Brain Malformations Flashcards
What is microcephaly an issue with?
cell division, specifically an error in neuroblast proliferation
extra neurons => megaencephaly
What is the pattern of development (at least neurologically)?
inside –> out
back –> front
helps to identify patients that may be genetic
What is the first step when considering genetic testing in a neurologic setting?
Is the developmental pattern representative of a genetic condition or an acquired one?
What is the pattern of inheritance for most brain malformations?
de novo
What is the inheritance pattern for most intellectual disabilities?
de novo
What head circumference percentile is considered microcephaly?
< 2 %
What is the inheritance pattern for most primary microcephaly cases?
autosomal recessive
What is the inheritance pattern for most postnatal microcephaly cases?
de novo
some are X-linked such as
* CDKL5
* MECR
* CASK
* MAC
this slide is based on photo in phone - need to check with notes
What is the pattern of inheritance for most cases of holoprosencephaly?
AD
autosomal dominant
What is the inheritance pattern for most cases of megaencephaly?
most are mosaic
some are X-linked?
post-zygotic change
What is a group o genetic diseases that is assocaited with megalencephaly?
lysosomal storage diseases
eg: Hunter, Hurler, etc.
What are two ongoing possible issues or causes for megalencephaly?
hydrocephalus (increased fluid)
extra neurons
Of the 3 germ layers, which one does blood originate from and which one does the brain develop from?
blood = mesoderm
brain development = ectoderm
endoderm is the third
When testing for a condition that is known to likely be mosaic, what is important to keep in mind in terms of the reliability of the genetic testing?
megalencephaly = mosaic
- depth of coverage
- mosaicism won’t be present in all reads
When assessing a patient in pediatric neurology, what is important to remember as opposed to memorizing single brain malformations which leas to differentials falling apart when more than one brain malformation is present?
patterns assocaited with genetic diagnoses
What are the basic classifications of CNS malformations?
- forebrain patterning
- cortical malformations
- midbrain/hindbrain malformations
What malformations are of forebrain patterning?
- anencephaly
- holoprosencephaly
- agenesis of the corpus callosum
- midline facial dysmorphology: clefting, close eyes (hypotelorism), single front incisor
face predicts the brain
What genetic disorders can mimic congenital CMV infection?
- deletion 1p36
- deletion 22q11
- some other chromosomal deletions
What is the most common inheritance pattern for congenital microcephaly and what is the most common assocaited gene?
- autosomal recessive
- ASPM - has no other malformaitons aside from simplication of the gyral pattern
What is the best genetic testing option for a patient with congenital microcephaly?
microcephaly gene panel
(not CMA as usually would be)
What is megalenchephaly?
large, heavy, often malfunctioning brain
What is macrocephaly?
large head, >98 %ile
How can you determine if a patient may have a megalencephaly syndrome without any imaging?
presence of skin or somatic growth findings that are consistent
If you are suspicious of a megalencephaly syndrome what is the best genetic test to order?
overgrowth/megalencephaly gene panel
(another exception to the CMA-before-sequencing rule)
What is the inheritance pattern for postcerebellar hypoplasia?
AR or XL
What is the single best genetic test according to peds neuro doc?
CMA
What genetic test should be ordered for postcerebellar hypoplasia?
sequencing panel of PCH genes
9another exception to CMA-before-sequencing rule)
all described genes are AR or XL
For nearly all brain malformations what is the best genetic test?
CMA first to catch chromosomal microdeletions/microduplications
What is the recommended test for holoprosencephaly?
karyotype to check for trisomy 13
Regarding brain malformations, if CMA comes back normal, what is the next step in testing?
sequencing studies
targeted brain malformation gene panel or exome sequencing
eventually whole genome testing will come first
