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Clinical and genetic analysis of a large pedigree with juvenile myoclonic epilepsy.

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Clinical and Genetic Analysis of
with Juvenile Myoclonic
T
JosC M. Serratosa, MD, PhD,*t$ Antonio V. Delgado-Escueta, MD,*?5 Marco T. Medina, MD,"'
Quanwei Zhang, MD,*?$ Reza Iranmanesh,*t$ and Robert S. Sparkes, MD*$
Juvenile myoclonic epilepsy is a common type of idiopathic generalized epilepsy characterized by myoclonic, generalized
tonic-clonic, and in 30% of patients, absence seizures. We studied a three-generation pedigree of 33 members, 10 of
whom were clinically affected with juvenile myoclonic epilepsy or presented with subclinical electroencephalographic
(EEG) 3.5- to 6.0-Hz diffuse polyspike-wave or spike-wave complexes. Juvenile myoclonic epilepsy and the EEG trait
segregated as an autosomal dominant trait with 70% penetrance. Linkage analysis using this model showed significant
linkage to four microsatellite markers centromeric to human leukocyte antigen (HLA) in chromosome 6p. Maximum
lod scores of 3.43 at 8,,f = 0.00 for D6S272, D6S466, D6S257, and D6S402 were obtained. Recombinant events in
2 affected members defined the gene region to a 43-CMinterval flanked by D6S258 (HLA region) and D6S313 (centromere). Our results in this large family provide evidence that a gene responsible for juvenile myoclonic epilepsy and the
subclinical, 3.5- to 6.0-Hz, polyspike-wave or spike-wave EEG pattern is located in chromosome 6p.
Serratosa JM, Delgado-Escueta AV, Medina MT, Zhang Q, Iraninanesh R, Sparkes RS. Clinical and genetic
analysis of a large pedigree with juvenile myoclonic epilepsy. Ann Neurol 1c)96;39:187- 195
The idiopathic generalized epilepsies (IGEs) [ 11, for
which a genetic cause is widely accepted, account for
39 to 59% of all epilepsies [2].Juvenile myoclonic epilepsy (JME), childhood absence epilepsy, and epilepsy
with grand ma1 on awakening are estimated to account
for most of the genetically determined IGEs. Previous
reports [3-61 estimated the frequency of JME to be
from 4.3 to 1I .4% of all epilepsies. In our database,
JME is the most common cause of generalized grand
ma1 epilepsy.
Multiple studies suggested that the IGEs have a genetic cause but despite their high frequency, efforts to
map their chromosomal sites have been limited by a
complex pattern of inheritance. Several modes of inheritance have been proposed for JME including recessive
[7],polygenic [8], two loci recessive dominant or recessive recessive [9], and single locus dominant [lo, 111.
In most families the clinical picture in affected family
members from the same pedigree is variable and one
often observes different syndromes, such as childhood
absence epilepsy, juvenile absence epilepsy, or epilepsy
with generalized tonic-clonic seizures on awakening, in
members of the same family. More striking is the finding of asymptomatic family members whose electroen-
cephalograms (EEGs) show typical 4.0- to 6.0-HZ polyspike-wave or spike-wave complexes similar to the
interictal discharges seen in affected members [8, 91.
These findings suggest that genes involved in the
pathogenesis of the IGEs express themselves in different ways, depending on how they interact with each
other or with other nongenetic factors.
In 1988, Greenberg and colleagues 1121 reported
that JME and the 3.5- to 6.0-HZ polyspike-wave EEG
pattern may be linked to the human leukocyte antigen
(HLA) region of chromosome 6p using serological
HLA and properdin (Bf) markers. In 11 small families
(11 informative for Bf and 4 for HLA) lod scores
summed to 3.04 at 8 , = 0.01 and 8f = 0.10, suggesting linkage between JME and EEG polyspike-wave
complexes to Bf-HLA. They concluded that the locus
was outside HLA because of the absence of association
to HLA alleles and the existence of one recombinant
family. This finding was confirmed by Weissbecker and
colleagues 1131 and Durner and colleagues [14]. However, more recently, a third report using families with
IGE failed to find evidence of linkage to chromosome
6p markers and excluded linkage at HLA,and from a
region 10 to 30 cM telomeric to HLA [ 151.
