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Molecular Foundations of Medicine > Trinucleotide Repeat Disorders > Flashcards

Trinucleotide Repeat Disorders Flashcards

1
Q

examples of trinucleotide repeat disorders

A
  • fragile x
  • friedreich’s ataxia
  • huntington’s disease
  • mytonic dystrophy
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2
Q

mechanism of trinucleotide repeat disorder

A
  • expansion of number of repeats

* likely due to slipped DNA mispairing

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3
Q

unstable repeat expansions

A
  • number of repeats may increase in offspring

* key: genetic abnormality changes over time

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4
Q

anticipation

A
  • phenomenon where disease severity worse in subsequent generations with earlier onset
  • due to more repeats accumulating in abnormal gene
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5
Q

fragile x inheritance

A

x linked dominant

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6
Q

gene involved in fragile x

A
  • FMR1 gene = fragile x mental retardation 1

* q arm of x chromosome

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7
Q

increase in CGG repeats in fragile x leads to

A

DNA methylation of FMR1 gene -> silencing

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8
Q

2nd most common cause of intellectual disability

A

fragile x (down syndrome 1st)

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9
Q

common features in fragile x

A
  • long narrow face
  • large ears
  • large jaw
  • macroorchidism (after puberty)
  • CT findings (joint laxity)
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10
Q

associated mental problems with fragile x

A
  • anxiety
  • ADHD
  • often features of autism
  • OCD
  • aggression
  • depression
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11
Q

friedreich’s ataxia inheritance

A

autosomal recessive

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12
Q

friedreich’s ataxia gene

A
  • frataxin (FXN) gene on chromosome 9

* needed for mitochondrial function

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13
Q

increased GAA repeats in freidreich’s ataxia causes

A

decreased frataxin levels -> mitochondrial dystunction

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14
Q

frataxin protein

A
  • mitochondrial protein
  • high levels in brain, heart, pancreas
  • abnormal -> mitochondrial dysfunction
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15
Q

presentation of friedreich’s ataxia

A
  • typical onset 5-15 yo

* cerebellar and spinal cord degeneration -> loss of balance and weakness

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16
Q

physical deformities that commonly develop in friedreich’s ataxia

A
  • kyphoscoliosis

* foot abnormalities (pes cavus)

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17
Q

common problem associated with friedreich’s ataxia

A
  • hypertrophic cardiomyopathy
  • a-fib -> tachycardia
  • diabetes
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18
Q

huntington’s disease inheritance

A

autosomal dominant

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19
Q

gene and location in huntington’s disease

A
  • HTT gene located at 4P16.3

* codes for protein huntington

20
Q

what does CAG expansion cause in huntington disease

A
  • CAG codes for glutamine

* polyglutamine disorder

21
Q

cause of symptoms in huntingtons disease

A
  • degeneration in basal ganglia (striatum)
  • leads to dementia, chorea, ataxia, dysarthria (difficulty with formation of speech)
  • death usually 10-20 years after diagnosis
22
Q

myotonic dystrophy inheritance

A

autosomal dominant

23
Q

type 1 myotonic dystrophy gene

A
  • DMPK gene on chromosome 19
  • codes for myotonic dystrophy protein kinase
  • abnormal gene transcribed to mRNA but not translated
24
Q

presentation of myotonic dystrophy

A
  • most commonly begins in adulthood (20-30yo)
  • progressive muscle wasting/weakness
  • myotonia (prolonged muscle contractions)
    • unable to relax muscle after use
    • cannot release grip
    • locking of jaw
25
Q

facial characteristics in myotonic dystrophy

A
  • facial muscles often affected -> weakness/wasting->

* long narrow face and hollowed cheeks

26
Q

other problems found in myotonic dystrophy

A
  • multisystem disorder:
  • hypogonadism
  • cataracts
  • cardiac arrhythmia
  • frontal balding
  • insulin resistance
  • arrhythmias (atrial flutter and fibrillation)
  • 1st degree AV vlock
  • bundle branch block
  • respiratory complications
  • intellectual disability (worse with earlier onset)
27
Q

where can trinucleotide repeat expansions occur

A

•coding or non-coding regions of gene (anywhere in gene)

28
Q

causes of trinucleotide repeat expansions

A

•gene conversion (unequal crossing over) during meiosis
OR
mistakes in:
•DNA replication
•double-stranded DNA break repair
•base excision repair of oxidative damage
•single-stranded DNA gap repair

29
Q

where would you find high expression of huntington protein

A

testes and brain

30
Q

function of huntington protein

A
  • found in nucleus and cytoplasm
  • regulates intracellular transport of many proteins
  • shuttles transcription factors in and out of nucleus
  • may sequester TFs
  • required for normal embryonic devand neurogenesis
31
Q

Expansion of CAG region in huntington disease results in

A

aggregation of the mutant protein into inclusion bodies

32
Q

where does the CAG repeat expansion occur in huntingtons disease

A

exon I

33
Q

hypothesis of expansion mechanism in huntington disease

A

meiotic instability in sperm -> unequal crossing over

34
Q

common differential diagnosis in patient with suspicion for fragile x

A
  • down syndrome
  • williams syndrome
  • angelman
  • autism spectrum disorer
35
Q

location of trinucleotide repeat expansion in fragile x

A
  • near the promoter in 5’ UTR of FMR-1 gene, which encodes FMRP
  • silences the promoter
36
Q

FMRP implicated in

A
  • dendritic spine maturation
  • synapse formation
  • synaptic plasticity
37
Q

associated problems with fragile x

A
  • mitral valve prolapse
  • HTN
  • sz activity
  • possible strabismus
  • hypotonia
  • pes planus
38
Q

common symptoms of freidreich ataxia

A
  • muscle weakness in arms/legs
  • loss of coordination
  • vision/hearing impairment
  • slurred speech
  • scoliosis
  • pes cavus
39
Q

spinal cord change in friedreich ataxia

A
  • spinal cord becomes thinner

* nerves lose part of myelin sheath

40
Q

what does frataxin protein do

A

•removes iron in the cytoplasm and around mitochondria

41
Q

iron buildup in mutant frataxin protein

A
  • causes free radical damage to mitochondrial membrane
  • oxidative stress
  • esp affects nerves and muscle cells
42
Q

location of trinucleotide expansion in friedreichs ataxia

A

first intron on FXN gene -> transcriptional repression

43
Q

compound heterozygotes in friedreichs ataxia

A
  • 4% of patients

* have expansion in 1 allele and some other mutation of FXN in other allele

44
Q

treatment of friedreichs ataxia

A
  • supportive: scoliosis surgery if indicated, cardia meds, DM meds, PT
  • genetic counseling:
    • 25% recurrence risk (AR)
    • carrier frequency is 1/110, affects 1/50,000 in US
45
Q

location of trinucleotide repeat expansion in myotonic dystrophy

A

3’ intron

46
Q

location of trinucleotide repeat expansion in huntington disease

A

exon 1

Molecular Foundations of Medicine (21 decks)

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