Personal Notes from ICNA 2006
Anti-epileptic drug and
apoptosis in developing brain
Dr. Chrysanthy
Ikonomidou
- Apoptosis is normal in dev.
- Alcohol and drugs affect this system
- Studies done in rodents
- Alcohol in 7d mouse, increased degeneration by
apoptosis
- Ethanol interferes with GLU and GABA to cause
apoptosis
- Anti-epileptic drugs affect GABA, GLU, and
voltage gated channels, can cause massive apoptosis in rodents, but is
this clinically relevant?
- VPA-treated rats have smaller brains and less
neurons on follow-up
- Behavioral sequelae in rodents also VPA causes
poorer learning of Morris water
maze
- Anaesthetic agents also cause widespread apoptosis and
cognitive deficits
- Phenobarbital for instance. Only levetiracetam and ACTH safe, and topiramate
at low doses (dose dissociated)
- AEDs impair intracellular signaling and neurotrophins
- ?concurrent use of neuroprotection,
e.g., estrogen compounds like 1-beta-estradiol
- Of note in prems with
sudden non-physiologic drop in estrogen at birth ???
Congenital muscular dystrophies
Dr. Haluk
Topaloglu
CMD (congenital muscular
dystrophy)
- EMG is myopathic or
normal, so muscle ultrasound is more useful
- Deficient protein
- Merosin deficiency
- motor delay, peripheral neuropathy, non-ambulatory,
contractures, wasting, and normal cognition. White matter changes on
MRI.
- Prenatal diagnosis possible @ 11 weeks (from
8-9 weeks)
- Collagen VI
- Bethlem myopathy (milder, in
adults, decreased fetal movement, clubbed foot, finger contractures,
normal CK)
- Ullrich (proximal contractures, hyperlaxity,
dermatitis)
- Prenatal diagnosis possible by 8-9 weeks
- Genotype/phenotype correlation
- Deficient protein glycosylation
- Remember eye abnormalities suggests brain
abnormalities
- Alpha-dystroglycan
disorders
- Fukuyama
- MEB
- LGMD2 1
- MDC1C
- WWS
- LARGE (MDC1D)
- Rigid spine syndrome
- Marinesco-Seogren
- merosin-positive CMD
Congenital
myopathies
Dr.
Monique Ryan
·
central core
o
autosomal
dominant, variable expression
o
walk 3-4 years, kyphoscoliosis
o
atypical forms (limb-girdle, Autosomal resessive
)
o
>90% have
mutated ryanodine receptor, malignant hyperthermia
·
nemaline myopathy
o
extraocular muscle and heart spared
o
nemaline bodies on Gomori trichrome
·
myotubular/centronuclear
o
X-linked myotubular myopathy
o
Dominant form dynamin 2
o
Recessive form
·
Multiminicore myopathy
o
Ophthalmoplegic
o
Older onset
o
Ryanodine receptor or selenoprotein
mutation
·
Congenital
fiber-type disproportion
·
Myofibrillar myopathy
o
Distal weakness,
dysphasia
o
Intermediate
filaments, e.g., desmin
·
Selenoproteinopathies
o
Rigid spine, multiminicore, myofibrillar
o
Marfanoid habitus, tubular nose, midface hypoplasia, respiratory involvement
Congenital muscular
dystrophies with structural brain involvement
Dr. Jiri
Vajsar
- Laminin alpha2 and alpha-dystroglycan
deficiencies
- Autosomal recessive, hypotonia,
motor delay, high CK
- Some have respiratory involvement
- MDC1A LAMA2 gene seizures in 30%, normal
internal capsule and corpus callosum
Classification of CNS
malformations
H. Sarnat
It is not birth, nor
marriage, nor death, but gastrulation that is truly
the most important day of your life.
Vertical,
longitudinal, and horizontal (medio-lateral or latero-medial) axes of the CNS. E.g. Emx2 gene expressed more rostrally.
Overexpression = hyperplasia/duplication
Underexprcssion = hypoplasia/dysplasia
E.g. diplomyelia
is overexpression of Shh
gene. Sacral agenesis from IDM (under expression). Rhombencephaloaynapsis (with septo-optic dysplasia)
from under expression. Holoprosencephaly is underexpression.
Neural crest migrates in
different streams.
- Epidermal nevus syndrome midline hyper or hypopigmentism
- Holoprosencephaly
- Or neural tube closes approx. 5 weeks
- Depends on timing and location of mesencephalic neural crest migration disturbance
Intercanthal ligament from prosencephalic
neural crest to cause forward facing eyes. Hypertelorisrn associated with agenesis of
corpus callosum + procencephlic neural crest. Hypotelorism is from mesencephalic
neural crest.
Face predicts the brain.
Neuroblast Migration
Takahashi
Ontogeny of 6-layer neocortex
- Neuronogenesis 7 - 17 wks
- Migration of neuroblast
from 10 wks by the inside-out rule
- Differentiation Of neocortex
until postnatal period
·
Cajal-Retzius cells produce Relin to stop
migration at the surface.
·
3 neuronal
populations arise from 3 progenitor populations with 2 migration patterns.
