Trinucleotide Repeat Disorders Flashcards
What is trinucleotide repeat disorder?
abnormal number of expansion of a repetitive sequence of nucleotides
How many nucleotides do repeat in the repetitive sequence?
3 (three)
Hence, it is called ‘trinucleotide repeat disorder’
What is anticipation?
Earlier age on onset in successive generations + high severity of symptoms (in most cases)
Anticipation is seen characteristically in which group of genetic disorders?
Trinucleotide repeat disorders
What is the underlying mechanism of anticipation?
expansions are unstable >>> may enlarge in repeat number >>> earlier age of onset + more severe symptoms
Which body system is commonly involved in trinucleotide repeat disorders?
Nervous system
dominance of neurological disorders
What is the mnemonic for trinucleotide repeat disorders?
Hunt a Fragile X & Fry Muscle Spine Dentin
What are the trinucleotide (Triplet) repeat disorders?
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
What is the sequence of repeated triplets in Huntingoton’s disease?
CAG
Recall: Hunt & CAGe
What is the sequence of repeated triplets in Fragile X disease?
CGG
Recall: See (C) a Gross Guy
(Gross guy because Fragile x has large ears, jaw, testis)
What is the sequence of repeated triplets in Myotonic dystrophy?
CTG
Recall: See (C) Tonic Gestures
(Myotonic dystrophy has tonic gestures)
What is the sequence of repeated triplets in Friedreich’s Ataxia?
GAA
Recall: Go AtAxic
(Friedreich’s ataxia has inherited ataxia)
What is another name of spinobulbar muscular atrophy?
Bulbospinal neuropathy or Kennedy’s disease
Which inherited ataxias show anticipation?
Friedreich’s ataxia
Spinocerebellar ataxia
What are the other names of Dentatorubral pallidoluysian atrophy?
Haw River Syndrome OR
Naito-Oyanagi disease
Name four diseases with CAG triplet repeats?
Huntington’s disease
Spinocerebellar ataxia
Kennedy disease/spinobulbar muscular atrophy/bulbospinal neuropathy
Dentatorubral pallidoluysian atrophy
What are the triplet repeats of Huntington’s disease, Fragile X syndrome, Friedreich’s ataxia and Myotonic dystrophy?
Huntington’s disease = CAG
Fragile X syndrome = CGG
Friedreich’s ataxia = GAA
Myotonic dystrophy = CTG
What is the inheritence pattern of Fragile X syndrome?
X-linked dominant (complex X-linked)
What is the inheritence pattern of Huntington’s disease?
Autosomal dominant
What is the inheritence pattern of myotonic dystrophy/Dystrophia myotonica?
Autosomal dominant
What is the inheritence pattern of Friedreich’s ataxia?
Autosomal recessive
Which type of myotonic dystrophy mainly has triplet expansion?
Myotonic dystrophy type 1
What is the inheritence pattern of Spinocerebellar ataxia?
Autosomal dominant (mostly)
What is the inheritence pattern of Kennedy syndrome (Spinobulbar muscular atrophy/bulbospinal atrophy)?
X-linked Recessive
What is the inheritence pattern of Dentatorubral pallidolusyian atrophy?
Autosomal dominant
Huntington’s diease: chromosome & gene
Chromosome 4:
gene HTT (aka IT15, or Huntingtin gene)
(HTT = Huntingtin; IT15 = Interesting type 15)
(Recall: CAGe has 4letters)
What is the protein encoded by HTT gene?
Huntington protein
What is the CAG repeats in normal person?
Around 11 to 34 (or 7 to 30)
What is the CAG repeats in Huntington’s disease?
>37
What is the CAG repeats in ‘full-penetrant’ Huntington’s disease?
>40
Fragile X syndrome: Chromosome & gene
X chromosome
Gene: FMR1
(Recall: Fragile X has X in it)
Friedreich’s ataxia: Chromosome & gene
Chromosome 9
Gene: FXN
Myotonic dystrophy type 1: Chromosome & gene
Chromosome 19
Gene: DMPK
(Recall: Dystrophia myotonica has 19 letters)
Which trinucleotide repeat disorder do NOT cause anticipation?
Firedreich’s Ataxia
Why anticipation is NOT seen in Friedreich’s ataxia?
Because it is Autosomal Recessive >>> skips generation +
Diease is usually not seen in more than one generation
In Friedreich’s ataxia, GAA repeats on FXN gene of chromosome 9 results in >>> ?
Defect in Frataxin (iron binding protein) >>> leads to impaired mitochondrial function
Degeneration of various spinal cord tracts
In myotonic dystrophy, CTG repeats in DMPK gene on chromosome 19 results in >>> ?
abnormal expression of ‘myotonin protein kinase’
Which has paternal anticipation?
Huntington’s disease
(If anticipation was seen in Friedreich’s ataxia >> it would be paternal; but friedreich do NOT have anticipation usually)
Which has maternal anticipation?
Fragile X syndrome, Myotonic dystrophy
(Following transmission from affected mother)
How gene mutation and triplet repeats are identified in the lab?
PCR (Polymerase chain reaction)
What is threshold and expansion?
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