From the *California Comprehensive Epilepsy Program, the tDepartment of Neurology and the $Division of Medical Generics (Department of Medicine), University of California Los Angeles, Los
Angeles; the SVA Southwest Regional Epilepsy Center, Neurology
and Research Services, West Los Angel= DVA Medical Center,
Los Angeles, CA; and the 'Direccion de Investigacibn Cientifica,
Universidad Nacional Autbnoma de Honduras, Tegucigalpa, Honduras.
Received Apr 27, 1995, and in revised form Jul 17 and Sep 28.
Accepted for publication Sep 28, 1995.
Address correspondence
Dr Delgado-Escuera, Comprehensive
Epilepsy Program (127B), Building 500, Room 3405, Wesr Los
hgeles
DVA Medical Cenrcr, 11301 Wilshire Bouicvard, Los
Angeles, CA 90073,
Copyright 0 1996 by the American Neurological Association
187
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D6S258
D6S313
D6S280
10 3
8 5
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Fig 1. LA-B/II pedigree presenting with ,juvenile myorlonus epilepy (]ME) (full black symbols) or subclinical 3.5- to 6.0-Hz
polyspike-wave or spike-wave electroencephalographic (EEG) patterns (half black symbols). Member II-3 is the proband (arrow).
Members III-2 and III-2' are identical twins. Genotypes are given for nine informative chromosome 6 markers after being haployped. The haplotype segregating with /ME or the EEG trait is boxed and the markers in the region containing the JME gene are
highlighted. Inferred haplotypes in deceased Member 1-1are bracketed. Recombination events are indicated by arrows. Members
III-5 and III-19 are recombinants that provide f i n k i n g marker information.
Because the above-mentioned conflicting reports on
linkage between chromosome 6p markers and JME can
be explained by interfamilial genetic heterogeneity, we
studied a large family from Los Angeles and Belize in
which 7 members are clinically affected with JME and
3 show 3.5- to 6.0-Hz polyspike-wave or spike-wave
complex EEG patterns not associated with clinical
symptoms. We describe in detail the clinical and EEG
phenotypes in all members of this kindred, their segregation pattern, results of pairwise and multipoint linkage analysis using microsatellite markers in chromosome 6, as well as analysis of recombinant events.
Subjects and Methods
Patient and Family Dutubase: Validation of State of
Affectedness for Linkage Analysis
We identified a Los Angeles-Belize (LA-BIJ 1) pedigree
through a JME proband (Fig 1). Each participating subject
or the responsible adult, in the case of minors, signed an
informed consent form as approved by the Human Subject
Protection Committee at the University of California Los
Angeles (UCLA) School of Medicine.
We validated the state of affectedness of 33 members of
LA-B/Jl including 6 unrelated subjects who married-in (see
Fig 1). All clinically affected subjects were examined by at
least two of the authors, with the exception of Member 1-1
188 Annals of Neurology
Vol 39
No 2
February 1996
who is deceased. For this subject, information leading to the
diagnosis of JME was obtained from the offspring and siblings of 1-1. To document the diagnosis of the proband (11-3),
we performed closed circuit television videotape (CCTV)EEG recordings and demonstrated myoclonic jerks accompanied by polyspike discharges followed by slow waves. Onehour awake and sleep EEGs were performed in all members
except Members 1-1 (deceased) and 11-7 (Fig 1). All EEGs
included 5 minutes of hyperventilation and most included
l were read
photic stimulation from 2 to 20 flashes/sec. d
independently and blindly by two investigators who completed
an EEG report form and both reports were then compared.
There were no disagreements in the reported findings.
