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Foundations 1 > Trinucleotide repeat diseases > Flashcards

Trinucleotide repeat diseases Flashcards

1
Q

What is the distinguishing feature of a karyotype of a patient with Fragile X?

A

Looks like the ends of the X chromosome are broken off; in reality they have uncoiled and stain differently

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2
Q

What gene is affected in Fragile X?

A

FMR1

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3
Q

Describe the important structural elements of the FMR1 gene.

A
  • 5’ CpG island

- CGG trinucleotide repeat in the first intron

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4
Q

How does number of repeats impact phenotype in Fragile X?

A

28 repeats = normal phenotype
55 - 200 = premutation but normal phenotype
> 200 = intellectual disability

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5
Q

How do pre-mutations expand to full mutations in fragile x?

A

> 55 CGG repeats are meiotically unstable in oogenesis and will expand (mitotically stable post-fertilization though)

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6
Q

How stable are full mutations in Fragile X?

A

> 200 CGG repeats are meiotically unstable in oogenesis and mitotically unstable (leading to mosaicism)

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7
Q

What is the penetrance of intellectual disability in affected male and female children with Fragile x?

A

m: 100%
f: 53%

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8
Q

What is the Sherman paradox?

A

Anomalous non-mendelian pattern of inheritance characterized by anticipation

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9
Q

What symptoms may Fragile X carriers express?

A

Male: 40% have tremor/ataxia syndrome after age 50, difficulties with movement, memory, and autonomic nervous system

Female: 20% have primary ovarian failure

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10
Q

Anticipation

A

Appearance of a genetic trait at an earlier age or with greater severity in successive generations

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11
Q

What trinucleotide repeat diseases have a repeat in a non-coding region?

A
  • Fragile x (intron)
  • Myotonic dystrophy (3’ UTR)
  • Friedrich’s ataxia (intron)
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12
Q

What trinucleotide repeat diseases have a repeat in a coding region?

A
  • SBMA (Kennedy)

- Huntington

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13
Q

How does increased CGG repeat length impact gene expression in Fragile x?

A

more CGG repeats => more methylation of upstream CpG island => transcriptional repression

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14
Q

What is the pattern of Fragile X inheritance?

A

Autosomal dominant

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15
Q

What is the pattern of inheritance of Friedrich’s ataxia?

A

Autosomal recessive

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16
Q

What trinucleotide repeat is associated with Friedrich’s ataxia?

A

Intronic GAA repeat

17
Q

What are the symptoms of Friedrich’s ataxia?

A
  • Onset < 20 yo
  • Ataxia of all 4 limbs
  • Cerebral dysarthia
  • Absent reflexes, sensory loss, pyramidal signs
  • Cardiomyopathy, skeletal deformaties
  • Glucose intolerance and diabetes
18
Q

How does repeat length affect Friedrich’s ataxia phenotype?

A
  • longer length (of shorter allele) = earlier onset
19
Q

What is the pattern of inheritance of myotonic dystrophy?

A

Autosomal dominant

20
Q

What trinucleotide repeat is associated with myotonic dystrophy?

A

CTG in 3’ UTR

21
Q

What are the symptoms of myotonic dystrophy?

A
  • Onset 20-30 yo
  • Progressive weakness and myotonia
  • Cataracts
  • Arrhythmia
  • Hypogonadism
  • Male pattern baldness
  • Cognitive impairment
22
Q

What mutation is associated with Complete Androgen Insensitivity Syndrome?

A

Loss of function mutation to the androgen receptor (x chromosome)

23
Q

What is the pattern of inheritance of complete androgen insensitivity syndrome?

A

X-linked, sex limited

24
Q

What are the symptoms of complete androgen insensitivity syndrome?

A
  • Chromosomal males look like females
  • Undescended testes, absent uterus, blind vagina
  • Failure of virilization at puberty
  • Aromatization of androgens to estrogens => female secondary sex characteristics
  • No neurologic disease
25
Q

What trinucleotide repeat is associated with SBMA/Kennedy disease?

A
  • Expansion (11-34 => 40-62) of poly-glu tract in exon 1 of androgen receptor gene
26
Q

What is the pattern of inheritance of SBMA?

A

X-linked recessive

27
Q

What are the symptoms of SBMA?

A
  • Onset in 3rd decade
  • Progressive loss of spinal cord and bulbar motor neurons
  • Muscle weakness
  • Gynecomastia, reduced fertility, testicular atrophy
28
Q

What trinucleotide repeat diseases are associated with loss of function mutations?

A
  • Fragile X

- Friedrich Ataxia

29
Q

What trinucleotide repeat diseases are associated with gain of function mutations?

A
  • Myotonic dystrophy
  • Fragile x associated ataxia/tremor syndrome
  • huntington
  • SBMA

Foundations 1 (26 decks)

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