Lecture 4: Neurodegenerative Disease and Neurofibromatosis Flashcards
Neurodegenerative Disorders (3)
- Alzheimer’s Disease
- Huntington’s disease
- Neurofibromatosis
Alzheimer’s Disease Overview (3)
- Most common form of dementia in older people
- usually begins after age 60 and risk increased with age
- progressive impairment of intellectual function, loss of memory, insight, judgement, abstraction, and language
Alzheimer’s Disease Mechanism (4)
- Normal communication between nerve cells is blocked
- loss of cholinergic neurons
- formation of plaque and tangles
- brain atrophy
Risk Factors of Alzheimer’s Disease (7)
- Aging
- Family hx of dementia
- lower educational level
- female gender
- hx of head injuries
- depression
- hypertension
Familial Alzheimer’s Disease
- “early onset” symptoms start before age 65
2. autosomal dominant
Familial Alzheimer’s Contributing Gene Mutations (3)
- Amyloid Precursor Protein (APP)
- Presenilin 1
- Presenilin 2
Amyloid Precursor Protein
- integral membrane protein-function unclear
- improper cleavage of APP generates beta amyloid component of amyloid plaques
* contributor to Familial Alzheimers
Presenilin 1 & 2
- sub-components of an enzyme involved in processing APP
* contributors to Familial Alzheimer’s
Amyloid-beta (3)
- AD pathogenesis is triggered by accumulation of Amyloid-beta
- due to overproduction and/or failure of clearance mechanisms - Amyloid-beta aggregates into oligomers, which can be of various sizes, and forms diffuse and neuritic plaques in the parenchyma of blood vessles
- amyloid antipathy - Amyloid-beta oligomers and plaques block proteasome function, inhibit mitochondrial activity, alter intracellular Ca2+ levels and stimulate inflammatory processes
Sporadic Alzheimer’s Disease (4)
- late onset, developed after age 65
- APOE gene found on chromosome 19
- AD risk increases with presence of one or two copies of APOE e4 allele
- incomplete penetrance of APOE e4
Normal function of ApoE protein (3)
- transports lipoproteins, fat soluble vitamins and cholesterol in blood and lymph system
- shown to enhance proteolytic breakdown of beta amyloid
- e4 allele not as affective in breakdown of beta amyloid
Neurofibrillary Tangles
- Form in Neurons of AD patients
2. abnormal collections of twisted threads formed by a protein (tau) that is hyperphosphorylated
Tau proteins and their mechanism in AD (3)
- bind and help stabilize microtubules
- altered in AD, changed chemically
- altered TAU twists into paired helical filaments-2 threads of tau wound around each other
Hyperphosphorylated tau and its mechanism in AD (4)
- in helical filaments
- insoluble
- disrupts microtubule function
- leads to cell death
Early Presentation AD
Diagnostic Clues (2)
- memory problems
2. visuospatial abilities
Later findings AD
Diagnostic clues (3)
- personality changes
- behavioral difficulties
- hallucinations
End-stage AD
Diagnostic clues (5)
- Near-mutism
- inability to sit up, hold head, track object with eyes
- difficulty with eating and swallowing, weight loss
- bowel or bladder incontinence
- recurrent respiratory or urinary tract infections
Huntington Disease overview (3)
- AKA Huntington’s Chorea
- Carriers for HD are almost always asymptomatic in childhood and adolescence
- age of onset is typically between 30-50 years
- Peak around 45 years
- rarely manifests before age 20
Characteristics of Huntingon’s Disease (5)
- autosomal dominant d/o characterized by involuntary movements of the body
- deterioration of cognitive function
- severe emotional disturbance
- mircoscopic deposits of amyloid-related protein in the basal ganglia
- onset of sx to death averages 15 years
Genetics of HD (5)
- most prevalent in white people of northwestern european ancestry
- most inherited- some due to spontaneous mutations
- mutation of HD gene on chromosome 4 codes for Huntington protein
- Appears to be only human d/o of complete dominance-manifestations of the disease does not significantly differ for homozygous and heterozygous carriers
- sex of affected parent exerts strong influence on expression of HD
- inheritance from father-clinical disease 3 years earlier than inheritance from mother
Genetics HD pt. II (5)
- expansion of poylglutamine sequence (CAG)n in the HTT gene on chromosome 4p16.3 which codes for huntington protein*
- 10-35 CAG repeats have no disease risk
- 36-39 repeats may or may not develop symptoms of Huntington disease (incomplete penetrance)
- beginning with 40 CAG repeats, all affected individuals will develop huntington dieseae
- inverse correlation between the number of repeats and the age of onset of the disease
- higher the number of repeats, the earlier the onset
HTT Anticipation (2)
- size of CAG trinucleotide repeat often increased in size from one generation to the next
- larger number of repeats is usually associated with earlier onset of signs and symptoms
Diagnostic clues of HD
Early changes
Behavioral
- irritability
- moodiness
- antisocial behavior
- psychiatric disturbance
- mild dyskinesia
Diagnostic clues of HD
Later signs and symptoms (4)
- choreiform movements
- dystonic posturing
- severe balance and coordination problems
- progressive dementia
Diagnostic Testing HD (4)
- through family hx and medical hx
- CT scan in established cases
- cerebral atrophy
- atrophy caudate nucleus - MRI and PET scans
- reduced glucose utilization in an anatomically normal caudate nucleus - Genetic testing and counseling for children od HD -affected parents
Treatment HD (5)
- symptomatic relief
- no cure or treatment to slow disease progression - Dopamine receptor blockers
- -may control dyskinesia and behavioral disturbance - Speech therapy
- Physical therapy
- occupational therapy
Neurofibroma (4)
- benign, encapsulated tumor
- proliferations of schwann cells that are of ectodermal (neural crest) origin
- form continuous envelope around each nerve fiber or peripheral nerves - autosomal dominant genetic d/o
- tumors grow on the coverings of nerves anywhere in body at any time
- 1:3,000-4,000 males and females of all races and ethnic groups worldwide and is the most common genetic d/o in U.S.
NF 1 (5)*
Neurofibromatosis type 1
“Von Reckling
- neurofibromas, neurofibromas-saromas
- optic nerve gliomas
- pigmented cutaneous macule (cafe au lait)
- pigmented nodules of iris (lisch nodules)
- caused by mutation in NF1 gene (chromosome 17, encodes for neurofibromin)
NF2 (3)*
Neurofibromatosis type 2
- bilateral schwannomas of CN VIII
- multiple meningiomas
- spinal cord ependymomas
NF basic characterization
- Variant characterized by the development of noncancerous tumors called schwannomas on nerves that control hearing and balance
- auditory and vestibular nerves
Genetics-NF1
- inherited in an autosomal dominant pattern
- 50% of those affected by this disease have a prior family hx of NF
- other 50% appear to be the first members of their family to have d/o
Chromosome 17
codes for neurofibromin
-mutation fond here in NF1
Neurofibromin
intracellular signaling molecule of RadGAP (Rad GTPas activating protein) signal cascade
Function of normal NF1 gene
tumor suppressor gene
-loss of tumor suppressor in NF1 allows neurofibromas to form
Genetics NF-2
- inherited autosomal dominant pattern caused by mutation in NF2 gene that encodes merlin
NF2 gene encodes
merlin
merlin
tumor suppressor gene and mutation leads to formation of shwannomas