·
Ventricular zone
makes excitatory non-GABAergic neurons
·
Radial migration
i.
Locomotion
ii.
Somal tronslocation
iii.
Multipolar migration
·
Tangential
migration
i.
Interneurons - from medial/caudal ganglionic
eminence
ii.
Cajal-Retzius cells 3 origins migrating tangentially to cover
brain surface (cortical hem)
Tuberous sclerosis complex
Paolo Curatolo
- 1:6000 live births
- TSC1 (9q34) Hamartin
- TSC2 (16p13) Tuberin
- Hamartin-tuberin complex is a tumor suppressor acting on mTor
- Either one inherited and one acquired, or both
acquired to cause hamartomas
- More than 1000 mutations involved in tuberous
sclerosis
- TSC1 more common than TSC2
- Epilepsy (focal complex partial and drop or
infantile spasms), behavior, sleep disorders
- TSC2 more severe tuber load, behavior, and
seizures
- Tubers, subependymal nodules, SEGA, agenesis of
corpus callosum
- Early onset seizures associated with more severe
phenotype later on
- Vigabatrin for infantile spasms in Tuberous Sclerosis
- Vigabatrin retinal toxicity in 10% in early childhood, 30%
in adults
- Migration disorder
- Abnormal cortical thickness dyslamination
- Tubers focal cortical dysplasia
- Arrested neuronoblast
migration
- Migration lines related to tendency to
generalized, intractible seizures
- TSC1 mutation found in focal cortical dysplasia = focal TSC1
- ? rapamycin can shrink
cortical tubers rapamycin works on mTor
Hemimegalencephaly
L. Flores-Sarnat
- Hamartomatous dysgenesis with
overgrowth of one hemisphere
- Unknown cause but easily confused with tumour
- Pathogencsis
- Cellular prolif
- Neuroblast migration
- Delayed maturation
- Defective genetics
- Mutated Symmetry genes
- Forms of megalencephaly
- Isolated
- Associated e.g. neurocutaneous,
Aicardi, etc.
- Total
- Proteus Syndrome, hypermelanosis
of Ito, hemilissencephaly, epidermal nevus
syndrome, tuberous sclerosis
Molecular Genetics of CNS tumours
Peter Collins
Cancer treatment gets personal.
Common tumours
- Pilocytic astrocytoma
- Ependymoma
- Medulloblastoma
Microarrays
- Whole genome 1 MB array
- Chromosome tile path array
Pilocytic
astrocytoma
- NF1 patients increased risk
- Reports of 17q loss
- Expression of NF1 in non-NF1 tumours
- No clear pattern of loss Single cases of tp53
and PTEN mutations
- Microarray can be used to detect extra or missing copies of
genes
- Adult tumours have more trisomies,
not in children
Ependymoma
- Grade II tumour
- Common in NF2 loss of chr
22q and NF2 mutations
- E.g intracerebral ependymona loss of chr 6
most common
Medulloblastoma
- Turcot syndrome type 2 APC on 5q21
- WNT pathway with mutations of beta-catenin most common
- PTCH pathway with mutations in SMO and GLI1
- Amplified chr 2 MYCN,
and other genes
- Breakpoint on 17q
- Atypical teratoid tumour loss of 22q11.2, gene SMARCB1
Drugs targeting molecular abnormalities include Gleevec
and Herceptin. Translate this to targeted therapy of
pediatric tumours.
Epidemiology of CNS tumours
Sergio Rosemberg
Epidemiology difficult due to classification
variations.
Genetic polymorphisms in preterm brain injury
Walter Allan
- Incidence of disability increasing in pretcrms, along with survival
- For every 100 children 500-990g, 18 more
survived, 11 handicapped
- Incidence of PVL stable, grade 3-4 IVH climbing
or not
- Does gender/genomics play a role
- Gender
- IVH and DEHSI more common in males
- Indomethacin prevents IVH and improves Peabody scores only in males
- Sexually dimorphic gene expression precedes gonadal differentiation
- XY cells more susceptible to toxicity and less oligo precursor development
- Genetics
- Concordance to IVH in twin pairs, but less than
BPD (not NEC)
- Col4a1 mutations segregate with porencephahy and IVH in family studies, and in mouse
models (C-section prevented hemorrhage)
White matter injury in cardiac disease
Steven Miller
- 6-8/1000 newborns have cardiac anomalies, 50%
require surgery
- Neurobehavioral anomalies in >50% pre-surgery
- At school age, type of bypass did not affect
performance
- >33% had brain injuries prior to surgery for
TGA, balloon atrial septostomy
was highest risk factor
- Brain lesions look like white matter injury in
premature infants
- Postoperatively, hypotension is highest risk
factor for white matter injury
- Stroke and white matter disease most common
finding
- Normal term injury patterns are watershed and
basal nuclei, relative sparing of white matter
- 3D MRS (NAA/choline,
lactate/choline) and DTI (average diffusivity,
fractional anisotropy)
- Maturity increases NAA, decreases lactate,
decreases relative diffusivity, increases fractional anisotropy
- Diffusion tensor tractography
increases over time, but increase in development of corticospinal
tracts impaired by early injury
Short and long-term effects of early seizures
Yu-Ju Jiang
- Recurrent seizures in neonatal rats causes
long-term NMDA receptor subunit expression in vitro and in vivo
- Changes in NMDA receptor may change Ca
homeostasis
Early diagnosis of neonatal stroke
Linda deVries
- Early neonatal stroke is DOL#1-3
- Late neonatal stroke is within 1 month
- AIS 70%, SVT 30% of neonatal stroke
- SVT
- sagittal, transverse, straight sinuses most commonly
involved
- Symptoms seizures, bulging fontanelle,
poor feeding, lethargy
- Diagnosis by colour doppler ultrasound, CTV, or MRV
- Term IVH can often be caused by SVT look for
it!
