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GEN 602 > Adult Conditions > Flashcards

Adult Conditions Flashcards

1
Q

what are the main characteristics of CMT? how common?

A

chronic moto and sensory neuropathy?

1:2500

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2
Q

what are the major features of CMT?

A

childhood-adulthood onset

slow progression

clinical findings: distal muscle weakness/atrophy (progresses from legs to arms); distal sensory loss

less common: pain, SNHL

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3
Q

what are the genes most commonly associated with CMT? more often inherited or de novo?

A

PMP22 duplication

GDAP1, GJB1, HINT1, MFN2, MPZ, SH3TC2, SORD

more often inherited (AR, AD, XL)

some reduced penetrance

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4
Q

what the traditional classifications of CMT? how are these classified?

A

demyelinating

axonal/non-demyelinating

dominant intermediate CMT

NCV rate

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5
Q

how is CMT dx?

A

clinical: peripheral neuropathy on exam (MNCV and EMG)

FHx

genetics: single gene for PMP22 w/ del/dup -> multigene panel, ES/GS

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6
Q

what is prognosis for those with CMT?

A

not life-limiting

difficult to predict

progression can result in disability

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7
Q

what is CADASIL? how is it characterized? gene?

A

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

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8
Q

what findings are suggestive of CADASIL?

A

recurrent strokes and TIA, executive dysfunction, migraine with aura, mood disturbances and apathy, brain imaging, FHx

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9
Q

what testing strategy would you employ is you suspected CADASIL?

A

NOTCH3 seq w/ del/dup

epilepsy, leukodystrophy and leukoencephalopathy panels, ES, known familial variant

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10
Q

what is the prognosis for someone with CADASIL?

A

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

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11
Q

what % of newly dx prion disease is genetic?

A

about 15%

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12
Q

what gene is associated with genetic prion disease?

A

PRNP

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13
Q

what are some general characteristics of prion diseases?

A

cognitive difficulty, ataxia, myoclonus, other findings

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14
Q

If phenotypes overlap, why is it important to determine type of prion disease?

A

can inform disease course

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15
Q

what % of CJD is genetic? how does it compare to sporadic CJD?

survival?

A

10-15%

earlier onset and longer duration compared to sporadic

median survival following onset is 6mo (can be up to 2 years)

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16
Q

what is the mean age of onset for GSS? disease duration?

A

52.5y -> 60mo duration

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17
Q

when do signs begin to appear for GSS?

A

4th to 6th decade of life

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18
Q

what proteins in CSF can point to genetic prion disease?

A

14-3-3 and tau

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19
Q

what clinical findings can indicate genetic prion disease?

A

dementia followed by ataxia, myoclonus, and extrapyramidal/pyramidal involvement

20
Q

how is someone dx with a genetic prion disease (CJD or GSS)?

A

suggestive findings AND PRNP variant

21
Q

what are the common mutations for gCJD? GSS? what is the risk codon?

A

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

22
Q

how many probands with gPrD will not have a FHx?

how effective is single gene testing?

A

up to 60%

seq w/ del/dup of PRNP detects almost all pathogenic variants

23
Q

what causes the features of Huntington disease?

A

death of neurons in the brain beginning in the basal ganglia (movement coordination) and spreading into frontal lobe (higher thinking

24
Q

what are the motor features seen with HD? cognitive? psychiatric?

A

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

25
Q

what the expected progression of HD?

A

median survival is 15-18yrs after onset

may start as clumsiness or forgetfulness

26
Q

what causes HD? what are the genotype/phenotype correlations?

A

trinucleotide repeat expansion (CAG) in HTT gene (4p16.3)

36-55 repeats: adult onset

60+ repeats: juvenile onset

27
Q

what repeats can modify HD development/onset?

A

CAA interruptions

no interruptions -> younger age of onset and increased somatic instability

28
Q

is there expansion seen in HD families?

A

yes

29
Q

when testing for HD, how you classified with 27-35 CAG repeats? 36-39? 40+?

how do we test for these repeats?

A

27-35: intermediate (may have subtle symptoms but won’t develop HD)

36-39: pathogenic but low penetrance

40+: pathogenic and fully penetrant

PCR

30
Q

is genetic testing necessary for a HD dx?

A

can be made with clinical features, but testing is helpful for confirmation and characterizing the # of repeats

31
Q

how would you describe spinocerebellar ataxia type 3?

A

disorder of brain function and is characterized by increasing problems with coordination

32
Q

what are some of the signs and symptoms of SCA3?

A

peripheral neuropathy, slow/staggering gait, dystonia, parkinsonism, ophthalmoplegia, exopthalmia, dysarthria, dysphagia, abn pulmonary function, sleep problems associated with restless leg syndrome, etc.

33
Q

what is the prognosis for someone dx with SCA3?

A

onset typically occurs btwn 20-50y (avg. 36y)

life expectancy ranges from mid30s to typical

progressive disease

34
Q

what causes SCA3?

A

ATXN3 gene (14q32.12)

produces protein ataxin-3 enzyme -> incorrect folding causes aggregation in nucleus and most severely affects neurons

35
Q

what repeat is associated with SCA3? #s

A

CAG
12-43: normal
44-60: intermediate
60-87: pathogenic/fully penetrant

36
Q

how can we test for SCA3?

A

PCR and Southern blot

37
Q

how would you describe early onset familial alzheimer’s disease (EOFAD)? symptoms?

A

subtle/slow progression of memory failure that becomes more severe and eventually incapacitating

confusion, anxiety, poor judgement, agitation, speech challenges

38
Q

what genes are associated with EOFAD? complete vs. incomplete penetrance?

A

APP and PSEN1: complete

PSEN2: incomplete

39
Q

what is the typical age of onset with EOFAD?

A

40s-50s, less than 5% of AD is early onset

40
Q

what proportion of EOFAD is associated with which gene?

A

APP (10-15%)
PSEN1 (20-70%)
PSEN2 (5%)

41
Q

what features in FHx may make us suspect EOFAD?

A

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

42
Q

what’s the prognosis?

A

typically individuals affected by AD live 8-10y after appearance of symptoms

43
Q

how might we test for EOFAD?

A

panel with APP, PSEN1/2 and APOE -> ES/GS if negative with unclear

single gene-testing not recommended

44
Q

what is the gen pop risk for developing AD? w/ FDR? FHx indicative of EOFAD?

A

10-12%
20-25%/2-3x baseline
assume affected parent: 50%

45
Q

how do APOE e_ alleles impact chances of developing AD?

A

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

GEN 602 (12 decks)

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