Trinucleotide Repeat Disorders

Question 1

What is trinucleotide repeat disorder?

Answer 1

abnormal number of expansion of a repetitive sequence of nucleotides

Question 2

How many nucleotides do repeat in the repetitive sequence?

Answer 2

3 (three)

Hence, it is called ‘trinucleotide repeat disorder’

Question 3

What is anticipation?

Answer 3

Earlier age on onset in successive generations + high severity of symptoms (in most cases)

Question 4

Anticipation is seen characteristically in which group of genetic disorders?

Answer 4

Trinucleotide repeat disorders

Question 5

What is the underlying mechanism of anticipation?

Answer 5

expansions are unstable >>> may enlarge in repeat number >>> earlier age of onset + more severe symptoms

Question 6

Which body system is commonly involved in trinucleotide repeat disorders?

Answer 6

Nervous system

dominance of neurological disorders

Question 7

What is the mnemonic for trinucleotide repeat disorders?

Answer 7

Hunt a Fragile X & Fry Muscle Spine Dentin

Question 8

What are the trinucleotide (Triplet) repeat disorders?

Answer 8

Hunt = Huntington’s disease

Fragile X = Fragile X syndrome

Fry = Friedreich’s ataxia

Muscle = Myotonic dystrophy (Dystrophia myotonica)

Spine = Spinocerebellar ataxia

Spinobulbar muscular atrophy (= Bulbospinal neuropathy)

Dentine = Dentatorubral pallidolusian atrophy

Question 9

What is the sequence of repeated triplets in Huntingoton’s disease?

Answer 9

CAG

Recall: Hunt & CAGe

Question 10

What is the sequence of repeated triplets in Fragile X disease?

Answer 10

CGG

Recall: See (C) a Gross Guy

(Gross guy because Fragile x has large ears, jaw, testis)

Question 11

What is the sequence of repeated triplets in Myotonic dystrophy?

Answer 11

CTG

Recall: See (C) Tonic Gestures

(Myotonic dystrophy has tonic gestures)

Question 12

What is the sequence of repeated triplets in Friedreich’s Ataxia?

Answer 12

GAA

Recall: Go AtAxic

(Friedreich’s ataxia has inherited ataxia)

Question 13

What is another name of spinobulbar muscular atrophy?

Answer 13

Bulbospinal neuropathy or Kennedy’s disease

Question 14

Which inherited ataxias show anticipation?

Answer 14

Friedreich’s ataxia

Spinocerebellar ataxia

Question 15

What are the other names of Dentatorubral pallidoluysian atrophy?

Answer 15

Haw River Syndrome OR

Naito-Oyanagi disease

Question 16

Name four diseases with CAG triplet repeats?

Answer 16

Huntington’s disease

Spinocerebellar ataxia

Kennedy disease/spinobulbar muscular atrophy/bulbospinal neuropathy

Dentatorubral pallidoluysian atrophy

Question 17

What are the triplet repeats of Huntington’s disease, Fragile X syndrome, Friedreich’s ataxia and Myotonic dystrophy?

Answer 17

Huntington’s disease = CAG

Fragile X syndrome = CGG

Friedreich’s ataxia = GAA

Myotonic dystrophy = CTG

Question 18

What is the inheritence pattern of Fragile X syndrome?

Answer 18

X-linked dominant (complex X-linked)

Question 19

What is the inheritence pattern of Huntington’s disease?

Answer 19

Autosomal dominant

Question 20

What is the inheritence pattern of myotonic dystrophy/Dystrophia myotonica?

Answer 20

Autosomal dominant

Question 21

What is the inheritence pattern of Friedreich’s ataxia?

Answer 21

Autosomal recessive

Question 22

Which type of myotonic dystrophy mainly has triplet expansion?

Answer 22

Myotonic dystrophy type 1

Question 23

What is the inheritence pattern of Spinocerebellar ataxia?

Answer 23

Autosomal dominant (mostly)

Question 24

What is the inheritence pattern of Kennedy syndrome (Spinobulbar muscular atrophy/bulbospinal atrophy)?

Answer 24

X-linked Recessive

Question 25

**What is the inheritence pattern of Dentatorubral pallidolusyian atrophy?**

Answer 25

**Autosomal dominant**

Question 26

**Huntington's diease: chromosome & gene**

Answer 26

**Chromosome 4:** **gene HTT (aka IT15, or Huntingtin gene)** (HTT = Huntingtin; IT15 = Interesting type 15) (Recall: CAGe has 4letters)

Question 27

**What is the protein encoded by HTT gene?**

Answer 27

**Huntington protein**

Question 28

**What is the CAG repeats in normal person?**

Answer 28

**Around 11 to 34 (or 7 to 30)**

Question 29

**What is the CAG repeats in Huntington's disease?**

Answer 29

**\>37**

Question 30

**What is the CAG repeats in 'full-penetrant' Huntington's disease?**

Answer 30

**\>40**

Question 31

**Fragile X syndrome: Chromosome & gene**

Answer 31

**X chromosome** **Gene: FMR1** (Recall: Fragile X has X in it)

Question 32

**Friedreich's ataxia: Chromosome & gene**

Answer 32

**Chromosome 9** **Gene: FXN**

Question 33

**Myotonic dystrophy type 1: Chromosome & gene**

Answer 33

**Chromosome 19** **Gene: DMPK** (Recall: Dystrophia myotonica has 19 letters)

Question 34

**Which trinucleotide repeat disorder do NOT cause anticipation?**

Answer 34

**Firedreich's Ataxia**

Question 35

**Why anticipation is NOT seen in Friedreich's ataxia?**

Answer 35

Because it is **Autosomal Recessive \>\>\> skips generation** + Diease is usually **not seen in more than one generation**

Question 36

**In Friedreich's ataxia, GAA repeats on FXN gene of chromosome 9 results in \>\>\> ?**

Answer 36

**Defect in Frataxin (iron binding protein) \>\>\> leads to impaired mitochondrial function** **Degeneration of various spinal cord tracts**

Question 37

**In myotonic dystrophy, CTG repeats in DMPK gene on chromosome 19 results in \>\>\> ?**

Answer 37

abnormal expression of **'myotonin protein kinase'**

Question 38

**Which has paternal anticipation?**

Answer 38

**Huntington's disease** ## Footnote (If anticipation was seen in Friedreich's ataxia \>\> it would be paternal; but friedreich do NOT have anticipation usually)

Question 39

**Which has maternal anticipation?**

Answer 39

**Fragile X syndrome, Myotonic dystrophy** ## Footnote (Following transmission from affected mother)

Question 40

**How gene mutation and triplet repeats are identified in the lab?**

Answer 40

**PCR (Polymerase chain reaction)**

Question 41

**What is threshold and expansion?**

Answer 41

**Threshold: in normal individual, number of repeats, + but remains below a defined threshold** **Expansion: Increased number of repeats in an affected patient + above the disease-causing threshold**