Predisposition Testing for Neurodegenerative Disease II Flashcards
What are the cognitive domains that characterize Dementia?
must involve at least two: memory executive function visuospatial abilities language personality/behavior
What is Dementia?
progressive cognitive impairment interferes with activities of daily living in the home, at work, or in social activities
misfolded protein transmission as mechanism for neurodegeneration
What are the causes of Dementia?
infections (neurosyphilis, Herpes encephalitis, HIV) Metabolic disorders (hypothyroidism, B12 deficiency, Wilson's disease) alcoholism, drugs toxins head trauma hydrocephalus brain tumor pseudodementia/depression
What neurodegeneraitve disorders causing dementia?
Alzheimer's disease (AD) Vascular dementia, CADASIL (VD) Dementia with Lewy Bodies (DLB) Frontotemporal dementia (FTD, Pick's) Corticobasal degeneration (CBD) Prion diseases- Creutzfeld-Jakob disease (CJD) Progressive supranuclear palsy (PSP) Huntington Disease (HD)
How is Dementia diagnosed?
symptoms due to the part of the brain that is affected NOT due to underlying pathology
diagnoses overlap with one another and is really the physician’s best guess using existing technology
diagnosis can change as disease progresses
knowing the correct diagnosis is key for genetic testing
What are targeted questions to ask about neurodegenerative diseases?
What were the earliest symptoms?
Was the person forgetful? Did they repeat themselves a lot? Did they forget appointments?
Did they get lost?
Did they have any mood changes such as depression?
Did their behavior change? Did they do anything they wouldn’t have done before? Did they lose interest in things and people?
Did their speech change?
Did they fall?
Did they have any other neurological symptoms?
How is Dementia diagnosed?
symptom history (onset, types and duration symptoms, other medical history, drug/alcohol use, environmental exposure)
family history (age of onset, number of affected family members, degree of relationship)
neurological exam
neuropsychological testing (Mini-mental state exam)
lumbar puncture
lab testing
genetic testing (only if appropriate)
definitive diagnosis is autopsy
What is noticed on autopsy of patients with Dementias?
visualize hyperphosphorylated Tau (in neurons and helps to maintain their structure) neurofibrillary tangle
amyloid plaque
Describe the different kinds of aggregations in neurodegenerative diseases.
amyloid plaques= AD tangles (Tau) = AD and FTD Lewy bodies (alpha-syn)= PD and DLB
Describe risk factors for Alzheimer’s Disease?
having a first degree relative with AD increases lifetime risk 2-3 fold
heritability is 70% (only 30% explained by known genes)
Describe the inheritance of Alzheimer’s disease.
AD: early onset familial (21q21.3 amyloid precursor protein), early onset familial (14q24.13 presenilin 1), early onset familial/ Volga (1q31.42 Presenilin 2)
Genetic Susceptibility Factor: late onset familial adn ~50% sporadic (19q13.2 APOE -epsilon4)
What genes are associated with Alzheimer’s disease?
APP (32 variants; onset in 40s-50s; 100% penetrance)
PSEN1 (>220 variants; onset 30s-60s usually; 100% penetrance; MOST COMMON GENETIC CAUSE)
PSEN2 (19 variants; onset 40s-70s; less than 100%)
What are the nuances of Next Gen sequencing for neurodegenerative diseases?
Pro: tests more genes for less money (more genes not necessarily better, order small panels when you can; databases are largely based on Western Caucasion populations; doesn’t test everything- will not detect triple repeat or expansion disorders or large deletions/duplications; some labs detect small del/dups but not others
cons: the more genes tested, the higher the chance for VUS
What are the APOE testing guidelines?
insuficient sensitivity or specificity to be used for diagnostic testing
neither necessary nor sufficient for teh development of AD so NOT recommended for predictive testing
What is Frontotemporal Degeneration (FTD)?
25-50% of presenile dementias (5-15% of all dementias reported on autopsy)
often misdiagnosed as Alzheimer disease or psychiatric disorder
age of onset: 40-75 (average 56)
What are the FTD subclasses and related diseases?
behavioral variant frontotemporal dementia (bvFTD)/Pick's Disease FTD/ALS PPA: Language variant FTD (PNFA- progressive nonfluent aphasia, problems with expressing but able to understand language; SD- semantic dementia, naming and word finding, comprehension problems with preservation of spoken language; Logopenic- AD pathology) related tauopathies (PSP- progressive supranuclear palsy; CBD- corticobasal degeneration)
What are the symptoms of bvFTD?
disinhibition
emotional blunting, apathy
decreased executive function (planning, problem solving, and judgement)
loss of personal awareness (hygeine and grooming)
ritualistic or perseverative behaviors and beliefs
loss of insight
utilization behavior (repeated use of objects within visual field)
hyperorality
changed speech (echolalia, perseveration, reduced output)
incontinence
What genes are associated with Autosomal Dominant FTD?
Tau gene (17q21-22; MAPT)
Progranulin (17q21; PGRN)
C9orf72 (FTD/ALS)
C9orf72…what?
hexanucleotide intronic repeat: GGGGCC
expansion >30 repeats
somatic mosaicism reported
possible anticipation
What is Motor Neuron Disease (MND)?
group of progressive neurological disorders caused by degeneration of motor neurons
motor neurons are cells that control voluntary muscle activity (speaking, walking, breathing, swallowing, etc.)
What are the disease classifications for motor neuron diseases?
Amyotrophic lateral sclerosis (ALS): both upper and lower motor neuron involvement
Primary lateral sclerosis (PLS): upper motor neuron involvement
Progressive Muscular Atrophy: affects only lower motor neurons in the spinal cord
What are the symptoms of motor neuron diseases?
upper motor neurons (spasticity, hyper-reflexia, pseudobulbar affect)
lower motor neurons (fasciculations, muscle atrophy)
other neuronal populations (fronto-executive circuits, movement disorders)
Describe the onset of symptoms for ALS.
commonly begin ~55-75 years of age bulbar onset (speed changes, difficulty swallowing) spinal onset (difficulty walking, increased falling, difficulty writing or using hands) variability in disease progression
What is Amylotrophic lateral sclerosis?
(meaning no muscle nourishment in the area of the spinal cord where neurons signal muscles with scaring due to neuronal deterioration)
progressive deterioration of the motor neurons resulting in the loss of ability of the brain to initiate and control muscle movements (voluntary muscles)
Prion Protein… discuss.
PRNP gene
prion is a proteinaceous infectious particle that self propigates misfolded prion proteins
causes mammalian transmissible spongiform encephalopathies (TSEs) such as BSV (mad cow disease), Scrapie (sheep), CWD (chronic wasting disease in sheep), Kuru (Paupa New Guinea)
What is Creutzfeld-Jakob disease (CJD)?
E200K most common pathogenic mutation
vCJD is mad cow disaese
List the human prion diseases.
Creutzfeld-Jakob disease (CJD)
Gerstmann-Straussler-Scheinker (GSS)
Fatal Familial Insomnia (FFI)
What is Fatal Familial Insomnia?
1 in 1,000,000
85% sporadic
10-15% hereditary
<1% iatrogenic (neurosurgical instrument contamination, corneal grafts, hGH injections, blood transfusions)
