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356
Abstracts
Riyahd, Saudi Arabia; f National Institute of Neurology and
Neurosurgery, Mexico City, Mexico; g Direccion de Investigation
Cientifica, Universidad National Autonoma de
Honguras, Tegulcigalpa, Honduras
Mutations in the EPM2A gene encoding a dual-specificity
phosphatase (laforin) cause an autosomal recessive
fatal disorder called Lafora’s disease (LD) classically
described as an adolescent onset stimulus sensitive
myoclonus, epilepsy and neurologic deterioration. We
present correlation between mutations in EPM2A and
phenotypes of 22 patients (14 families). In addition to
classical LD associated mainly with mutations in exon 4
(P ¼ 0:0007), we identified atypical LD with childhood
onset dyslexia and learning disorder followed by epilepsy
and neurologic deterioration associated mainly with mutations
in exon 1 (P ¼ 0:0015). To understand the two
subsyndromes better, we investigated the effect of five
missense mutations in the carbohydrate binding domain
(CBD-4; coded by exon 1) and three missense mutations
in the dual phosphatase domain (DSPD; coded by exons 3
and 4) on laforin’s intracellular localization in HeLa cells.
Expression of three mutant proteins (T194I, G279S and
Y294N) in DSPD formed ubiquitin positive cytoplasmic
aggregates suggesting they were folding mutants set for
degradation. In contrast, none of the three CBD-4 mutants
showed cytoplasmic clumping. However, CBD-4 mutants
W32G and R108C targeted both cytoplasm and nucleus
suggesting that laforin had diminished its usual affinity
for polysomes. Our data, thus, represents the first report
of a novel childhood syndrome for LD. Our results also
provide clues for distinct roles for the CBD-4 and DSP
domains of laforin in the etiology of two subsyndromes
of LD. To study the ontogenesis of LD pathology and
laforin functions, we disrupted the Epm2a gene in mice.
Supporting the concept of childhood onset or atypical
human LD, homozygous null mutants developed widespread
degeneration of neurons, most of which occurred
in the absence of Lafora bodies, as early as 1–2 months
of age. Dying neurons characteristically exhibited swelling
in the endoplasmic reticulum, Golgi networks and mitochondria
in the absence of apoptotic bodies or fragmentation
of DNA. As Lafora bodies became more prominent at
4–12 months, organelles and nuclei were disrupted. The
Lafora bodies, present both in neuronal and non-neural
tissues, were positive for ubiquitin and advanced glycation
end products only in neurons, suggesting different pathological
consequence for Lafora inclusions in neuronal
tissues. Neuronal degeneration and Lafora inclusion bodies
predate the onset of impaired behavioral responses, ataxia,
spontaneous myoclonic seizures and EEG epileptiform
activity. Our results suggest that LD is a primary neurodegenerative
disorder that may utilize a non-apoptotic
mechanism of cell death.
SY-5
Neuroimaging
SY-05-1
Introduction: focused on functional neuroimaging
K. Iinuma
Tohoku University School of Medicine, Sendai, Japan
During the last two decades of the 20th century, various
neuroimaging techniques have strikingly developed.
Among various neuroimaging methods, functional imagings
give us valuable information about the pathophysiological
mechanisms and condition of neurological disorders. In this
symposium, the several neuroimaging techniques and their
applications will be explained. PET as relatively early
developed imaging method is recently shifting to understand
the receptor binding or brain metabolism. The functional
MRI will give us more detailed mapping of the brain
for fine functions by the development of various methods of
tasks. Magnetic resonance spectroscopy can give us the
information about characteristics of the tissues and/or cells
of the brain, moreover is capable to give the information on,
for example, GABA transmission, etc. Optical topography
recently has been developed by means of near-infrared spectroscopy
(NIRS). This method is multichannel NIRS that
makes spacial expression, and has an advantage of excellent
time resolution. This may have a possibility to analyze the
various phenomena concerning of the brain function, such
as epileptic seizures, motor and mental activity, etc.
SY-05-2
Applications of PET scanning in pediatric neurology
H.T. Chugani
Division of Pediatric Neurology, Positron Emission Tomography
(PET) Center, Children’s Hospital of Michigan,
Wayne State University, Detroit, MI, USA
The clinical role of PET scanning is mainly in localization
of epileptic foci for surgical treatment in refractory epilepsy.
PET tracers used in epilepsy include 2-deoxy-2 ( 18 F) fluorod-glucose
(FDG) and various ligands for evaluating neurotransmitter
function. In temporal lobe epilepsy, interictal
FDG-PET identifies areas of decreased glucose utilization
that correspond to epileptogenic areas (sensitivity: 80–
90%). In nonlesional extratemporal lobe epilepsy, FDG-
PET provides useful lateralization and localization data to
guide the placement of intracranial electrodes. Neurophysiological
correlations based on coregistration of MRI, PET and
subdural electrodes indicate that the seizure onset zone typically
lies in the periphery or boundary of the cortical hypometabolism
rather than within the hypometabolic zone. Our
data also show that the size of the hypometabolic zone
increases along the major propagation pathways as a function
of duration of intractable epilepsy, thus supporting the