A Case of Zellweger Syndrome with Extensive MRI Abnormalities and Unusual EEG Findings

Abstract

Differential diagnosis in a newborn with dysmorphic features and profound neurologic dysfunction should include the cerebro-hepato-renal syndrome of Zellweger. Its distinct clinical features, markedly elevated plasma levels of very long chain fatty acids and characteristic radiological findings support the diagnosis, which can now be confirmed by genetic markers. Quite consistent abnormalities of the neurophysiological studies in this syndrome have also been reported. We report a case with typical clinical and biochemical findings in whom distinctive brain MRI abnormalities were found. The results of neurophysiological studies with an unusual EEG pattern of continuous negative vertex sharp waves and spikes are discussed. We believe that such a pattern could be considered as a pathognomonic EEG finding, especially in cases of Zellweger syndrome with extensive brain abnormalities and may even be closely associated with cortical dysplasias.

Full text

A
Case of Zel lweger
Synd
rome
with Extensive
MRlAbnormalities
and Unusual EEG
Findings
Darja Paro
Panjan,
Nu5ka Peiarid Meglid
and
David
Neubauer
KeyWords
Conlinuous Rolandic
Sharp Waves and
Spikes
Distinctive
EEG
Pattern
Electroencephalography
Zellweger
Syndrome
ABSTBACT
Differential diagnosis
in
a newborn with
dysmorphic fea-
tures and
profound
neurologicdysfunction
should
includethe
cerebro-hepato-renal
syndrome
of
Zellweger.
lts distinct
clini-
cal features, markedly
elevated
plasma
levels
of very long
chain fatty acids and
characteristic radiologicalfindings
sup-
port
the
diagnosis,
which
can now
be confirmed
by
genetic
markers.
Quite
consistent abnormalities
of the
neurophysio-
logical
studies
in
this
syndrome have also
been reported. We
report
a case
with
typical clinical
and biochemicalfindings
in
whom
distinctive brain MRI
abnormalities were found.
The
results
of
neurophysiological
studies
with
an unusual EEG
pattem
of continuous negative
vertexsharp waves
and
spikes
are
discussed. We
believe that
such a
patlern
could
be
con-
sideredas
apathognomonic EEGfinding,
especially in
cases
of
Zellweger
syndromewith
extensive brain
abnormalities and
mayeven
be closelyassociated
with cortical
dysplasias.
INTRODUCTION
The
peroxisomaldisorders
are a
group
of inherited
dis-
eases in
which there is impairment
in one
or
more
peroxiso-
malfunctions.Thedisordersaresubdivided
intothreegroups
depending
upon
whetherthere
is
a
more
generalized,
multi-
ple
or
single
loss
of
peroxisomal
functions. Zellweger syn-
drome is
a
neonatal
peroxisomal
disorder with
general
impairment
of
peroxisomal
functions
and
a severely reduced
number
of
peroxisomes.r
lt
is
usually a lethal disease
char-
acterized
by
severe
clinical,
pathological
and biochemical
abnormalities, including
atypical
craniofacial dysmorphism
and
neuronal
migration
disturbances.
The
