1
Q
- Cafe-au-lait spots (1st clinical feature)
- Lisch nodules (pigmented iris hamartomas)
- Freckling
- Peripheral neurofibromas
- Optic gliomas
- Pheochromocytomas
- Autosomal dominant, 100% penetrance, variable expressivity
- Mutated NF1 (neurofibromin – negative regulator of RAS)
- Chr 17
A
Neurofibromatosis type 1
von Recklinghausen dz
2
Q
- Type of neurofibroma affecting multiple branches of large nerves
- One of the MC causes of morbidity in NF1
- May invade adjacent structures and impinge on organs
A
Plexiform neurofibromatosis
3
Q
- Bilateral vestibular schwannomas * (early hearing loss w/ tinnitus or vertigo *)
- Juvenile cataracts *
- Cafe-au-lait spots
- Peripheral nerve tumors
- Less common than NF1
- Later age of onset (age 18–24)
- Meningiomas (severe form), ependymomas
- Autosomal dominant , almost complete penetrance by age 60
- Mutated NF2 (merlin)
- Chr 22
A
Neurofibromatosis type 2
4
Q
- HGPRT deficiency
- X-linked (mostly seen in males)
- Sx @ 3-6 months (orange-colored urate crystals in diaper *)
- Hyperreflexia and spasticity of legs
- Hyperuricemia»_space; gout
- Self-mutilation * – biting/chewing finger tips, lips and buccal mucosa
A
Lesch-Nyhan syndrome
5
Q
List 2 triplet repeat disorders.
A
- Fragile X syndrome
- Huntington Disease
6
Q
Triplet repeat disorders, like Fragile X and Huntington’s, are explained via what DNA model?
A
DNA polymerase slippage model
7
Q
What is the repeat in Fragile X
How many repeats are seen in Fragile X?
A
- CGG
- Dz range = 200+
8
Q
What is the repeat in Huntington Dz?
How many repeats are seen in HD?
A
- CAG
- Dz range = 37-121
9
Q
- X-linked
- Mutated FMR1 gene
- Trinucleotide repeat = CGG *
- Enlarged testes *
- Long face w/ large jaw *
- Large ears
- Delayed motor development
- Females with full mutation in one allele have variable presentations because of lyonization
A
Fragile X syndrome
“eXtra large tests, jaw, ears.”
10
Q
- Trinucleotide repeat: CAG * (aggregates of poly-glutamine (polyQ))
- Chr 4
- Genetic anticipation * (triplet expansion»_space; earlier onset/more severe sx)
- Depression
- Dementia *
- Chorea *
- Rigidity
A
Huntington Disease
11
Q
What are 3 areas directly affected by mutated Huntingtin protein?
A
- Cerebellum
- Cortex
- Striatum (caudate, putamen, NAc severely atrophied)
12
Q
What is the fundamental unit of sphingolipids?
A
Ceramide
13
Q
What is the most complex group of sphingoglycolipids?
A
Gangliosides
14
Q
What are the 2 diseases assoc w/ gangliosides?
A
- Tay-Sachs dz
- Sandhoff dz
15
Q
What are the 4 diseases assoc w/ sphingolipids?
A
- Krabbe dz
- Fabry dz
- Gaucher dz
- Niemann-Pick dz
16
Q
What are the 3 diseases assoc w/ mucopolysaccharides?