- AIS
- MCA most common, and 70-80% L>R
- Focal seizures are most common presenting
symptom
- Lipoprotein a,
factor V leiden, MTHFR
- Classic wedge shaped lesion on head ultrasound,
but usually already MRl by time this can be
seen
- Cavitation by 3 months
- In prems, left side
also more common affected
- Prem risks are CTG abnormalities, TTTS,
hypoglycemia, low Apgars
- MRS high lactate, low NAA
Genetics Of Rett
Syndrome
Alan Percy
- Female predominance all over the world
- Profound cog impairment, communication, stereotypies, growth failure
- normal early development - quiet and hypotonic
- Deceleration of growth, loss of purposeful hand
movement
- Evolve hypotonia to
rigidity, loss of walking
- Variable clinical expression
- Phenotype
- Seizures, behavioral patterns
- Breathing irregularities (only during wakefulness)
- GI difficulties (constipation, GERD)
- nutrition requirement (more Calories and
protein)
- Scoliosis (surgery)
- Ambulation
- Significant longevity
- Mutation in MECP2 but can be without MECP2 and
mutation can exist without Rett
- Some males survive pregnancy, but are very ill
from birth (fatal encephalopathy)
- Imaging
- Reduced brain weight, volume, melanin
- Small neurons, simplified gyri
- Genetics
- MECP2 mutations methyl-CpG-binding
protein
- Maintains maturation of neurons
- Caudal-rostal
expression
- Usually new mutations, familial forms tend to be
large deletions
- Rett mutations increase mobility of protein binding
- Mouse knock-out or knock.-in mutants
- Role in BDNF transcription
Organic acidurias
Bruce Korf
Glutaric aciduria type 1
- Diagnosis by urine Glutaric
acid
- Dystonia, sudden acute attacks with neurological collapse
like an encephalitic disorder, poor recovery to baseline, bright and
anxious look, preserved visual function
- Rapid increase in head circumference, macrocephaly
- Prenatal diagnosis possible
- Presentations
- Acute 1 classic
- Insidious/late
- Asymptomatic
- Macrocephalic variant
- Congenital
- Adult with leukodystrophy
- Management low protein, no lysine, carnitine supplementation
- Acute management Avoid catabolism, IV calories
and buffering
- Diazepam helps for dystonia,
as does intrathecal baclofen
- Amish, Oji-Cree, Irish, Spanish, Nordic, and
other multiethnic mutation
- Glutaryl-CoA
dehydrogenase (GCDH) in mitochondrial matrix
- Acute striated necrosis symmetrically during
metabolic crisis, neuronal loss in putamen in
infancy, white matter in adults
Early cerebellar injury in premature infants
Catherine Limperopoulos
- Germinal matrices are vulnerable to hemorrhage
- Major events in cerebellar development are
vulnerable to failure
- Cerebellar migration from Germinal matrix
- To deep nuclei
- To Purkinje cell layer
- To the secondary germinal matrix and the
granular cell layer
- Mastoid fontanelle
ultrasound imaging to study posterior fossa in prems
- Cerebellar hemorrhage significant in extreme low birthweight babies
- Risk factors- emergency C-section, PDA, 5d acidotic pH
- Unilateral hemorrhage most common, mostly
associated with supratentorial lesions
- Inferomedial predilection for injury
Normal cerebellum with cerebral injury
- Still has smaller cerebellum, perhaps from trophic withdrawal
Normal cerebellum and cerebrum on MRl
- 3rd trimester is important for
cerebellar growth
- Prems at corrected term age have smaller cerebellum
than normal babies born term
Outcome in cerebellar hemorrhage
- Hypotonia
- Gait problems
- Extraocular abnormalities
- Microcephaly
- Expressive/receptive language
- Visuo-motor deficit
- Functional and behavioral/socialization deficits,
autistic features
Developmental disorders of the cerebellum
Eugen Boltshauser
- Cerebellar disorderd
- Hypoplasia vs. Dysplasia
- Focal vs. Generalized
- Syndromes
- Joubert syndrome (cerebello-ocular-renal
syndromes)
- Recessive inheritance
- <50% have respiratory difficulties
- Hypotonia, late ambulation
- Oculomotor apraxia, retinitis pigmentosa
- Low cognitive, and behavioral abnormalities
- Molar tooth sign, not pathognomonic
other syndromes as well
- Cerebellar hypoplasia