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Genetics Of Neuromuscular Disorders > Huntington Disease > Flashcards

Huntington Disease Flashcards

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1
Q

What is the mode of inheritance for Huntington disease?

A

Autosomal dominant (with anticipation leading to age-related Penetrance)

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2
Q

What is the incidence of Huntington disease?

A

3-10 in 100,000

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3
Q

What are the clinical symptoms of HD?

A
  • Involuntary movement: chorea and later dystonia, bradykinesia and decreased voluntary movements
  • Psychiatric disturbance - mood swings, paranoid ideation, rigid thought processes and depression
  • Dementia
  • Slurred speech and swallowing difficulties
  • weight loss
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4
Q

how long a course does HD take?

A

15-20 years

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5
Q

What is the peak age of onset for HD?

A

40-45 years

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6
Q

What is the term for HD occurring in individuals under 20 yrs?

A

Juvenile HD (~4.5%) - nearly always paternally inherited and usually have more than 65 rpts (and can be up to 250)

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7
Q

What percentage of HD patients have an age of onset over 60yrs?

A

~8%

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8
Q

What are 2 potential differential diagnoses for juvenile onset HD?

A
  1. Benign familial chorea - onset in early childhood of isolated chorea (autosomal dominant)
  2. Wilson disease - autosomal recessive - onset in mid childhood
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9
Q

What are the allele classifications for HD?

A 
Normal = less than 27
Intermediate = 27-35 rpts
HD allele (reduced penetrance) = 36-39 rpts
HD allele = more than 39 rpts
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10
Q

What is difficult about the intermediate range?

A

May be unstable and expand in future generations

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11
Q

Results that land in what range carry a risk of symptoms in later life?

A

Reduced Penetrance range

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12
Q

What percentage of individuals at 50% risk of HD come forward for a presymptomatic test?

A

Only 15-25%

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13
Q

What is the major issue surrounding prenatal testing in HD?

A

Requires careful ethical and psychosocial consideration as without termination the team have effectively performed a presymptomatic test on an unborn child

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14
Q

What is HD caused by?

A
  • Expansion of a CAG trinucleotide repeat tract in exon 1 of the huntingtin HTT gene
  • Translated into a polyglutamine tract which is thought to acquire a novel deleterious function when abnormally expanded
  • Leads to neuronal dysfunction and neurodegeneration
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15
Q

How does the CAG rpt number correlate with mean age of onset?

A

Inverse correlation (i.e. juvenile onset display largest number of rpts)

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16
Q

What percentage of variability in age of onset is related to CAG rpt length?

A

~70% - remainder likely to be due to modifying genes and environmental factors

17
Q

Describe the concept of anticipation in Huntington disease

A

Number of CAG rpts can increase on transmission to offspring resulting in earlier age of onset and/or increased severity of disease in successive generations

18
Q

Is anticipation in Huntington disease more likely to occur through maternal or paternal transmission?

A

Paternal transmission due to expansion of unstable CAG rpt during spermatogenesis

19
Q

What does the risk of expansion for intermediate alleles depend on?

A
  • The rpt length of the intermediate allele in the parent
  • Age/sex of transmitting parent (expansion rare in maternal transmission)
  • Family history: if intermediate allele already shown to expand in family it is more likely to be unstable and expand again
  • Sequence surrounding the HTT CAG expanded region
20
Q

What genes are linked to differential diagnoses for HD?

A
  • HD-like 1 = PRNP gene
  • HD-like 2 = JPH3 gene
  • DRPLA = ATN1 gene
  • HD-like 4 (SCA17) = TBP gene
  • Friedreich ataxia = FXN gene
21
Q

What is the standard testing procedure for HD?

A

Cy5 CAG PCR

  • Primers flank the CAG rpt region
  • Two primer pairs used (HD1A + HD3; HD1alt + HD2)
  • Internal controls used for accurate sizing of CAG rpt
22
Q

When is the primer pair HD1alt + HD2 used?

A

Used if 1A + 3 shows two close normal alleles or homozygous normal allele

23
Q

Provide some details on use of HD1A + 3 PCR primers

A
  • Used for accurate sizing of CAG rpt expansions
  • HD1A is adapted from the HD1 primer to avoid rare polymorphism at 3’ end which causes allele dropout
  • Rare polymorphism in HD3 may also disrupt primer binding and result in false negative result
24
Q

What can Observation of a single allele from the HD1A+3 assay represent?

A
  • True homozygote
  • Normal allele and an unamplifiable large expansion
  • Normal allele and small expansion that has not been amplified due to polymorphism present under HD3 primer
25
Q

Provide details on the HD1alt + HD2 PCR

A
  • CAG rpts in HTT gene are immediately 5’ of a CCG rpt which is also polymorphic in length
  • Primers HD1alt and HD2 encompass both the CAG and CCG rpt region
  • Incorporation of the CCG rpt region enables two normal alleles to be resolved in cases where both alleles have identical numbers of CAG rpts but different numbers of CCG rpts
  • These primers are not used to determine CAG rpt length
26
Q

When are testing procedures additional to CAG F-PCR needed?

A
  • If patients are homozygous for a normal allele in both PCRs
  • This is particularly important in cases of suspected juvenile HD
  • Techniques to detect larger alleles = TP-PCR and southern blotting
27
Q

Predictive (presymptomatic) testing can be only be offered to which individuals?

A
  • Those at 50% or 25% prior risk
  • Only accepted from clinical genetics
  • requires comprehensive genetic counselling and informed consent
28
Q

Provided some details on preimplantation genetic diagnosis (PGD) in the context of HD

A
  • Possible option for couples who wish to avoid transmitting the disease without revealing their own status or avoid termination of a pregnancy
  • Embryos are cultured to the 8 cell stage
  • biopsy and genetic testing are carried out to allow replacement of those with a normal HD gene
  • Exclusion testing may also be possible in this scenario
29
Q

What is exclusion testing and when is it used in context of HD?

A
  • Used for prenatal testing when the foetus is at 25% risk and the future parent is at 50% risk but does not want to be informed of their HD status
  • Testing uses polymorphic markers closely linked to HTT gene
  • Determine which grandparental haplotype inherited by foetus
  • If from the affected grandparent = 50% risk, and from unaffected = 0% risk
30
Q

What are the risks involved with exclusion testing?

A
  • Risk of recombination across HD gene is ~2%
  • Testing may not be informative
  • Small risk of double recombination would result in an affected individual with a ‘low risk’ haplotype
  • Termination of possibly unaffected pregnancy

Genetics Of Neuromuscular Disorders (7 decks)

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