Triplet Repeat Disorders

Fragile X - Nucleotides

CGG

"Check Giant Gonads"

*AGG interruptions lessen severeity of symptoms, a for affects the presentation

Friedrichs Ataxia - Nucleotides

GAA

"Gait Ataxia Always"

Myotonic Dystrophy - Nucleotides

CTG (type 1) - CCTG (type 2)

"Check The Grip"

"CAREFULLY Check The Grip"

Huntington Disease - Nucleotides

CAG

"Can't Age Gracefully"

Spinocerebellum Ataxia Type 1 - Nucleotides

CAG in ATXN7/ATXN1

"Cerebellar - Ataxia - Gait"

Fragile X Syndrome - Features

Males affected more severely, female carriers can still present with symptoms

ID, long narrow face, prominent ears, marcoorchidism (large gonads, hypotonia

Expansion more likely when maternally inherited

Fragile X repeat sizes

Normal alleles: 5-44 repeats

Intermediate/"gray" zone: 45-54 repeats

Premutation: 55-200 repeats

Full mutation: >200 repeats

Fragile X Intermediate range consideration

Intermediate: 45-54

No chance of expansion to full mutation in children, can expand to premutation range (55-200)

Fragile X Premutation range considerations

Premutation: 55-200

FXTAS (tremor/ataxia)

FXPOI (primary ovarian insufficiency)

Friedrichs Ataxia

FXN, AR

Slowly progressive ataxia with onset before 25 years

Dysarthria (slow or slurred speech)

- Cardiomyopathy in 2/3

- Diabetes in 1/3

Uncommon but: if repeat expansion is not detected in someone with symptoms, perform sequencing na del/dup analysis for pathogenic variant (4%)

Friedrichs Ataxia repeat sizes

Typical: <33

Premutation: 34-65

Reduced Penetrance: 44-66

Pathogenic: >66

Myotonic Dystrophy Type 1

DMPK, AD

Mild: Mild myotonia, normal life span, onset 20-70

Classic: cataracts, baldness, muscle weakness and wasting, cardiac conduction issues, shortened life span, onset 10-30

Congenital: hypotonia at birth, respiratory insufficiency and early death, ID

DM1 repeat sizes

Premutation: 35-49

Mild: 50-150

Classic 100-1000

Congintal: >1000

Myotonic Dystrophy type 2 features

CNBP, AD

Myotonia

Less common: cataracts, cardiac condiction defects, type 2 diabetes

Onset 20-40s

DM2 repeat sizes

CCTG

Typical: <30

Gray zone: 27-29

Premutation: 30-74

Pathogenic: >75

No correlation between pathogenic repeat size and onset of severity of symptoms, unlike DM1

Spinocerebellar Ataxia

Typically AD, many genes but mainly ATXN

Type 1 CAG trinucleotide expansion in ATXN7/1

Progressive cerebellar ataxia

Uncoordinated muscle movement due to cerebellum issues

Less coordination of eyes, hands, speech, shaky gait

Onset 30-40s, lifespan depends on when symptoms appear

Huntington's features

HTT, AD

Progresive motor disability, disability with chorea and loss of voluntary movement

Cognitive decline, changes in personality, depression

Onset ~45yrs

Huntington's repeat sizes

Typical <26

Intermediate: 27-35

Reduced Penetrance: 36-39

Pathogenic: >40

Juvenile: >60

Expansion more likely when paternally inherited

Contraction of repeats is rare but can be seen

New mutation rate 10%

Juvenile Huntington's Disease

>60 repeats

5-10% of HD, onset before 20yrs

Huntington's testing protocol

Active psychiatric problems must be stabilized before someone has predictive testing

Local counselor should be identified

Patient should have a support person who is not at risk to accompany them through the testing process (though ppl without a support person cannot be excluded from the process)

Huntinton's testing process

Telephone contact - GC informs patient of process

Visit 1: GC, informed consent, mental health assessment, neuro exam, blood draw

Visit 2: disclose results in person, arrange follow-up

Follow up

Triplet Repeat Expansions - Pathogenic

FX: >200

FA: >66

DM1: 100-1000 classic, >1000 congenital

DM2: >75

HT: >40, >60 juvenile

Huntington's disease is caused by an expanded tribucleotide repeat in the ___________ region of the gene.