Week 2: Testing, var int, pharmaco, DTC Flashcards
(31 cards)
Tell me about Miller-Dieker syndrome
Lissencephaly!
-Usually de novo deletion or unbalanced translocation resulting in deletion of critical gene
-Gene: LIS1, or microdeletion of 17p (variants in LIS1 also cause isolated lissencephaly w/o dysmorphic features)
-Congenital anomalies: cardiac defects, omphalocele, inguinal hernia, duodenal atresia, cystic/pelvic kidney, cryptorchidism, clinodactyly
-D/t severe health issues, usually don’t survive beyond childhood
-Dysmorphic features: bitemporal wasting, small jaw, flattened midface, short upturned nose, low-set posteriorly rotated ears, frontal bossing, prominent nasal folds
Tell me about Walker-Warburg syndrome
-AR
-Gene: POMT1, POMT2, etc., 9q34.13
-Main features: severe congenital muscular dystrophy, brain anomalies, eye defects
-Specifically: macrocephaly, hydrocephalus, cobblestone lissencephaly, retinal malformations, microphthalmia, buphthalmia, cataracts, optic nerve hypoplasia, congenital muscular dystrophy/hypotonia, cerebellar malformations
Tell me about holoprosencephaly
-Incomplete separation of the brain into left and right hemispheres
-Causes: exposures (maternal diabetes, statins, alc, retinoic acid), inherited syndromes
-Clinical features: microcephaly, cleft L/P, seizures, developmental disabilities, pituitary dysgenesis, poor swallowing and risk for aspiration, hypotelorism, cyclopia w or w/o proboscis formation
Generally describe the spectrum of holoprocencepahly
Big range!
-Alobar: complete failure of division
-Semilobar: fusion of prontal and parietal lobes
-Lobar: fusion of the anterior frontal lobes
-MIH (midline interhemispheric): usually confined to posterior frontal and parietal lobes
Mortality is high in newborns with holoprosencephaly. What factors correlate with higher mortality?
-Severity of brain malformation
-Severity of facial malformation
-Presence of chromosome abnormalities
-Presence of multiple congenital anomaly syndrome or other organ involvement
Name some conditions with holoprosencephaly
-T13
-T18
-SLO
-Pallister Killian
-Way more but these are big ones
Tell me about L1 syndrome
-Congenital hydrocephalus
-XL
-Gene: L1CAM
-Presentation varies but overall includes: hydrocephalus, adducted thumbs, spasticity, ID
Phenotypic spectrum divided into 3 clinical phenotypes (most to least severe):
1. XL hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS)
2. MASA (mental ID, aphasia, spastic paraplegia, adducted thumbs)
3. XL complicated corpus callosum agenesis
Tell me about Fredreich’s ataxia
-Progressive neurodegenerative movement disorder
-AR
-Gene: FXN
-Onset typically between 10-15y
Features:
-Muscle weakness
-Ataxia
-Loss of balance and coordination
-Slurred speech, difficulty swallowing
-Vision and hearing loss
-Scoliosis
-Foot deformities: inward turning and high arches
-Cardiac issues: myopathy and arrhythmias
-Diabetes
Tell me about Huntington’s
-Progressive disorder of involuntary movements, cognitive decline, personality and mood disturbances
-AD: Repeat expansion (CAG)
-Gene: HTT
-Adult onset: >90% cases, usually onset mid 30s-40s
-Juvenile onset: <10% cases, onset in childhood or teens. >60 repeats associated with onset before 20y
-More common in individuals with northern european ancestry. Less frequent in Asian and Finnish populations
Features:
-Behavior changes: hallucinations, irritability, restlessness, paranoia, issues with decision making
-Abnormal movements: chorea (uncontrolled movements)
-Memory impairment
-Rigidity
-Anxiety, stress, tension
-Difficulty swallowing
-Speech hesitation or slurring
What are the ranges of CAG repeats and phenotypes for Huntington’s
Full penetrance: 40+
Reduced penetrance: 36-39. May be at risk of HD but may never develop symptoms. If they do, usually later age onset and slower progression
Intermediate: 27-35. Not at risk for HD but offspring may be.
