neurogenetic diseases

Question 1

Recognize that there is a broad range of neurogenetic disorders.

Answer 1

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…

Question 2

Apply the clinical diagnostic criteria for neurofibromatosis type 1 (NF1).

Answer 2

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

Question 3

Recognize the clinical features of Tuberous Sclerosis Complex (TSC).

Answer 3

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

Question 4

Contrast the genetic test modalities for autism spectrum disorder (ASD).

Answer 4

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

Question 5

Neurofibromatoses

Answer 5

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.

Question 6

nf1 is ad with:

Answer 6

complete penetrance in adults and high variability of expression

Question 7

____ of people with nf1 will be diagnosed by age 11

Answer 7

95%

Question 8

nf1 has ____ effect which means a single ____ can effect _____

Answer 8

pleiotropic effects, single gene, effects multiple systems

Question 9

TEST: nf1 shows ____ that is caused by _______

Answer 9

pleiotropic effects caused by spontaneous gene mutations in 50% of cases

Question 10

if someone’s child has nf1 because the parent is affected, the chance they will pass it on is:

Answer 10

50%

Question 11

nf1 has ____ effect which means a single ____ can effect _____

Answer 11

pleiotropic effects, single gene, effects multiple systems

Question 12

of the characteristics of nf1, if you have ____ you are considered to have the disease:

Answer 12

2 or more

Question 13

Cafe au le macules:

Answer 13

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

Question 14

skinfold freckling

Answer 14

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

Question 15

Neurofibromas

Answer 15

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

Question 16

Plexiform neurofibromas

Answer 16

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 transformationneurofibrosarcoma
Associated with pain, rapid growth

Question 17

Lisch nodules

Answer 17

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

Question 18

Optic glioma

Answer 18

In 5% of cases visual loss, severe proptosis, +/- hydrocephalus

If involving the optic chiasm, may cause precocious puberty

Chemotherapy may be necessary if

Question 19

msk abnormalities of nf:

Answer 19

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

Question 20

_____ is a msk abnormality of nf that pushes the eye orbit forward in the face

Answer 20

sphenoid dyslplasia

Question 21

bones of the limbs that are twisted and malformed in nf?

Answer 21

Pseudarthrosis

Question 22

nf 1 is Caused by mutations in the:

Answer 22

Caused by mutations in the neurofibromin gene on chromosome 17

Question 23

Neurofibromin acts as a:

Answer 23

tumor suppressor
The heritable gene mutation acts as a “first hit”
“Second hits” occur in tumors that develop subsequently

Question 24

TEST: on the germline level, nf 1 is___ and at the _____ it is _____

Answer 24

autosomal dominant, cellular tumor level, autosomal recessive (knudson 2 hit hypothesis)

Question 25

TEST: on the germline level, nf 1 is___ and at the _____ it is _____

Answer 25

autosomal dominant, cellular tumor level, autosomal recessive (knudson 2 hit hypothesis)

Question 26

TSC

Answer 26

tuberous sclerosis complex:
Autosomal dominant condition
80% of cases represent spontaneous mutations
Pleiotropic (single gene, effects multiple systems) affecting eyes, brain, skin, heart, kidneys, lungs
Shows broad variability of expression and, depending on method of ascertainment, can have reduced penetrance

Question 27

hypomelanotic macule (ash leaf spot)

Answer 27

most distinguishing feature

Question 28

the major cause of morbidity/mortality in TSC

Answer 28

SEGAS

_subendymal giant cell astrocytomas develop in 6-14% of affected individuals

Question 29

Individuals with TSC are at increased risk for

Answer 29

Seizures (80%)
Intellectual disability (50%)
Attention deficit hyperactivity disorder
Behavioral disturbances
Autism spectrum disorders (~40%)

Question 30

There are 2 causative genes identified:

Answer 30

TSC1 (9q34) encodes “hamartin”

TSC2 (16p13.3) encodes “tuberin”

Question 31

TEST: the ____ mutation is found using the _____ testing modality in which:

Answer 31

22q11.2 deletion is found using FISH in which a tag is made with a fluoresence and you should see the centromere for 22 and a lit up part. If you only see the one lit up part with no pair (green and red), then it has been deleted

Question 32

with FISH, the ASD is__ while with microarray, the asd testing is _____

Answer 32

low, up to 20%

Question 33

if you have a patient with nonsyndromic ASD and you don’t have the funds to send the whole dna for sequencing ____

Answer 33

microarray is the test of choice because it has 20% effectiveness of finding gene and it’s economical

Question 34

testing for abnormalities in single genes is:

Answer 34

not practical and yield less than 1%

gene panels are also low yield and not worth it 5%