neurogenetic diseases Flashcards
Recognize that there is a broad range of neurogenetic disorders.
Are many and varied and include Behavioral disorders Psychiatric disorders Learning disabilities Sleep disorders Substance abuse Brain malformations Myriad diseases Dementias, seizure disorders, neurocutaneous syndromes, neuropathies, neuromuscular diseases, inborn errors of metabolism, myopathies, and more…
Apply the clinical diagnostic criteria for neurofibromatosis type 1 (NF1).
2 or more of the following allow for diagnosis:
6 café-au-lait macules (CALMs) measuring 5mm before puberty/1.5 cm after
skinfold freckling (axillae, groin most common)
2 neurofibromas or one plexiform neurofibroma
2 iris Lisch nodules
optic glioma
distinctive bone lesion, e.g., sphenoid dysplasia
affected 1st degree relative
Recognize the clinical features of Tuberous Sclerosis Complex (TSC).
MAJOR FEATURES Facial angiofibromas or forehead plaque Non-traumatic ungual or periungual fibromas >3 hypomelanotic macules Shagreen patch Multiple retinal nodular hamartomas Cortical tuber Subependymal nodule
Contrast the genetic test modalities for autism spectrum disorder (ASD).
chromosome testing (karyotype)- has to be a really big difference to find 3-10 million base pairs missing or extra to find (ony found 3-5%)
can’t find submicroscopic deletions and crypic translocations
FISH:
create a seg of DNA with fuorescent tag that goes to the area of interest
for 22q11, you make the tag and look for 2 areas to light up. If only 1 area lights up, there is one missing
Neurofibromatoses
A group of conditions characterized by café-au-lait macules in combination with benign tumors arising from peripheral nerve sheaths
There is general agreement that there are at least 2 distinct types (NF1 and NF2) with up to 11 other types described by some authors.
nf1 is ad with:
complete penetrance in adults and high variability of expression
____ of people with nf1 will be diagnosed by age 11
95%
nf1 has ____ effect which means a single ____ can effect _____
pleiotropic effects, single gene, effects multiple systems
TEST: nf1 shows ____ that is caused by _______
pleiotropic effects caused by spontaneous gene mutations in 50% of cases
if someone’s child has nf1 because the parent is affected, the chance they will pass it on is:
50%
nf1 has ____ effect which means a single ____ can effect _____
pleiotropic effects, single gene, effects multiple systems
of the characteristics of nf1, if you have ____ you are considered to have the disease:
2 or more
Cafe au le macules:
Tend to arise in the first year of life and are usually the first sign of NF1
~80% of those who have NF1 will have >5 CALMs by age one
Should be measured at their greatest diameter
May be more easily appreciated in light skinned individuals with a Woods (UV) lamp
Darken or “appear” with sun exposure
Usually have a “coast of California” border
skinfold freckling
Is the second diagnostic sign to appear
Typically occurs between 3 and 5 years of age
Is present in 75% of individuals with NF1
Most commonly in the axillary and inguinal regions but can occur in any intertriginous area
Can be most easily appreciated with a Woods lamp in light-skinned individuals
Neurofibromas
May be dermal or plexiform
Dermal (cutaneous/subcutaneous) neurofibromas
Often herald the onset of puberty
May increase in size and number during pregnancy
Are always benign
Plexiform neurofibromas
Are found in up to 50% of individuals with NF1
Some may only be detected on imaging studies
Are usually congenital, especially in the face and neck
Can compress normal structures
Can undergo malignant transformationneurofibrosarcoma
Associated with pain, rapid growth
Lisch nodules
Do NOt MEAN YOu HAVE NF!
Are iris hamartomas
Can be seen in light irises with a direct ophthalmoscope
Are detected in dark irises with a slit lamp
Usually develop in early adolescence and are present in 95% of persons with NF1 by early 20’s
Have no impact on health
Optic glioma
In 5% of cases visual loss, severe proptosis, +/- hydrocephalus
If involving the optic chiasm, may cause precocious puberty
Chemotherapy may be necessary if
msk abnormalities of nf:
Sphenoid wing dysplasia-5% Pseudarthrosis of long bones-5% Scoliosis-10-30% “Idiopathic” Dystrophic—due to plexiform neurofibromas, abnormal bone formation "Pseudarthrosis"
when in legs, weight bearing can cause fractures
_____ is a msk abnormality of nf that pushes the eye orbit forward in the face
sphenoid dyslplasia
bones of the limbs that are twisted and malformed in nf?
Pseudarthrosis
nf 1 is Caused by mutations in the:
Caused by mutations in the neurofibromin gene on chromosome 17
Neurofibromin acts as a:
tumor suppressor
The heritable gene mutation acts as a “first hit”
“Second hits” occur in tumors that develop subsequently
TEST: on the germline level, nf 1 is___ and at the _____ it is _____
autosomal dominant, cellular tumor level, autosomal recessive (knudson 2 hit hypothesis)
