer IE, Crossland K, Berkovic SF. Generalised
epilepsy with febrile seizures plus: a common childhood-onset
genetic epilepsy syndrome. Ann Neurol 1999;45:75– 81.
25. Yu FH, Catterall WA. Overview of the voltage-gated sodium
channel family. Genome Biol 2003;4:207.
26. Escayg A, Macdonald BT, Meisler MH, et al. Mutations of
SCN1A, encoding a neuronal sodium channel, in two families
with GEFS⫹2. Nat Genet 2000;24:343–345.
27. Wallace RH, Scheffer IE, Barnett S, et al. Neuronal sodium
channel ␣1 subunit (SCN1A) mutations in generalised epilepsy
with febrile seizures plus. Am J Hum Genet 2001; 68:
859 – 865.
28. Abou-Khalil B, Ge Q, Desai R, et al. Partial and generalized
epilepsy with febrile seizures plus and a novel SCN1A mutation.
Neurology 2001;57: 2265–2272.
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