Karoly Viragh
February 1, 2006
GENETIC DETERMINANTS OF NEUROLOGICAL DISORDERS
(Neurologic Disorders w/ a strong genetic component)
Key principle:
Brain circuits are influenced by both genes (“nature”) and the environment (“nurture”).
Illustrate the genetic component of neurological diseases w/ 5 clinical examples:
PKU –
mutation in
a single
gene
1.
HD –
mutation in
a single
gene
2.
Prion
Disease –
mutation in
a single
gene
3.
PKU (Phenylketonuria)
a. Definition:
i. Phenylketonuria = rare (1:15,000) inborn-error of metabolism affecting phenylalanine
catabolism
b. Etiology:
i. Autosomal recessive mutation in phenylalanine hydroxylase (most common cause)
ii. Phe ====Phenylalanine Hydroxylase == Tyr  catecholamine NTs (E, NE, DA),
proteins)
c. Pathogenesis:
i. Phe in diet cannot be metabolized to Tyr  build-up of Phe in body and brain
(neurotoxic!!!)  progressive cerebral demyelination
d. Clinical: mental retardation, musty body odor, skin abnormalities, etc.
e. Tx (treatment):
i. newborn screening, dietary restrictions (change in diet can rescue the genetic defect)
HD (Huntington’s Disease)
a. Definition:
i. HD is fatal neurodegenerative disorder
b. Etiology:
i. Mutation in the Huntingtin gene on chr4 (unknown function)
ii. Autosomal dominant w/ full penetrance
1. inherit gene  develop disease
2. identical twins (monozygotic, same genes) – 100% concordance
3. fraternal twins (dizygotic, 50% genes identical) – 50%
c. Pathogenesis:
i. Normal gene has 11-34 CAG trinucleotide repeats (CAG  Glutamine).
ii. Due to genetic instability DNA polymerase cannot faithfully replicate this region 
mutation!
iii. Mutation leads to trinucleotide expansion (34+ copies of CAG  Poly-glutamine)
iv. Neuronal cell death in the striatum (caudate + putamen) – GRAPHIC!
d. Clinical:
i. Chorea (abnl invol mov), progressive deterioration and death.
e. Anticipation = severity of a genetic disorder increases with each generation
i. That is, children of parents w/ HD inherit longer TNRs and develop HD at an earlier age
f. Other TNR diseases (PNS: Table 3-1, p. 55)
Prion Diseases
a. Definition:
i. Fatal infectious diseases characterized by spongiform neurodegeneration (BRAIN looses
substance and becomes SPONGE-like)
b. Etiology:
i. Caused by PrPs (Prion Proteins), which are highly infectious particles
ii. PrP encoded by the PRNP gene (chr 20)
c. Pathogenesis: (GRAPHIC!)
i. genetic mutations in PRNP (inherited or sporadic)
ii. abnormal folding of the PrP (becomes resistant to degradation by heat/proteases)
iii. neuronal cell death (mech not well-understood) w/ NO INFLAMMATION
d. Clinical
i. : neurological disorders (dementia, impaired movement  death)
1. CJD (Creutzfeld-Jacob Disease) – most common
2. FFI (Fatal Familial Insomnia)
3. GSSD (Gerstmann-Straüssler-Scheinker Disease)
4. kuru
5. In animals MAD COW DISEASE (BSE), scrapies, etc.
e. Tx: nada !
Karoly Viragh
February 1, 2006
AD –
multigenic
disorder
4.
AD (Alzheimer’s Disease)
a. Definition:
i. AD is a progressive neurodegenerative disorder
ii. Most common cause of dementia
b. Etiology:
i. Genetic:
1. APP – chr 21
2. APO-E4 – chr 19
3. Presenilin 1 and 2 – chr 14 and 1
ii. Possible environmental factors:
1. Immunologic
2. Infectious?
3. Toxic?
c. Pathogenesis:
i. unknown, but the following characteristics are observed:
1. neural atrophy
2. senile plaques (amyloid!)
a. APP w/in the Down-region of chromosome 21
3. neurofibrillary tangles
Depression
– single
gene
mutation
affecting
human
emotions
5.
Role of Serotonin (5HT) and depression
a. 5HT involved in the regulation of mood states (e.g. depression, anxiety, violence, eating)
b. Serotonin Transporter – responsible for the “reuptake” of 5HT from synaptic cleft
c. Several allelic variants
i. If “short” variant  predisposition to depression and anxiety under stress
d. Depression – complex neurophsychiatric disorder
GLIA
Location:
Function:
Structure:
Neuronal
injury:
Oligodendrocytes
Schwann cells
CNS
PNS
Myelinate axons
Same
(1 oligo – many axons)
(1 SC – 1 axon)
Myelination – important for saltatory conduction
GRAPHIC illustrating
myelin sheath
node of Ranvier (rich in Na channels)
paranodal regions (rich in K channels)
paranodal loops (rich in CAMs = cell adhesion molecules that link myelin to axons)
Demyelination (e.g. MS) results in conduction failure b/c of redistribution of Na and K channels  current leaks
Inhibits axonal regeneration
Supports axonal regeneration
Ependymal cells
Loc: Line the ventricles in the CNS
Func: Produce CSF
Struct: have cilia, which helps the movement of CSF
Microglia
 Origin: derive from monocytes in the bone-marrow, enter the CNS during embryonic development
 Loc: move around in the CNS
 Func:
 APCs: Provide immune surveillance of the CNS  capture and present antigens to T cells
 Phagocytosis - Can become macrophages and ingest debris
 Role in CNS autoimmune diseases