We established three affected status classes and one unknown class for linkage analysis. For class I affected status,
subjects had to meet all the following criteria: (1) frequent,
severe, awakening myoclonic seizures of shoulders and
arms-patient throws objects soon after waking up (generalized tonic-clonic or absence seizures may or may not be present); (2) age at onset of myoclonic seizures between 8 and
25 years; and (3) normal neurological examination and intelligence. For class 2 affected stntus, subjects had to meet all
the following criteria: (1) infrequent, mild myoclonic seizures; (2) age at onset of myoclonic seizures between 8 and
25 years; (3) normal neurological examination and intelligence; and (4)EEG with diffuse, bilateral, synchronous 3.5to 6.0-Hz polyspike-wave or spike-wave complexes or diffuse, bilateral, synchronous 3.0- to 6.0-Hz irregular sharp or
slow waves mixed with random spikes. For class 3 ufficted
stutus, subjects had to be clinically asymptomatic and show on
their EEGs the fast variety (3.5-6.0 Hz) of polyspike-wave
or spike-wave complexes with or without diffuse, bilateral,
synchronous 3.0- to 6.0-Hz irregular sharp or slow waves
mixed with random spikes. Because we do not know if other
epilepsy phenotypes showing EEG patterns similar to those
seen in JME are an expression of the JME genotype, we
classified as unknown those subjects presenting another form
of epilepsy distinct from JME and an EEG with diffuse,
bilateral discharges of 3.5- to 6.0-Hz polyspike-wave or
spike-wave complexes or diffuse, bilateral, synchronous 3.0to 6.0-Hz irregular sharp or slow waves mixed with random
spikes. Members not meeting any of the described criteria
(for class 1, 2, or 3 affected status or for unknown status)
were classified as unaffected for linkage analysis purposes.
Exclusion criteria for any of the above status were structural
lesions of the central nervous system (CNS), metabolic or
degenerative diseases, stimulus-sensitive myoclonic seizures,
partial or tonic seizures, myoclonic absences, and alcohol or
other substance abuse. Based on these criteria, 10 family
members were considered affected. Four members (I- 1,
11-3, 111-14, 111-17) met the criteria for class 1 (severe JME),
3 members (111-4, 111-5, and 111-15) met the criteria for class
2 (mild JME), and 3 members (11-2, 111-8, and 111-19) met
the criteria for class 3 (asymptomatic members with EEG
spike-wave or polyspike-wave complexes). Member 11-6 had
transient neonatal and febrile convulsions and her EEG
showed bursts of diffuse, bilateral, synchronous, 3.0- to 6.0Hz irregular sharp waves and slow waves mixed with spikes.
Thus, she was classified as unknown for linkage analysis.
W e attempted to extend this pedigree further by clinical
and EEG validation and failed to identify any of the common IGEs in the families of 2 maternal grand uncles and 1
paternal great grandfather of the proband.
Microsatellite Murker Analysis
High-molecular-weight genomic DNA was prepared by
phenol/chloroform extraction followed by isopropanol precipitation [ 161. The polymerase chain reaction (PCR) was
used to amplify total genomic DNA. Amplification reactions
were performed as described by Weber and May [ 171. Genotypes were scored blindly by two readers without knowledge
of affection status or position in the pedigree.
Loci Studied
A total of 3 1 microsatellite markers covering chromosome 6
from 6p23 to 6q14 were typed. All markers, except D6S89
[18], D6S105 [19], tumor necrosis factor (TNF) 1201, and
TCTE-1 [21], were from the GCnithon collection [22], and
all except D6S313 and D6S280 were in the short arm of
chromosome 6. The T N F locus is located in the middle of
the HLA region, which is estimated to cover 4 cM of chromosome 6p. Markers D6S436, D6S438, and D6S459 were
excluded from the analysis because of noiimeiidelian inheritance or equivocal allele-band patterns.