A
- MPS I – Hurler
- MPS II – Hunter
- MPS III – Sanfilippo
17
Q
- Hexosaminidase A (HEXA) deficiency *
- Accumulation of GM2 ganglioside *
- “Cherry-red” macula *
- Neurodegeneration
- Developmental delay
- More common in Ashkenazi Jewish populations
A
Tay-Sachs disease
18
Q
- Clinically indeterminable from Tay-Sachs dz
- HEXB mutation *
- Optic atrophy
- Seizures
- Spasticity
A
Sandhoff disease
19
Q
- Galactocerebrosidase deficiency
- Accumulation of galactocerebroside
- Developmental delay
- Peripheral neuropathy
- Optic atrophy (blindness)
- Globoid cells
A
Krabbe disease
20
Q
- Alpha-galactosidase A deficiency
- Accumulation of Ceramide trihexoside
- X-linked recessive *
- Angiokeratomas
- Cardiovascular dz
- Peripheral neuropathy in hands/feet
- Renal dz
A
Fabry disease
21
Q
- Glucocerebrosidase (Beta-glucosidase) deficiency
- Accumulation of glucocerebroside
- Lipid-laden macrophages resembling crumpled up paper
- Hepatosplenomegaly
- Bone crises
- Aseptic necrosis of femur
- Erlenmeyer flask deformity
- Pancytopenia (»_space; anemia)
- MC lysosomal storage dz (sphingolipidoses)
A
Gaucher disease
22
Q
- Sphingomyelinase deficiency *
- Accumulation of sphingomyelin
- “Cherry-red” macula *
- Hepatosplenomegaly (liver dz)
- Neurodegeneration (dementia)
- Foam cells (lipid-laden macrophages) *
- Increase prevalence in Jewish populations
- Pulmonary infiltrates
A
Niemann-Pick disease
23
Q
- Autosomal recessive
- Most severe of MPS
- Alpha-L-iduronidase
- Accumulation of heparan sulfate AND dermatan sulfate
- Gargoylism * (coarse facies)
- Airway obstruction *
- Corneal clouding *
- Developmental delay
- Hepatosplenomegaly
- Death by age 10
A
Hurler syndrome
MPS I
24
Q
- X-linked recessive *
- Iduronate sulfatase deficiency *
- Accumulation of heparan sulfate AND dermatan sulfate
- Mild Hurler + aggressive behavior
- NO corneal clouding *
- Protruding tongue
- Clubbing of all fingers
- Left-sided inguinal hernias
- Death by age 15
A
Hunter syndrome
MPS II
25
Which MPS type has an accumulation of ONLY heparan sulfate?
Sanfilippo (MPS IIIA-D)
26
- Milder form of Hurler syndrome (same allele)
- Normal intelligence
- Possible to see compound heterozygote
Scheie syndrome
27
- Intellectual and behavioral problems evident before physical changes
- Severe CNS degeneration w/ progressive neuro dz
- Results from 1 of 4 enzyme mutations
Sanfilippo syndrome (MPS IIIA-D)
28
- MC neurodegenerative dz
- Amyloid plaques
- Neurofibrillary tangles
- Oxidative stress
- Gross cerebral cortical atrophy
Alzheimer disease
29
Name the gene, protein, and proportion with EOFAD assoc w/ AD3.
```
Gene = PS1
Protein = Presenilin 1 (gamma-secretase protein)
EOFAD = 20-70%
```
30
Name the gene, protein, and proportion with EOFAD assoc w/ AD1.
```
Gene = APP
Protein = Amyloid-beta precursor protein
EOFAD = 10-15%
```
Assoc w/ Trisomy 21 as well.
31
Name the gene, protein, and proportion with EOFAD assoc w/ AD4.
```
Gene = PS2
Protein = Presenilin 2 (gamma-secretase protein)
EOFAD = Rare
```
32
EOFAD show mutations in what two proteins (or protein complexes)?
- APP
| - Gamma-secretase (PS1, PS2, Nicastrin, APH1)
33
Which amyloid-beta subtype is toxic – 40 or 42?
42 = toxic
34
If the APP protein is cleaved at Beta-secretase, what are the 3 products?
- Amyloid-beta 40
- Amyloid-beta 42 (toxic)
- APP-ICD
35
If the APP protein is cleaved at Alpha-secretase, what are the 2 products?
- P3 (non-toxic)
| - APP-ICD
36
What is the predominant apolipoprotein in the brain?
ApoE
37
What ApoE genotype is most at risk for Alzheimer dz at an earlier age?
E4/E4
E4 is also a risk factor for:
- Atherosclerosis
- HIV progression
- Other neuro disorders
38
Which ApoE genotype is considered to be protective?
E2
Therefore, E2/E2 would have the least risk for developing AD.
39
Give the order of alleles in terms of their symptoms.
E4 > E3 > E2
| Most toxic >> Most protective
40
Neurofibrillary tangles occur from what procesS?
Hyper-phosphorylation of tau protein
41
Inflammation can cause oxidative damage. What cells function to clear amyloid-beta?
Microglia
42
What is the major source of reactive oxygen species (ROS) in CNS?
Mitochondria
43
What are the 2 products of mitochondrial oxidative stress?
- Peroxynitrite (O2- reacts with NO and MnSOD to form peroxynitrites)
- Super oxide
44
In AD, there's an increase in the number of mutations in what organelle?
The mutations cause increased dysfunction and lead to what?
- Mitochondria
| - Apoptosis
45
What activates inflammation in the brain?
Amyloid-beta
46
Systemic inflammation is characterized by an increase in what 3 cytokines?
- C-reactive protein
- TNFa
- IL-6
47
Increased TNFa and IL-6 cause a behavioral response known as what?
Sickness behavior
- Increased anxiety
- Depression
- Apathy
Neuro 2 Final
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