Triplet Repeat Disorders

How do triplet repeat disorders occur?

Too many repeating segments of 3 nucleotides leads to sx.

What can happen to repeat segments within each generation and what is the called and with risk of?

Can expand with each generation and is called anticipation where an increase in repeats can result in more severe sx.

How can we test for triplet repeat disorders?

PCR with reflex to southern blot.

What is PCR and its limitations?

Determines the number of repeats but cannot tell the number of repeats if a pathogenic expansion.

What is Southern Blot and its limitations?

determines how much protein is made and therefore the repeat number. It cannot tell the repeat number if it is a smaller number of repeats.

General Info of FXS and Features

- More common in M>F
- 1/200 (f) carriers w/o Fhx
- Prevalence = 1/4000
- Features = ID, long narrow face, prominent ears, macroorchidism (large testicles), and hypotonia.

What are the genetics of FXS?

- FMR1 gene
- CGG Repeats (Check Giant Gonads)
- Normal = 5-44
- Intermediate = 45-54
- Premutation = 55-200
- Full Mutation = 200+

What is the Intermediate Zone for FXS?

Also known as the gray zone with no risk to full mutation but risk for premutation.

What is the premutation for FXS?

Cam expand to full mutation; Associated with FXTAS and FXPOI

How do expansions occur in FXS?

maternally inherited.

Friedrich's Ataxia: Features

progressive ataxia (onset 25yo+)
dysarthria (slow/slurred speech)
cardiomyopathy (2/3)
diabetes (1/3)

FriedRich's Ataxia: Genetics

- FXN Gene (AR)
- GAA Repeats
- Typical = below 33
- Premutation = 34-65
- Reduced Penetrance = 44-66
- Pathogenic = 66+

What should you do if repeat expansion is not detected for Friedrich's Ataxia in an individual with sx?

gene seq/del/dup for pathogenic variant (4%)

FXS Repeats

CGG

Friedrich's Ataxia Repeats

GAA

Myotonia Dystrophy generally presents with

inability to release closed grip

What are the subtypes for Myotonia Dystrophy Type 1

Mild
Classic
Congenital

Mild Features of MDT1 and repeats

mild myotonia, normal life span w/ onset btw 20-70y; 50-100 CTG repeats

Classic Features of MDT1 and repeats

cataracts, baldness, muscle wasting/weakness, cardiac conduction issues, shortened life span with onset 10-30yo; 100-1000 CTG repeats

Congenital features of MDT1 and repeats

hypotonia, respiratory insufficiency, early death and ID; 1000+ CTG repeats

Genetics of Myotonia Dystrophy Type 1

- DMPK gene (AD)
- CTG Repeats (Check The Grip)
- Premutation = 35-49 CTG
- Mild = 50-100 CTG
- Classic = 100-1000 CTG
- Congenital = 1000+ CTG

Myotonic Dystrophy Type 2 Features

myotonia and lesser common feature includes cataracts, cardiac conduction defects, and DM2. Onset at 20-30yo

Myotonic Dystrophy Type 2 Genetics

- AD CNBP Gene
- CCTG Repeats (Complex Repeat Region = TGnTCTGnCCTGn)
- Typical = below 30
- Gray zone = 27-29
- Premutation = 30-74
- Pathogenic = 75+

What is the correlation between repeat size and onset/severity/sx of Myotonic Dystrophy Type 2

There is no correlation

Spinocerebellar Ataxia Features

- progressive cerebellar ataxia (uncoordinated muscle movement due to cerebellum issues; less coordination of eyes, hands, speech, and shaky gait.)
- Onset in 30s-40s (lifespan depends on when sx appears)

Spinocerebellar Ataxia Genetics

- typically AD in ATXN Genes.
- Type 1 due to CAG repeats in ATXN(7) and ATXN(1)

Huntington Disease Genetics

- HTT gene (AD)
- CAG Repeats
- Typical = below 26
- Intermediate = 27-35
- Reduced Penetrance = 36-39
- Pathogenic = 40+
- Juvenile = 60+

In whom are expansions more likely to occur for HD?

paternally

In what condition can reduction of repeats, although rarely, can occur?

HD

What % is Juvenile HD and when is onset?

Makes up 5-10% of HD and onset before 20yo

HD Features

- progressive motor disability w/ chorea and loss of voluntary mvt.
- cognitive decline, changes in personality, and depression
- Onset around 45yo

Testing Protocol for HD

-Psych/Mental Health Eval to determine if patient in stable state for predictive testing
- Local counselor to be find to address mental health needs
- Pt should have a support system established to accompany throughout the process (if no support--should not proceed)

Testing Process for HD

(1) Telephone Contact (inform about the process)
(2) Visit 1 = GC, informed consent, psych/mental health eval, neuro exam, and Blood draw
(3) Visit 2 = Results disclosure (in person) and FUV
(4) FUV