Adult Conditions Flashcards
what are the main characteristics of CMT? how common?
chronic moto and sensory neuropathy?
1:2500
what are the major features of CMT?
childhood-adulthood onset
slow progression
clinical findings: distal muscle weakness/atrophy (progresses from legs to arms); distal sensory loss
less common: pain, SNHL
what are the genes most commonly associated with CMT? more often inherited or de novo?
PMP22 duplication
GDAP1, GJB1, HINT1, MFN2, MPZ, SH3TC2, SORD
more often inherited (AR, AD, XL)
some reduced penetrance
what the traditional classifications of CMT? how are these classified?
demyelinating
axonal/non-demyelinating
dominant intermediate CMT
NCV rate
how is CMT dx?
clinical: peripheral neuropathy on exam (MNCV and EMG)
FHx
genetics: single gene for PMP22 w/ del/dup -> multigene panel, ES/GS
what is prognosis for those with CMT?
not life-limiting
difficult to predict
progression can result in disability
what is CADASIL? how is it characterized? gene?
hereditary multi-infarct dementia
recurrent strokes, cognitive decline, migraine w/ aura, psychiatric disturbances
other: epilepsy, other body systems may be invovled
mid-adulthood onset
NOTCH3
what findings are suggestive of CADASIL?
recurrent strokes and TIA, executive dysfunction, migraine with aura, mood disturbances and apathy, brain imaging, FHx
what testing strategy would you employ is you suspected CADASIL?
NOTCH3 seq w/ del/dup
epilepsy, leukodystrophy and leukoencephalopathy panels, ES, known familial variant
what is the prognosis for someone with CADASIL?
symptoms usually progress slowly
some lose ability to walk due to strokes
life expectancy significantly shortened in AMAB individuals
most common cause of death is pneumonia
what % of newly dx prion disease is genetic?
about 15%
what gene is associated with genetic prion disease?
PRNP
what are some general characteristics of prion diseases?
cognitive difficulty, ataxia, myoclonus, other findings
If phenotypes overlap, why is it important to determine type of prion disease?
can inform disease course
what % of CJD is genetic? how does it compare to sporadic CJD?
survival?
10-15%
earlier onset and longer duration compared to sporadic
median survival following onset is 6mo (can be up to 2 years)
what is the mean age of onset for GSS? disease duration?
52.5y -> 60mo duration
when do signs begin to appear for GSS?
4th to 6th decade of life
what proteins in CSF can point to genetic prion disease?
14-3-3 and tau
what clinical findings can indicate genetic prion disease?
dementia followed by ataxia, myoclonus, and extrapyramidal/pyramidal involvement
how is someone dx with a genetic prion disease (CJD or GSS)?
suggestive findings AND PRNP variant
what are the common mutations for gCJD? GSS? what is the risk codon?
CJD: D178N, E200K, V180I, V210I
GSS: P102L
risk: SNP at 129 - Val or Met**
those homozygous for Met at 129 have been shown to ave earlier onset and more rapid progression
how many probands with gPrD will not have a FHx?
how effective is single gene testing?
up to 60%
seq w/ del/dup of PRNP detects almost all pathogenic variants
what causes the features of Huntington disease?
death of neurons in the brain beginning in the basal ganglia (movement coordination) and spreading into frontal lobe (higher thinking
what are the motor features seen with HD? cognitive? psychiatric?
motor: chorea, athetosis, rigidity, bradykinesia, akinesia -> generally involuntary or difficulty with voluntary movement (impacts entire body)
cognitive: forgetfulness, slowness of thought, impaired visiospatial ability, impaired planning and judgement
psychiatric: personality changes, psychosis, depression, irritability
what the expected progression of HD?
median survival is 15-18yrs after onset
may start as clumsiness or forgetfulness
what causes HD? what are the genotype/phenotype correlations?
trinucleotide repeat expansion (CAG) in HTT gene (4p16.3)
36-55 repeats: adult onset
60+ repeats: juvenile onset
what repeats can modify HD development/onset?
CAA interruptions
no interruptions -> younger age of onset and increased somatic instability
is there expansion seen in HD families?
yes
when testing for HD, how you classified with 27-35 CAG repeats? 36-39? 40+?
how do we test for these repeats?
27-35: intermediate (may have subtle symptoms but won’t develop HD)
36-39: pathogenic but low penetrance
40+: pathogenic and fully penetrant
PCR
is genetic testing necessary for a HD dx?
can be made with clinical features, but testing is helpful for confirmation and characterizing the # of repeats
how would you describe spinocerebellar ataxia type 3?
disorder of brain function and is characterized by increasing problems with coordination
what are some of the signs and symptoms of SCA3?
peripheral neuropathy, slow/staggering gait, dystonia, parkinsonism, ophthalmoplegia, exopthalmia, dysarthria, dysphagia, abn pulmonary function, sleep problems associated with restless leg syndrome, etc.
what is the prognosis for someone dx with SCA3?
onset typically occurs btwn 20-50y (avg. 36y)
life expectancy ranges from mid30s to typical
progressive disease
what causes SCA3?
ATXN3 gene (14q32.12)
produces protein ataxin-3 enzyme -> incorrect folding causes aggregation in nucleus and most severely affects neurons
what repeat is associated with SCA3? #s
CAG
12-43: normal
44-60: intermediate
60-87: pathogenic/fully penetrant
how can we test for SCA3?
PCR and Southern blot
how would you describe early onset familial alzheimer’s disease (EOFAD)? symptoms?
subtle/slow progression of memory failure that becomes more severe and eventually incapacitating
confusion, anxiety, poor judgement, agitation, speech challenges
what genes are associated with EOFAD? complete vs. incomplete penetrance?
APP and PSEN1: complete
PSEN2: incomplete
what is the typical age of onset with EOFAD?
40s-50s, less than 5% of AD is early onset
what proportion of EOFAD is associated with which gene?
APP (10-15%)
PSEN1 (20-70%)
PSEN2 (5%)
what features in FHx may make us suspect EOFAD?
early-onset dementia (at least 3 affected individuals) and age of onset
negative FHx cannot be assumed unless GT has been conducted because young deaths and smaller
what’s the prognosis?
typically individuals affected by AD live 8-10y after appearance of symptoms
how might we test for EOFAD?
panel with APP, PSEN1/2 and APOE -> ES/GS if negative with unclear
single gene-testing not recommended
what is the gen pop risk for developing AD? w/ FDR? FHx indicative of EOFAD?
10-12%
20-25%/2-3x baseline
assume affected parent: 50%
how do APOE e_ alleles impact chances of developing AD?
homozygous XX w/ e4: 40-45%
homozygous XY w/ e4: 25-30%
hetero e3/e4 alleles: 15-25%
e2 allele seems to be a protective factor