Lod Score Linkage Analysis
Two-point linkage lod score analysis was performed using
the computer program MLINK from the LINKAGE soft-
ware package version 5.1 [23]. Marker allele frequencies were
derived from ethnically matched control subjects. The frequency for the disease allele was estimated to be 0.001. Lod
scores were calculated ar recombination fractions equal for
males and females of 0,,= = 0.00, 0.001, 0.051, 0.101,
0.151, 0.201, 0.251, 0.301, and 0.351. Phenocopy and gene
mutation rates were set at 0. W e used an autosomal dominant model with 70% penetrance according to results of our
segregation analysis. An age of onset penetrance curve derived from 101 JME patients was used to assign each subject
to a liability class. Multipoint linkage analysis was performed
with the program LINKMAP using nine of the most informative markers and sliding the JME locus from the left of
D6S89 to the right of D6S280. Marker order and recombination fractions were obtained using combined information
from the GCnkthon human genetic linkage map [22] and
the report of the second International Workshop on Human Chromosome 6 [24]. Recombination fractions were
converted into centimorgans (cMs) using the Haldane mapping function. Marker order was DGS89-D6S258-D6S282DbS272-DbS466-DbS257-D6S402-DGS3
13-DbS280 and
intermarker recombination fractions were 0.1627, 0.190 1 ,
0.0672, 0.04, 0.0291, 0.01, 0.0296, and 0.03.
Haplotype Analysis
W e used the computer program Cyrillic (Chenvell Scientific)
to haplotype 28 markers in this pedigree. Nine informative
markers were used to construct the haplotypes shown in Figure 1.
Results
Clinical and Electroencephalographic Findings
The proband was 51 years old at the time
of writing and presented with generalized tonic-clonic and
myoclonic seizures since the age of 9 years. Myoclonias of
limbs occurred daily in the morning after waking up and
forced the patient ro drop objects such as spoons, forks, or
cups. Frequent, uncontrolled generalized tonic-clonic seizures forced the patient to drop out of school. Despite treatment with primidone and phenobarbital, generalized tonicclonic seizures and myoclonias persisted through adolescence.
Absence seizures were not reported. Valproic acid controlled
seizures but rare myoclonias and generalized tonic-clonic seizures were still induced by sleep deprivation. Findings on
general and neurological examinations were normal. A routine EEG demonstrated frequent, high-amplitude, diffuse,
10.0- to 20.0-Hz polyspikes and diffuse 3.5- to 6.0-Hz
polyspike-wave complexes lasting from 1 to 2 seconds, some
accompanied by myoclonic seizures (Fig 2A). The frequency
of the discharges increased during sleep. Overnight CCTVEEG recorded several awakening myoclonias with simultaneous diffuse 18.0- to 20.0-Hz polyspikes.
PATIENT 11-3.
MEMBER 11-6. This 54-year-old woman presented with
transient, afebrile neonatal convulsions between the ages of
3 days and 6 months and rare febrile seizures between the
ages of 3 and 5 years. Her EEG showed diffuse, bilateral,
synchronous 3.0- to 6.0-Hz irregular sharp or slow waves
mixed with spikes.
Serratosa et al: Juvenile Myoclonic Epilepsy
189
1 sec
1 sec
Fig 2.
190 Annals of Neurology
Vol 39 No 2
February 1396
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~~~
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~~
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2. The spectwm of electroencephalogrdphic (EEG) abnormalities jiund in Family LA-Bul.
Fast variety ofpolyspike-wave
4 Fig
complexes in Member 11-3: 3.5- 60-Hz d&se polyspike-wave complexes. (B) Asymptomatic Member II-2: burst ?f dguse
(A)
5.0to 60-Hz spike-wave and polyspike-wave complexes (BI) and burst of 10.0- to 20.0-Hz dzfise polyspikes followed by slow waves
to
(B2). (C) Asymptomatic Member III-8: bilateral frontally and centrally accentuated 5.0-Hz single spike-wave complex mixed with
4.0- to 60-Hz difise sharp waves and spikes ( C l ) and burst of 4.0 to 6.0-Hz sharp waues mixed with spikes (C2). (0)
Asymptomatic Member III-19: burst of dzfise 4.5- to 5.0-H~polyspike-wave complexes.
