Neurodegenerative Disorders Flashcards
What is the testing strategy for Fragile X disorder?
PCR with reflex to southern blot
PCR determines the number of repeats
Southern blot identified expanded repeats to check methylation (too many repeats leads to hypermethylation and loss of gene expression)
What are the features of Friedrichs Ataxia?
Slowly progressive ataxia with onset before 25 years
Dysarthria - slow or slurred speech
Cardiomyopathy in 2/3
Diabetes in 1/3
What is the genetic cause of Friedrichs Ataxia?
GAA repeats
FXN gene
Typical: <33
Premutation: 34-65
Reduced Penetrance: 44-66
Pathogenic: >66
What percentage of Friedrichs Ataxia is caused by SNV or del/dup pathogenic variants?
4%
What are the features of Spinocerebellar Ataxia?
Progressive cerebellar ataxia:
*uncoordinated muscle movement due to cerebellum issues
*less coordination of eyes, hands, speech, shaky gait
What is the age of onset of Spinocerebellar Ataxia?
30-40 years (lifespan depend on when symptoms appear)
What is the genetic cause of Spinocerebellar Ataxia?
Main genes ATXN genes
Type I is due to CAG trinucleotide repeats in ATXN7 and ATXN1
What are the features of Huntington Disease?
Progressive motor disability with chorea and loss of voluntary movement
Cognitive decline
Changes in personality
Depression
What is the genetic cause of Huntington Disease?
CAG repeats in HTT
What is the CAG repeat range for Huntington Disease?
Typical: <26
Intermediate: 27-35
Reduced penetrance: 36-39
Pathogenic: >40
Juvenile: >60
Expansion of CAG repeats in Huntington Disease is more common when it is inherited maternally or paternally?
Paternal anticipation
What is the new mutation rate in Huntington Disease?
10%
What percentage of Huntington Disease is juvenile and what is the age of onset?
5-10%
Onset before 20 years
What are the features of Ataxia Telangiectasia?
Gait and truncal ataxia, head tilting, slurred speech
Oculomotor apraxia (inability to follow an object across visual field)
Telangiectasias in the eyes
Immunodeficiency
Hypersensitivity to ionizing radiation
What is the genetic cause of Ataxia Telangiectasia?
ATM gene (AR)
What is the age of onset of Ataxia Telangiectasia?
1-4 years
What are carriers of Ataxia Telangiectasia at an increased risk for?
Breast cancer
What is the name of the condition where there is abnormal development or destruction of the white matter (myelin sheath) of the brain?
Leukodystrophy
What are the general symptoms of leukodystrophies?
Balance, breathing, cognition, swallowing, hearing, vision, speech, coordination
What is the genetic cause of CADASIL?
NOTCH3 (AD)
What does CADASIL stand for?
Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy
What are the features of CADASIL?
Recurrent ischemic strokes
Cognitive decline/dementia
Migraine with aura
Mood disturbances
What disorders result from hexanucleotide expansion in C9orf72?
ALS, motor neuron disease, frontotemporal lobar degeneration, and Parkinsonism (some may have both FTD and ALS)
What percentage of individuals with C9orf72 repeat expansions live symptom-free into their late 50s?
50%
Almost all will be symptomatic by age 80
What percentage of AD is estimated to be familial?
25%
What percentage of AD is classified as hereditary early-onset?
5%
What genes are responsible for early-onset Alzheimer’s Disease?
APP
PSEN1
PSEN2
What percentage of FTD have a positive family hx?
20-50%
What are three genes associated with FTD?
MAPT
GRN
C9orf72
What are genes associated with AD Parkinson’s?
GBA
LRRK2
SNCA
VPS35
What are genes are associated with AR Parkinson’s?
APT13A2
DJ1
DNAJC6
FBXO7
PINK1
PODXI
PRKN
SLC6A3
SYNJ1
VSP13C
What are the genes associated with ALS?
C9orf72
SOD1
FUS
TARDBP
What are the names of some inherited prion diseases?
Creutzfeldt-Jakob
Germann-Staussuler-Scheinker
Fatal familial insomnia
What percentage of Parkinson’s is genetic?
5-10%
What gene is related to prion disease?
PNRP
What percentage of genetic ALS is caused by expansion of hexanucleotide repeat in C9orf72?
40% familial
5% sporadic
What percentage of prion disease is genetic?
15%
What is the framework for performing predictive genetic testing?
1) are highly accurate in determining the genotype(s) of interest (analytic validity)
2) possess suitable positive predictive value (clinical validity)
3) inform medical care related to disease prevention or early detection (clinical utility
What is the lifetime risk of dementia in APOE E4 homozygotes?
35-40%
What are hereditary ataxias?
A group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements.
What types of disorders are characterized by:
Dysfunction of the cerebellum and its associated systems
Lesions in the spinal cord
Peripheral sensory loss
Hereditary ataxias
What are the most common ataxias?
SCA3 followed by SCA1, 2, 6, and 7
Autosomal dominant ataxias can be caused by what trinucleotide repeat?
CAG
Which two ataxias have particularly unstable CAG repeats so that children with early-onset may die before a parent is diagnosed?
ATN1 (DRPLA) and ATXN7 (SCA7)
What is an episodic ataxia?
Periods of unsteady gait often associated with nystagmus or dysarthria.
Myokymia, vertigo or hearing loss may occur in some subtypes.
What are some genes associated with episodic ataxia?
ATP1A3
KCNA1
CACNA1A
SCN2A
What are some common autosomal recessive ataxias?
Freidreich ataxia (FRDA) cause by mutations in FXN
Ataxia with oculomotor apraxia type 1 (AOA1) with APTX gene
Ataxia with oculomotor apraxia type 2 (AOA2) with SETX gene
Ataxia-telangiectasia with the ATM gene
Which AR ataxia do you treat with riboflavin?
Brown-Vialetto-Van Laere syndrome
SLC52A2 gene mutations
-Optic atrophy
-Hearing loss
What is the genetic cause of Friedreich ataxia?
GAA triplet-repeat expansion in FXN (AR)
Rare individuals have a pathogenic missense variant in one FXN allele with the GAA repeat in the other allele
What is a more common X-linked cerebellar ataxia?
Fragile X tremor ataxia syndrome (FXTAS)
Explain the genetics of the most common types of ataxias: SCA1, SCA2, SCA3, SCA6, and SCA7
AD trinucleotide repeat expansions
Which ataxias are treatable?
vitamin E deficiency deficiency
Refsum disease
cerebrotendinous xanthomatosis
