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Case
Report: Summary and Discussion
Gary
D. Clark,
M.D.
Professor of Pediatrics, Neurology, Neuroscience
Diagnosis:
Infantile Spasms, Lissencephaly
Infantile
Spasms:
The
patient presented with repetitive spells of rapid flexion of the neck,
extension of the arms, flexion of the hip and knee, and flexion of the
abdominal muscles. These spells occurred in flurries, often upon
awaking from sleep. The mother recognized them as unusual, but
described them as excessive startle responses that were not provoked.
Other
parents of children with this disorder describe their child as colicky
and ascribe these spells to abdominal pain (the child seemingly flexes
the abdominal musculature to guard). In children with colic (excessive
crying in infancy), sudden flexion of the hips and knees may be seen.
However, in colic there is not the extension of the arms nor the
flexion of the neck described in this case. Also, the patient presented
here did not have the excessive crying seen in colic.
A
benign myoclonic condition with spells resembling this child's has been
described in some infants. These children have normal development, a
normal EEG and no other spells. Since the child presented here had
visual inattentiveness (abnormal development) and hypsarrhythmia
(abnormal EEG), he does not have this benign condition.
The
spells described above combined with evidence of abnormal development
(this is not always seen in this condition) and an abnormal EEG make
infantile spasms the most likely diagnosis. These are seizures peculiar
to infancy that usually present between 3 months and 8 months of age.
Infantile spasms are myoclonic seizures often accompanying severe brain
malformations; they may occur in otherwise normal children. If
accompanying brain disease, these seizures are termed symptomatic
infantile spasms (85%). If no brain disease can be identified, these
seizures are termed cryptogenic infantile spasms (15%). The prognosis
and the response to treatment is poor in the symptomatic patients.
Since brain disease, such as structural malformations, can accompany
this disorder and since these brain malformations may impact upon the
child more than the infantile spasms, it is prudent to perform
neuroimaging in the child with infantile spasms.
Lissencephaly:
Both
CT and MRI scans revealed a brain malformation consisting of a smooth
brain (lissencephaly). It is important to properly identify brain
malformations since the genetics vary with the type of brain
malformation seen. In microcephaly, the brain may appear simple, but it
is almost never smooth. This patient did not have microcephaly at
birth, but has acquired it postnatally.
In
pachygyria (part of the lissencephalic spectrum), there are areas of
large simple gyri that may be near areas with normal gyrations. On CT
scans, the brains of patients with pachygyria may appear smooth; MRI
will usually distinguish pachygyria from lissencephaly. Polymicrogyria
(many small gyrations), may give the appearance of a smooth brain but
the MRI will usually distinguish these malformations from the
lissencephalies.
So
called cobblestone lissencephaly (named because of the pebbled
appearance of the surface of the brain) accompanies Walker-Warburg
syndrome and Fukyama Muscular Dystrophy. Hydrocephalus usually
accompanies this form of lissencephaly.
This
patient appears to have classic or type 1 lissencephaly such as that
seen in Miller-Dieker lissencephaly (MDL), isolated lissencephaly
sequence (ILS) or X-linked lissencephaly. These forms of lissencephaly
are characterized by an extensive heterotopic zone of neurons that
appear to have been arrested in the process of migration and the brain
has a smooth cortical surface especially posteriorly. The brain is
smooth owing to a lack of complexity of the outermost surface of the
brain.
This
patient had a deletion
in the short arm of one 17th chromosome
that is only detectable by
fluorescent in situ hybridization (FISH) for the gene LIS-1.
This gene deficit in one chromosome leads one to conclude that this
patient has Miller-Dieker lissencephaly. Both the mother
and father
had normal FISH for LIS-1, therefore,
they are unlikely to be
carriers of a balanced translocation that could put them at risk for
further affected children.
A Review of
Lissencephaly
Lissencephaly
(smooth brain) refers to the configuration of the cortical mantle in
human disorders in which the cerebral cortex is severely malformed such
that the surface of the cortex lacks the gyri and sulci seen in normal
brain. In Miller-Dieker lissencephaly (MDL), the cortical malformation
results from the arrest of migrating neurons in the formation of the
cortical plate (Alvarez et al., 1986; Daube and Chou, 1966; Dieker et
al., 1969; Miller, 1963). MDL and some cases of isolated lissencephaly
sequence (ILS) result from the deletion of one copy of a gene on the
short arm of the 17th chromosome, LIS-1
(Dobyns et al., 1993;
Ledbetter et al., 1992; Reiner et al., 1993).
Patients
with this brain malformation are severely mentally retarded, visually
inattentive due to cortical blindness, and 80% have infantile spasms.
Over 90% of patients with this disorder have seizures at some point in
their life. Head circumference is typically normal at birth but a
developing microcephaly is characteristic. This is due to the lack of
complexity of the brain, improper synapse formation, and thus poor
brain growth. A normal head size at birth is typical because the normal
complement of neurons and cells are present. It is the location of
these cells that is abnormal.
Miller-Dieker
lissencephaly is a gene deletion syndrome. The minimal deletion
necessary to result in lissencephaly involves one copy of the gene LIS-1.
Most patients with isolated lissencephaly will have a deletion of this
gene or they may have a deletion of another gene on the X chromosome as
discussed below. This LIS-1
gene encodes a subunit of a brain
platelet-activating factor acetylhydrolase, an enzyme that degrades
platelet-activating factor. The deletion of one copy of this gene is
all that is necessary to result in the lissencephaly phenotype.