PATIENT 111.4.
At the time of writing this 26-year-old
woman was asymptomatic except for rare myoclonic jerks of
shoulders and arms. At 1 7 years old she developed myoclonic
jerks and numerous generalized tonic-clonic seizures with fever. Repeated generalized tonic-clonic seizures required therapy with antiepileptic drugs for 1 year. At the age of 22
years, three generalized tonic-clonic seizures occurred after a
surgical procedure. Her EEG at age 26 showed diffuse, bilateral, synchronous, 4.0- to 6.0-Hz irregular sharp or slow
waves mixed with spikes. These paroxysms lasted less than
1 second. Bifrontal and scattered spikes were also present.
PATIENT 111-5. This daughter of the proband was 21 years
old at the time of writing. She was 1 3 years old when myoclonic jerks followed by a generalized tonic-clonic seizure
first appeared afrer a night of only 4 hours of sleep. Phenobarbital did not stop a second convulsion from occurring 2
months later, at 4 AM, after she had stayed awake all night.
No further seizures appeared. A 1-hour EEG showed two
bursts of diffuse, bilateral, synchronous, 4.0- to 6.0-Hz polyspike-wave complexes lasting from 0.5 to 2.0 seconds without any accompanying clinical signs. Many bursts of diffuse,
bilateral, synchronous, 4.0- to 6.0-Hz irregular sharp or slow
waves mixed with spikes also occurred.
This 19-year-old presented with myoclonic seizures at the age of 10 years. Myoclonic seizures
occurred daily and affected the arms and legs. She had her
P A T E N 1 111-14.
first tonic-clonic convulsion at the age of 13 years. Also a t
the age of 13, she began presenting frequent, brief episodes
in which she would stare and miss a conversation. Since then
one to three grand ma1 convulsions have occurred each year.
Carbamazepine, phenobarbital, and phenyroin failed to stop
seizures. At the time of writing, she was taking valproic acid,
which controlled tonic-clonic and myoclonic seizures but not
absences. Myoclonic seizures were recorded on EEG-electromyographic (EMG) recordings.
t'ArIwr 111-15. This 18-year-old woman had febrile convulsions at the age of 2 years. At 7 years old, she presented
with an episode of loss of consciousness without convulsions.
Frequent syncope characterized adolescence. Myoclonic jerks
appeared rarely during childhood and adolescence. Short episodes of losing contact with the environment occurred rarely
or infrequently since age 8. At the time of writing, she was
not taking any medication. An EEG showed bursts of bifrontal sharp waves mixed with spikes of right predominance.
PATIENT 111-17. At the time of writing, this man was 27
years old. At the age of 7 years, very frequent, daily, morning
myoclonic seizures caused him to drop items during meals
or during tasks at work. At the same time, he began presenting staring episodes that lasted 1 second. At the age of 21
years he had a generalized t o n i c - c h i c seizure related to alcohol intake and sleep deprivation. Since then, generalized
Serratosa et al: Juvenile Myoclonic Epilepsy
191
tonic-clonic seizures have occurred once a year, always related
to alcohol intake and sleep deprivation. Myoclonic seizures
have persisted to the present, with increased intensity and
frequency on alcohol intake. An EEG obtained during valproic acid therapy showed 110 abnormalities.
Two female offsprings of Members 11-11 and 11-12,
who are not represented in Figure 1, drowned, one
at age 10 years and one at age 18 years. The offspring
who drowned a t age I S had generalized tonic-clonic
and myoclonic seizures with onset at age 8 years.
Three asymptomatic family members (11-2, 111-8,
and 111-19) presented abnormal paroxysmal discharges
of diffuse, symmetrical, and synchronous 3.5- to 6.0Hz polyspike-wave or spike-wave complexes on their
EEGs (see Figs 2s-D). No clinical seizure activity was
observed during these discharges. Discharges of diffuse,
bilateral, synchronous, 3 .O- to 6.0-Hz irregular sharp
or slow waves mixed with spikes were also present on
the EEGs of Members 111-8 (see Fig 2, C2) and 111-19.