classic type
of
Zellweger
syndrome is
characterized
bythe association of: dysmorphogenesis,
severe neurologi-
cal
dysfunction, neurosensorydefects,
regressive
changes,
renal cysts,
calcific stippling, failure to
thrive, early death
and absence
of
recognizable
liver
peroxisomes.e3
We
present
clinical features,
biochemical abnormalities
and
neuroimaging
findings in
a neonate with
Zellweger syn-
drome. The
neurophysiological
studies
are
presented
and
@2001
voL.
32
NO
1
cittrrcRr eucrRoENcEpHALoGRApHv
typical EEG
finding
of centrally
generated,
repetitive
and
regular
(3
Hz) negative
sharpwaves
and
spikes
is
discussed.
CASEREPORT
The
baby boy was
born
to a 39-year-old female who
already had four
healthy
children, while
one
pregnancy
ended with
a stillbirth. There
was no
consanguinity
and no
family
history of
any metabolic
disorder. The
pregnancy
was
uncomplicated.
Labor started
at 34 weeks
gestation
and
was
terminated
by Caesarian
section. A
male infant was
born
with birth weight
20 1
0
g.
He
was appropriate for gestational
age
with
Apgar scores
of 5
and 6 at 1
and 5 minutes respec-
tively.
Physicalexamination
showed
dysmorphiccraniofacial
features
with a high
bulging forehead,
widely-opened
fontanels
and
split
sutures,
hypoplastic
supraorbital ridges,
ocular hypertelorism,
epicanthic
folds,
low-set
ears
with
abnormal helices,
high-arched
palate
and
webbed
short
neck
(Figurel
).
(A
signed
release was
obtained from the
patient's
father.)
Ocular findings
included
corneal
cloudi-
ness
and cataracts
in both eyes.
Limb
anomalieswere noted
with camptodactyly,
transverse
palmar
crease
and talipes
equinovarus. Examination
of the
genitalia
revealed crypt-
orchidism. The
newborn
was
profoundly
hypotonic,
with
absent
deep
tendon
reflexes,
and was
never alert. He had
frequent
myoclonic
and tonic
convulsionsand apneic
spells.
Laboratory
studies
including
those
for
glucose,
elec-
trolytes, BUN, bloodammonia
and liverenzymes
were normal
while
serum
bilirubin was
slightly elevated.
Chromosomal
analysis revealed
a karyotype
of 46XY.Abdominal
ultrasound
revealed
normal liver
echogenicity
and hyperechogenic renal
cortexwith subcortical
cysts.
X-ray of the knee revealed
patel-
la stippling.
Biochemical laboratory
tests
showed elevated
levels
of
pipecolicacid
in serum
and urine. Peroxlsomalfunc-
tion tests revealed
increased
values of VLCFAwith
elevated
C26 and raised C24lC22andC26lC22
ratios.
MRI
ol the
head
showed diminished
myelination,
dys-
plastic
changes
of the corlex
and
germinolytic
cysts.
On
T2
Fromlhe
Departmentsof
Neonatology
(Darja
Paro
Panjan,
MD) and Child
Neurology
(David
Neubauer,PhD),
Univ-ersityChildren's Hospital,
andClini-
cal Inslitute
of
Radiology (Nuika
Pecard
Megl[),
University
Medicat
Centre,
Liubljana, Slovenia.
Requestslorrepriilsshuldbeaddressedto
David
Neubauer,
PhD,
Depart-
ment
ot
Child
Neurology,
University
Children's Hospital, Vrazov
trg
1, 1525
Llubljana,
Slovenia.