Other
genes close to the lissencephaly gene are probably necessary for some
of the other characteristics of Miller-Dieker lissencephaly. Those
other features include an upturned nares, micrognathia, a sacral dimple
in 70% of patients, cardiac anomalies in 50% of patients, and deep
palmer creases in 50 to 70% of patients. Somatic abnormalities are
typically not seen in the isolated lissencephaly patients, thus
Miller-Dieker lissencephaly is probably a contiguous gene deletion
syndrome.
The
LIS-1
gene encodes a protein that is a subunit of a brain
platelet-activating factor (PAF) acetylhydrolase, an enzyme that
degrades the lipid messenger, PAF. This enzyme complex is a novel
serine esterase that is perhaps best classified as a
calcium-independent phospholipase A2; it is pharmacologically related
to brain acetylcholinesterase (Hattori et al., 1994a; Hattori et al.,
1993; Hattori et al., 1994b). In addition, this form of brain PAF
acetylhydrolase may serve as a signaling G-protein like complex (Ho et
al., 1997). However, it is not known how LIS-1
functions in the
development of the cortical plate, nor is it known how a hemideletion
of LIS-1 and
the resulting alteration in PAF degradation (or
signaling) cause a neuronal migration disorder. It has been proposed
that PAF serves as a neuronal cytoskeletal altering signal that can
alter the process of neuronal migration (Clark et al., 1995).
Patients
with lissencephaly are severely mentally retarded and require total
supportive care. The lifespan of the patient with lissencephaly is not
normal. These patients usually succumb to pulmonary infections owing to
a lack of control of secretions.
At
least one other classic lissencephaly locus exists. That locus appears
to be on the X chromosome (Xq22.3) and only males have this form of
lissencephaly. Female carriers of this gene have subcortical band
heterotopia. The gene for this disorder has not been isolated. The
brain pathology appears to be nearly identical to that of Miller-Dieker
lissencephaly.
Review of
Infantile Spasms
Infantile
spasms are a myoclonic seizure type seen in infancy. The typical age of
presentation is between three and eight months. Infantile spasms can
either be symptomatic of an underlying neurologic or metabolic
disorder, or can be cryptogenic which means that no underlying cause
for the seizure can be found. The prognosis for infantile spasms in the
symptomatic group is dismal. Prognosis in the cryptogenic group can be
good, and some authors feel that early treatment with steroids, such as
ACTH, improves the developmental outcome in these patients. This
patient clearly had symptomatic infantile spasms. The EEG showed
hypsarrhythmia (high voltage, disorganized, polyspikes) which is
characteristic of infantile spasms. In this pattern of EEG, the
recording of the electroencephalogram cannot be made at the standard
amplitudes.
The
seizures in lissencephaly are usually very difficult to control. The
use of steroids (ACTH and prednisone) though typical for treatment of
infantile spasms, may or may not be successful in the treatment of
these seizures. In addition, seizures will return following treatment
with steroids. Therefore, initiation of other anticonvulsants is
appropriate in this condition.
For
further information for parents and physcians, click to go to the Lissencephaly
Network.
References
-
Alvarez
LA, Yamamoto T, Wong B, Resnick TJ, Llena JF,
and Moshe SL (1986) Miller-Dieker syndrome: a disorder affecting
specific pathways of neuronal migration. Neurology, 36:489-493.
-
Clark
GD, McNeil RS, Bix GJ, and Swann JW (1995)
Platelet-activating factor produces neuronal growth cone collapse.
NeuroReport, 6:2569-2575.
-
Daube
JR, Chou SM (1966) Lissencephaly: two cases.
Neurology, 16:179-191.
-
Dieker
H, Edwards RH, and ZuRhein G (1969) The
lissencephaly syndrome. Birth Defects, 5:53-64.
-
Dobyns
WB, Reiner O, Carrozzo R, and Ledbetter DH (1993)
Lissencephaly: a human brain malformation associated with deletion of
the LIS1 gene located at chromosome 17p13. JAMA, 270:2838-2842.
-
Hattori
M, Arai H, and Inoue K (1993) Purification and
characterization of bovine brain platelet-activating factor
acetylhydrolase. J Biol Chem 268:18748-18753
-
Hattori
M, Adachi H, Tsujimoto M, Arai H, and Inoue K
(1994a) Miller-Dieker lissencephaly gene encodes a subunit of brain
platelet-activating factor acetylhydrolase. Nature, 370:216-218.
-
Hattori
M, Adachi H, Tsujimoto M, Arai H, and Inoue K
(1994b) Catalytic subunit of bovine brain platelet-activating factor
acetylhydrolase is a novel type of serine esterase. J Biol Chem,
269:23150-23155.
-
Ho YS,
Swenson L, Derewenda U, Serre L, Wei Y, Zbysek D,
Harrori M, Adachi T, Aoki J, Arai H, Inoue K, and Derewenda ZS (1997)
Brain acetylhydrolase that inactivates platelet-activating factor is a
G-protein-like trimer. Nature, 385:89-93.
-
Ledbetter
SA, Kuwano A, Dobyns WB, and Ledbetter DH
(1992) Microdeletions of chromosome 17p13 as a cause of isolated
lissencephaly. Am J Hum Genet, 50:182-189.
-
Reiner
O, Carrozzo R, Shen Y, Wehnert M, Faustinella F,
Dobyns WB, Caskey CT, and Ledbetter DH (1993) Isolation of a
Miller-Dieker lissencephaly gene containing G protein -subunit-like
repeats. Nature, 364:717-721.
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Last Modified:
September 17, 2009
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