The EEGs performed on other asymptomatic family
members were all normal.
Mode of InheTitance
Segregation of JME and the related 3.5- to 6.0-Hz polyspike-wave or spike-wave complex EEG pattern followed an autosomal dominant mode with incomplete
penetrance. Member 11-1 1 was clearly an asymptomatic
carrier as 4 of his offspring were affected. Prior to linkage analysis, we calculated the number of symptomatic
(presenting seizures) and asymptomatic (presenting
EEG paroxysms) family members across sibships and
estimated the penetrance at 70%. After linkage to chromosome 6p markers was confirmed, we reevaluated the
penetrance of the gene using haplotype analysis. Ten
of 15 family members showing the haplotype segregating with the disease were clinically or EEG affected,
indicating a penetrance of 66.6% and confirming our
estimated penetrance.
Lod Score Linkage Anal3,sis
Initially, we obtained slightly positive lod scores for
marker TNF, which lies in the middle of the 4-cM
HLA area. We then genotyped and analyzed markers
centromeric and telomeric to HLA. Four chromosome
6p markers centromeric to HLA (D6S272, D6S466,
D6S257, and DbS402; see Fig 2) showed linkage to
the disease phenotype (lod score of 3.43 at On,+ =
0.00, Table). No recombinant events were observed between the disease phenotype and these loci. Changing
the penetrance to 50 or 90% had minor effects in the
lod scores (for D6S272, D6S466, D6S257, and
D6S402 the lod scores were 3.35 for 50% penetrance
and 3.02 for 90% penetrance). Linkage analysis was
also performed using an affecteds-only analysis, in
which all the unaffecteds were classified as unknown.
192 Annals of Neurology
Vol 39 No 2
February 1996
With this approach, markers D6S272, D6S466,
D6S257, and D6S402 all resulted in a lod score of
2.64 at 8,,,,f = 0.00. Because affected Member 1-1 is
deceased and could not be examined, we performed
two more analyses changing his affected status. When
Member 1-1 was classified as unknown, the lod score
was 3.13 at Om=f = 0.00 and when he was considered
unaffected, the lod score was 2.79 at O,,+ = 0.00.
Maximum multipoint lod scores of 3.38 were obtained
for a region flanked by markers D6S466 and D6S257
[22]. The multipoint 3-lod-unit support interval covered most of the region between D6S258 (HLA region) and D6S313 (centromere).
Analysis of Recombinant Events
We found two informative recombinant events in affected Members 111-5 and 111-19 (see Fig 1). The recombination in Member 111-5 placed the gene locus
centromeric to D6S258 in 6p. The recombination in
Member 11-19 placed the gene locus centromeric to or
above D6S313 which is in 6q on the other side of the
centromere [24]. 'Thus, we were able to position the
JME gene in an interval flanked by DbS258 and
D6S313. This area covers 43 cM of chromosome 6.
Individual 111-1 (see Fig 1) shows a recombination that
could potentially reduce the candidate gene region below D6S282. However, recombination events in unaffecteds have a very limited value in genetic diseases
where reduced penetrance is present.
Discussion
Previous studies on the genetics of the ICES 114, 15,
25, 261 showed that different epilepsy syndromes commonly occur in members of the same family, prompting the query of who is affected for purposes of linkage
analysis. In the LA-B/J1 pedigree presented here, the
clinical spectrum ranged from clinically asymptomatic
family members with EEG 3.5- to 6.0-HZ polyspikewave or spike-wave complexes to individuals with frequent myoclonic and generalized tonic-clonic seizures
requiring lifetime treatment. In the middle of the spectrum were family members with rare myoclonic seizures with or without generalized tonic-clonic seizures
whose EEGs showed 3.5- to 6.0-Hz polyspike-wave
complexes or diffuse, bilateral, synchronous, 3 .O- to
6.0-HZ irregular sharp or slow waves mixed with
spikes, confirming their affected status. Because EEG
3.5- to 6.0-Hz polyspike-wave complexes are associated
with myoclonic and grand ma1 seizures, their presence
in asymptomatic family members may be significant.