Normal: 26 or less (avg 17)
Define anticipation
Anticipation refers to the tendency of some genetic
conditions for individuals in successive generations to present at an earlier age and/or more severe symptoms
Explain difference between symptomatic and asymptomatic testing for HD
Symptomatic patients
*Referred by neurologist
*Confirm diagnosis of “manifest” HD
Asymptomatic patients
*Referred by primary care provider
*Self-referral
*“At-risk” based on family history
*Predictive genetic testing: determine risk of
developing HD
Name some reasons someone might want predictive testing for HD
To be certain
-To plan for the future
-Reproductive decision making
-To inform children
-Uptake of predictive genetic testing in 50% at-risk individuals: 5-20%
Name some reasons someone would NOT want predictive testing for HD
-Concern for possible increased risk for children
-Absence of treatment
-Financial cost of testing
-Inability to use knowledge
-Fear of being unable to cope with a high-risk result
Tell me about spinocerebellar ataxia type 1 (SCA1)
-AD: CAG repeat
-Gene: ATXN1
Features:
-Progressive issues with movement
-Ataxia
-Speech and swallowing difficulty
-muscle stiffness
-Nystagmus
-Cognitive impairment
-May develop neuropathy and chorea over time
-People with SCA1 typically survive 10-20 years after symptom onset
What is the acronym and features of hereditary ataxia clinical symptoms
DANISH
D: dysmetria (lack of coordination, over or undershoot of intended position) & dysdiadochokinesia (inability to perform coordinated, rapid muscle movements)
A: ataxia
N: nystagmus
I: Intention tremor
S: slurred speech
H: hyperreflexia or hypotonia
Tell me about spinocerebellar ataxia type 7 (SCA7)
-AD: CAG repeat
-Gene: ATXN7
Features:
-comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death
-Retinal degeneration hallmark feature and precedes ataxia symptoms (can also have color defects and day blindness)
-Common childhood onset compared to SCA1
Tell me about Parkinson’s disease
-Progressive, degenerative movement disorder that primarily affects the brain and nervous system.
-Gradual decline in movement control, leading to symptoms like tremors, stiffness, slow movements, and difficulty with balance
-Mendelian (<10%) and non-mendelian (>90%)
-AD, AR, XL: many many genes
-Juvenile onset: <20y, more likely to be mendelian
-Early onset: <50y
-Late onset: >50y
What’s the acronym for features of Parkinson’s disease
TRAP!
T: tremor
R: rigidity
A: akinesia
P: postural instability
-Dementia and/or psychosis occur in 30-40% cases
What is roughly the risk to family members for Parkinson’s disease for relatives with non-mendelian PD?
first degree relatives of affected individual have increased lifetime risk of 3-7% to develop PD
Tell me about Alzheimer’s disease
-Irreversible, progressive brain disorder that slowly destroys
memory and thinking skills, and eventually the ability to carry
out simple tasks of daily living.
-Most common form of dementia (60-80% of cases)
-Sporadic: 75-85% cases
-Familial: 15-25% cases
-Overall, <5% of all AD inherited in AD manner
-Genes associated: PSEN1, APP, PSEN2
APOE alleles:
* A single e4 allele increases lifetime risk 2-3 times
* Two e4 alleles (e4/e4 genotype) increases lifetime risk 15 times
* The e2 allele is thought to be “protective”
-In most people with AD, symptoms first appear in their mid- 60s
- Causes toxic deposits of proteins form abnormal clumps (β- amyloid plaques) and tangled bundles of fibers (neurofibrillary,
or tau, tangles). These plaques and tangles cause neurons to
stop functioning and lose connections with other neurons. - Common duration of disease ~8-10 years, up to 25 years from
onset (so can cause shortened lifespan, but not always)
-AD is divided into familial and sporadic, and early-onset (<65 years) vs.
late-onset (>65 years)
Tell me about ALS
-progressive neurological disease that affects nerve cells in the brain and spinal cord, leading to the loss of voluntary muscle control
-Inheritance of FALS: AD (most common), AR (rare), XL (very rare, gene is UBQULN2)
-Gene: C9orf72 HEXAnucleotide repeat expansion GGGGCC (~40% of cases)
- Diagnosis based on clinical criteria
- Definite Diagnosis: must have motor neuron disease
- Parkinsonism, chorea
- Problems: balance, vision, speech, movement,
swallowing - Behavioral and cognitive issues: progressive behavioral impairment, memory loss, frontotemporal dementia
- Wide variability: presentation, progression, and survival
- Some cases FALS have slow progression (some live decades
after onset) - Many cases FALS have rapid progression (survival in months to
~5 years after onset) - Wide variability: presentation, progression, and survival
- Muscle atrophy and weakness spread to other regions of the body
- Eventually (facial) muscles used in communication and movement
become paralyzed (“locked in”) - Eye muscles can remain resistant/intact: special communication
devices - Mortality: weakness of respiratory muscles, bleed/clot, heart
arrhythmia - Average age of onset in sporadic ALS is 55 (males) – 65 (females); early onset is <55-65 y/o
What do testing guidelines say about recommendation for genetic testing in ALS
Unless a known variant, always start with C9orf72 repeat expansion analysis with concurrent or second tier multigene NGS panel of additional genes.
Most cases of AD, PD, and ALS are ____
Non-Mendelian
<5-10% have monogenic cause