CLI NICAL
ELECTROENCEPHALOGRAPHY
Figure 2a.
MRI
of the
head.
Axial
spin-echo
(3000/120)
image
shows diminished
normal low
signal
in
he
posterior por
tions
of
the
posteri-
or limbs ol
the
internal
capsules,
revealing impaired
myelination. Low
signal is seen in
the ventrolateral
thalami, indicating
myelination in these
structures.
Microgyric
pattem
is
presenl
in
the frontal cortex and double cortex is seen in the insular regions.
weighted
images no low
signal intensity, normally seen atthis
age, was
present
in
the cerebralwhite matter
in
perirolandic
regions
and diminished low signalwas
presenl
in
the
poste-
rior
portions
of the
posterior
limbs
ol the internal
capsule,
both indicating impaired myelination. Low
signalwas seen in
the ventrolateral thalami,
in
the
superior cerebellar
peduncles
and in the dorsal
brainstem
showing
myelination in these
structures
(Figure
2a). Dysplastic
changes
involved
almost
the entire cerebral
corlex. Abnormal
polymicrogyric pattern
was seen in the
perirolandic
regions
with
irregular
corticaF
white matter
junction
and
large
infoldingsof the cortexwhile
frontal
cortex appeared
microgyric
(Figures
2a
and 2b).
Pachygyric
pattern
was seen
in the
temporal
and in the
pari.
etallobes. In the
perirolandic
and
insular
regions, corlexwas
thickened with an
intervening
layer of white matter intensity
seen between
athin outer and
athicker
inner
layerof the
gray
matter.Two
germinolytic
cysts, isointensewith
cerebrospinal
fluid,
separated
from it by a
lhin circular
hypointense line,
were
present
at the caudothalamic
notches
bilaterally, best
seen
on the sagittal T1
weighted images,
but
also
recog-
nized on axialT2weighted
image
(Figure
2b).
The
neurophysiological studies were
performed
during
thefirst
month of
life:no
responsewasobtained bv
brainstem
@2001
VOL. 32
NO
1
Figure
1.
our
patient
showing typical dysmorphic
tacial
teatures.
Figure
2b.
MRI
ofthe
head.
Axial spin-echo
(3000/120) image
shows an
abnor-
mal
polymicrogyric
paftern
in the
perirolandic
regions
with ineg-
ular
cortical
white
matter
iunction.
Large
perirolandic
infoldings
ol
cortex
are
seen
bilateral-
ly.
Frontal
corlex
appears mrcro-
gyric.
Bilateral
germinolytic
cysb, isoinlense with cerebrospinal
fluid, separaled fiom it
by
a hin circular hypintense line,
are
seen between anterior
and
middle
third of
the
corpus
of
lateral
ventricles.
auditory evoked
potentials
(BAEP)
while
motor
nerye
con-
duction
velocities
(NCV)
were
normal. Electroretinogram
(ERG)
was
extinguished. There was no response
on
flash
visual evoked
potentials (VEP).
An EEG
was
performed
on
day 20 and
revealed
a
peculiar pattern
which
emerged sud-
denly during the
recording.
Over all the
cenlral
(rolandic)
leads repetitive episodes of
continuous negative sharp
waves and
spikes
were recorded
appearing in a monomor-
phous
mannerwith a
constantfrequency
of3
Hz.
ltappeared
as if
this
focus was
generated
only
from
the rolandic areas
(Figure3,
a, b and c). Exactlythe
samepatternwas recorded
on
afollow-up
EEG l4dayslater.
Furtherclinicalcourseof the
boy was slowly
downhill.
The
boy had feeding difficulties,
seizures and
apneicspells and he diedat4 monthsofage.
Dlscussl0t{
Zellweger Syndrome is
an
autosomal recessively
inherited
disorderwith
an estimated
incidence
of
1
:100,000live
births.
Two
different
loci have
been
identified,
one at chromosome
7q1
l .23and asecondat l
p22-p2l
,
thesiteofthe
peroxisomal
membrane
protein
gene.'
lt
appears that the clinical findings
and
biochemical
abnormalities in
patients
with
Zellweger
syn-
drome are
generally
due to a defect in
peroxisomal
biogene-
sis.t6 Recent research indicates
thatthe
basic defect
consists
29