Rarely do 3.5- to 6.0-Hz polyspike-wave complexes occur in EEGs of normal children and adolescents. Gerken and Doose [27] found spike waves during wakefulness in only 12 (1.8%) of 685 normal children.
Cavazzuti and colleagues [28] reported diffuse polyspike-wave complexes in 37 (1%) of 3,726 awake
Pairwise Lod Scores Between the Juvenile Myoclonic Epilepsy Trait and 22 Infarmative Chromosome 6p Markers“
Recombination Fraction
Locus
D6S89
D6S 105
D6S306
D6S258
TNF
TCTE-1
D6S271
D6S282
D6S269
D6S465
D6S427
D6S272
D6S466
D6S294
D6S428
D6S257
D6S4 14
D6S402
D6S430
D6S467
D6S3 I3
D6S280
0.000
-5.83
-3.03
- 5.43
- 2.69
- 2.69
2.58
2.58
2.57
1.66
0.70
2.99
3.43
3.43
2.75
2.96
3.43
I .80
3.43
1.61
2.95
- 1.53
-4.87
0.001
5.72
-1.91
-4.73
- 1.40
- 1.40
2.58
2.58
2.58
1.66
0.69
2.99
3.43
3.43
2.74
2.96
3.43
1.81
3.43
1.62
2.94
- 1.07
-2.97
-
0.051
-2.76
-0.01
- 1.27
0.45
0.45
2.54
2.54
2.54
1.54
0.63
2.78
3.20
3.20
2.54
2.86
3.20
1.84
3.20
1.63
2.73
0.36
0.18
0.101
-1.77
0.38
-0.57
0.78
0.78
2.40
2.40
2.40
1.42
0.56
2.55
2.94
2.94
2.3 1
2.68
2.94
1.78
2.94
1.56
2.50
0.55
0.60
0.151
0.201
-1.19
0.55
-0.19
0.90
0.90
2.21
2.21
2.21
1.28
0.48
2.30
2.65
2.65
2.07
2.44
2.65
1.66
2.65
1.44
2.26
0.61
0.76
-
0.79
0.62
0.02
0.92
0.9 1
1.98
1.98
1.98
1.13
0.40
2.03
2.33
2.33
1.80
2.16
2.33
1.50
2.33
1.28
1.99
0.61
0.8 1
0.251
0.301
0.35 I
-0.50
0.62
0.14
0.86
0.86
1.71
1.71
1.71
0.97
0.31
1.75
1.99
1.99
1.52
1.85
1.99
1.31
1.99
1.10
1.71
0.57
0.78
-
--0.15
-0.29
0.56
0.20
0.75
0.75
1.41
1.41
1.41
0.79
0.22
1.44
1.63
1.63
1.22
1.52
1.63
1.08
1.63
0.90
1.40
0.50
0.70
0.46
0.20
0.60
0.60
1.08
1.08
1.08
0.61
0.14
1.11
1.24
1.24
0.90
1.16
1.24
0.84
1.24
0.69
1.08
0.41
0.58
”Autosomai dominant model, 70% penetrance.
EEGs performed in normal children from 6 to 13 years
old. In 1994, Okubo and colleagues [29] recorded
EEG generalized bursts of multiple spike and wave
complexes and multifocal spikes in 2 (0.2%) of 1,057
healthy children. The relative specificity, epileptogenic
nature, and rarity in the normal population prompted
us to consider clinically asymptomatic subjects with
3.5- to 6.0-HZ diffuse polyspike-wave or spike-wave
complexes as affected for purposes of linkage analysis.
What is not clear is whether asymptomatic members
with diffuse, bilateral, synchronous, 3.0- to 6.0-Hz irregular sharp or slow waves mixed with spikes should
be considered affected with the JME trait (see Fig 2,
C2 for an example of this pattern). Although these
abnormalities are “epileptiform,” Eeg-Oloffson and
colleagues [30] observed similar irregularly formed
“diffuse, bilateral synchronous bursts of 2.0- to 5.0-Hz
slow waves, with amplitudes exceeding 100 pV, with
a random, poorly developed spike between the slow
waves” in 2.3% of awake EEGs (during rest, hyperventilation, or photic stimulation) and 7.9% of drowsy
and sleep EEGs of normal children and adolescents.
These patterns can also be caused by diseases other
than epilepsy. In our present family, such epileptiform
patterns always appeared with the more specific diffuse
3.5- to 6.0-HZ polyspike-wave or spike-wave complexes
when members were asymptomatic (Members 111-8
and 111-19).
This is the first large family expressing JME or the
3.5- to 6.0-HZ polyspike-wave or spike-wave complex
EEG trait that independently shows linkage to chromosome 6p markers. Four markers spanning 8 cM of
chromosome 6p (D6S272, D6S466, D6S257, and
D6S402) resulted in lod scores higher than 3.3, the
asymptotic threshold corresponding to a genome-wide
significance of 5% for standard linkage analysis with
one free parameter [31]. Haplotype construction and
analysis of recombinant events allowed us to place the
gene in a 43-cM region between D6S258 (HLA area)
and D6S313 (just below the centromere in 6q). As
Lander and Schork [31] stated, “in linkage analysis the
simplest situation is when unequivocal linkage can be
demonstrated in a single large pedigree (with lod score
>3).” It is likely that restricting linkage studies to large
families with multiple affected members who present
only JME or 3.5- to 6.0-Hz polyspike-wave or spikewave complexes in their EEGs will help identify more
families linked to chromosome 6p markers. By narrowing the definition of a disease or restricting the patient population, it is often possible to work with a
Serratosa et al: Juvenile Myoclonic Epilepsy
193
trait that is more nearly mendelian in its inheritance
pattern and more likely homogeneous. Concerning the
matter of segregation analysis, pooling small pedigrees
may yield incorrect results since genetic heterogeneity
is highly suspected in JME and different modes of inheritance may occur in different families, some cases
even representing sporadic mutations.
While two other studies [13, 141 confirmed our initial report of a chromosome 6p locus for JME [12], a
recent study from the United Kingdom (UK) and Sweden [15] did not find evidence in favor of linkage to
any of eight chromosome 6p markers. However, linkage to most of the region centromeric to HLA was not
excluded in the UK-Sweden study and DNA markers
below TCTE-1 were not studied [15]. Differences in
the methods of recruitment and clinical and EEG validations may also explain why positive lod scores at
TCTE-1 were not obtained. The UK-Sweden study
included pedigrees in which there was 1 patient with
JME and a first- or second-degree relative with JME
or another form of idiopathic generalized epilepsy [ 1 51.
This method of recruitment can mix families of JME
with families of childhood or juvenile absence epilepsy
since families in which the predominant phenotype is
childhood or juvenile absence can have members with
JME. Another possible reason why linkage was not
found is that EEGs were not performed in family
members of the UK-Sweden study, reducing the power
to detect linkage. Finally, another possible reason why
linkage was not detected in the UK-Sweden study is
that genetic heterogeneity exists within JME.
This work was primarily supported by National Institute of Neurological Disorders and Stroke, National Institutes of Health program
project grant 5P01-NS21908 (to A. V. D-E.), the VA Southwest
Regional Epilepsy Center, Neurology and Research Services, West
Los Angeles DVA Medical Center, and contributions from our patients and their families. D r Serratosa was partly supported by the
Wilder Penfield and Victor Horsley fellowships and a research grant
from the Epilepsy Foundation of America.
The authors wish to thank all patients and family members who
participated in this study, Drs Greg Castillo (Belize City Hospital)
and Baldorino Barbosa (Corozal Hospital) for helping with data
collection in Belize, Dr James L. Weber (Marshfield Medical Foundation) for providing training for high-output microsatellite genotyping, and Joan Spellman for coordinating the family study.
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