"i,*,"o.
aaaar.oENcEPHALocRAPHY
of adefective
importof
matrix
proteins
into
pre-existing
perox-
isomes which
originate
lrom
germ
cells.
lf
the matrix
proteins
fail to reach
the
peroxisomes,
no further
peroxisomes
are
formed.Astate of absent
or
diminished
oeroxisomes
ensues.
which has aprofound
impacton metabolism.rg
The
antenatal history
ofthe
patients
is usually unreveal-
ing,
although fetal movements may be decreased. There is
prenatal
growth
failure
withfullterm
birth
weights
below3000
g
and
2500
g
in
50o/o and25o/o ol cases respectively.'gA
litera-
ture survey
provides
clinical
criteria
for
classic Zellweger
syndrome, most of which were
also
present
in
our
patient.
Craniofacial dysmorphic features include large fontanels,
flat
occiput,
high forehead
with
shallow supraorbital
ridges
and flat
facies,
anteverted
nares,
eaf anomalies,
inner
epi-
canthal tolds,
Brushfield
spots, mild micrognathia,
and
redundantskin
of the neck. Limbanomalies
arevery
common
and consisl of variable
contractures
with
camptodactyly,
lim-
ited knee
exlension, equinovarus
deformity and
simian
crease.
Radiographic
stippling
of
patellae,
greater
trochanlers and triradiate cartilages may
be
present.
Apart from
the dysmorphic features,
severe
neurological
dysfunction is characteristic:
profound
muscular hypolonia
with areflexia,
cerebral depression,
nonresponsiveness,
attacks
of apnea and convulsions.
Gross
defects
of early
brain
development are
present
including
pachymicrogyria,
heterotopias,
abnormal migration,
subependymal
cysts,
hypoplastic corpus
callosum
and olfactory lobes. lt isthought
that ependymal abnormalities may
contribute to the
patho-
genesis
of cerebral dysgenesis in
Zellweger syndrome.l0
Barkovitch and Peck"
determinated characteristic MR imag-
ing features and
concluded that the combination
of
hypomyelination, cortical malformalions and
germinolytic
cysts,
which all were
also
present
in our
patient,
are
highly
suggestive of Zellweger syndrome.
Severe
abnormalities could also be demonstrated by
neurophysiological
studies,
reflecting
diffuse
cerebral dys-
lunction as wellas long
myelinated
fibertract
dysfunction.
In
the study of Govaerts etal,'2characteristic
abnormalities of
the
EEG in 9/1 1
patients
with
Zellweger syndrome
consisted
of continuous
negative sharpwaves
and
spikes atthevertex.
Our
patient
showed
similar EEG morphology
(negative
sharp
wave
and spike) which was detected over the central
electrodes
(Figure
3c), and this
pattern
seemed
to
be
gen-
erated
from the rolandic
areas
of the brain.
Takahashi
et
al.'3 described
infrequent
bilateral
independent multifocal
spikes,
predominantly
in the
frontal motorcortex and its sur-
rounding
regions,
while in
the
patient
described by Volpe
and Adamsl4 EEG
showed
well{ormed
spikes
with
phase
reversals in both temporal
areas. lt seems that
this type
of
frequent,
continuous
epileptiform activity may be associated
with cortical dysplasias
being
located
in
different areas
vary-
ing
from
patienl
to
patient.
Many EEG
patterns
are
quite
consistenl with typical
neuroradiological brain
abnormalities
and syndromesls
and
some can
even
be
the common hall-
mark of certain
syndromes.J6
lT
We believe that
the charac-
teristically
abnormal EEG in
our Zellweger
case
is
consislent
with
extensive brain
abnormailities found
on brain MRl.
lt
is
further
suggested that
characteristic and
extensive brain
abnormalities can influence
the neurophysiological func-
tions
and
produce
the
associated,
quite
easily
recognized
EEG
pattern
of
generated,
continuous, rolandic
sharp waves
and spikes.
02001
vol.
32 NO
1
6n
T14
0&l
0rF
1*ffiffi"'rm
l---::;
-'---
-:"^
''-"-=::--'1"-.-
,--
l;-'--
Figure 3,
The EEG record of our
patient:
a) revealing sudden emergence of centrally located
negative sharp waves; b) evolving to slow sharp
waves and spikes of continuous,
ralher
monomorphous
1
Hz
frequency
and
c) appearing
in
a typical
3
Hz spike and wave
pattem
gener-
ated
from
the
rolandic brain
areas. Note
phase
reversal
lrom the
C, efectrode.
30

CLI
NICAL ELECTROENCEPHALOGRAPHY
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